CN101390838A - Method for preparing micronization medicine - Google Patents
Method for preparing micronization medicine Download PDFInfo
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- CN101390838A CN101390838A CNA200810223969XA CN200810223969A CN101390838A CN 101390838 A CN101390838 A CN 101390838A CN A200810223969X A CNA200810223969X A CN A200810223969XA CN 200810223969 A CN200810223969 A CN 200810223969A CN 101390838 A CN101390838 A CN 101390838A
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Abstract
Disclosed is a micronization medicine preparation method which belongs to the medicine preparation field and solves the problem of uneven particle size caused by the uneven stirring in a traditional stirring kettle during the medicine preparation process. The method includes steps: raw material medicine is dissolved in organic solvent to prepare raw material medicine solution with certain concentration; the volume ratio of the raw material medicine solution and the anti-solvent is 1:5-1:30; the concentration of the raw material medicine solution is 5%-98% of the concentration of the saturation solution under the same temperature; the raw material medicine solution and the anti-solvent are added to a micro-reactor simultaneously through a solution inlet and an anti-solvent inlet and mixed in the intersection of the micro-reactor to process the anti-solvent recrystallization process after mixing quickly and completely; the flow velocity of the raw material medicine solution and the anti-solvent when flowing into the micro-reactor is 1ml/min to 80ml/min; the recrystallization temperature is minus 10 DEG C to 50 DEG C; the paste obtained through recrystallization is filtrated, washed and dried to obtain micronization medicine. The micronization medicine preparation method has the advantages of obtaining medicine granules with controllable and even average particle size, easy split packing as preparation and having higher bioavailability.
Description
Technical field
The present invention relates to a kind of method for preparing micronized medicine, make that particle diameter is controlled, the nanoscale of narrow particle size distribution or micron-sized medicament powder.
Background technology
Medicine in the market comprises dosage forms such as Foradil Aerolizer formoterol fumarate, aerosol, tablet, capsule and suspensoid.
Carry out administration for inhalant dosage forms such as Foradil Aerolizer formoterol fumarate and aerosol (as beclometasone) by pulmonary.Because the special physiological structure of pulmonary will reach pulmonary deposition preferably, the granule that sucks medicine is all had certain requirement: (1) particle diameter: particle diameter enters bronchus and brings into play drug effect fast in that the medicine of 0.5-5 μ m is the easiest; (2) particle size distribution of medicine is narrow; (3) medicine will have reasonable dispersibility and flowability etc.; (4) because unformed medicine has thermodynamic phase, so medicine should be crystal type.In above-mentioned influence factor, particle grain size is the key factor that can the decision medicine reach site of action, and therefore, the micronization of medicine is to improve the key point that sucks medicine effect.
For oral formulations such as tablet, capsule and suspensoids, the water solublity of some medicine (as azithromycin and danazol) is low, bioavailability is poor, so not only causes very big waste clinically, but also can increase side effect.For oral formulations, the dissolution rate of medicine activity component in body determined the size of bioavailability.Get rid of other factor affecting, the dissolution rate of solid drugs depends primarily on the size of the granule surface area that contacts with solvent liquid.Therefore, particle diameter is more little, and dissolution rate is fast more.By insoluble drug is carried out micronization,, very important meaning is arranged to improving bioavailability to reduce the drug particles particle diameter and then to increase its specific surface area.
Comminution by gas stream (preparation of ultra-fine azithromycin and sign. Long Tao etc. the chemical industry progress, 2005,24 (7): though 763-766) and ball-milling method be the common method that reduces drug particle size, but, exist generally that energy consumption is big, efficient is low, Granularity Distribution is wide, easily make shortcomings such as the structural deterioration of thermally labile medicine and degraded, in addition, also can cause problems such as dust pollution and electrostatic safety.Though spray drying method and supercritical fluid technology can make the micronized medicine of narrow particle size distribution, but the equipment manufacturing cost height.The operating procedure and the operating equipment of anti-solvent recrystallization method are simpler, are easy to large-scale production, have excellent industrial application foreground.(Micronization of anti-Inflammatory drugs for pulmonary delivery bya controlled crystallization process.Norbert Rasenack such as NorbertRasenack, et al.Journal ofPharmaceutical Sciences, 2003,92 (1): 35-44) adopt anti-solvent recrystallization method to prepare the needle-like beclometasone, but use hydroxypropyl emthylcellulose in the recrystallization process as stabilizing agent, and hydroxypropyl emthylcellulose is not used in inhalation so far, does not have relevant toxicology data.At United States Patent (USP) 20020081334, a kind of micron order or nano level danazol preparation method have been described in 20040067251: danazol solution is sprayed in the deionized water solution that is added with surfactant, then organic solvent is vapored away, thus the dispersion liquid of formation danazol fine particle.Particle diameter is controlled, pattern is controlled and the danazol powder of narrow particle size distribution but this method of this patent introduction can not prepare, and also there is inhomogeneous, the local oversaturated problem of mixing at the solvent precipitation that traditional stirred tank carries out, thereby influences the quality of danazol powder.And the adding of surfactant has increased the difficulty of cost and operation, has also increased potential medicine side effect.In addition, the method of utilizing the ultrasonic emulsification solvent diffusion method to prepare the azithromycin superfine powder has been described: among the Chinese patent CN1634113A under ultransonic condition, the azithromycin alcoholic solution is splashed in the aqueous solution that contains stabilizing agent, become muddy until system, again after the solution system ageing a period of time with muddiness, high speed centrifugation separate solid matter, and washing, drying have made the azithromycin superfine powder.The method relates to ultrasound condition, and the introducing of not only energy consumption height, and emulsifying agent is made troubles to subsequent processes, has increased the cost of raw material.
Summary of the invention
The purpose of this invention is to provide that nanoscale or micron-sized mean diameter are controlled, the method for the medicament powder of narrow particle size distribution, have that technology is simple, handling safety, low cost and other advantages, prepared nanoscale or micron-sized drug particles have characteristics such as particle diameter is controlled, narrow particle size distribution.
The invention provides a kind of method for preparing micronized medicine, comprise the steps:
(1) crude drug is dissolved in the certain density raw material medicine solution of preparation in the organic solvent; The volume ratio of raw material medicine solution and anti-solvent is 1: 5 to 1: 30; The concentration of raw material medicine solution be under the uniform temp saturated solution concentration 5% to 98%;
(2) make raw material medicine solution and anti-solvent enter microreactor simultaneously through solution inlet and anti-colvent inlet respectively, intersect, and mix the anti-solvent recrystallization process of carrying out fully rapidly in the crossing of microreactor by constant-flux pump; The flow velocity that raw material medicine solution and anti-solvent enter microreactor is 1ml/min to 80ml/min; Recrystallization temperature is-10 ℃ to 50 ℃;
(3) slurry that recrystallization is obtained filter, wash, drying, promptly get micronized medicine.
In the inventive method, employed raw material medicine solution is the solution of crude drug in methanol, ethanol, acetone, isopropyl alcohol, propylene glycol, glycerol, n-butyl alcohol, the tert-butyl alcohol, amylalcohol, capryl alcohol, dichloromethane, chloroform or their mixture, but is not limited to above-mentioned solvent.So-called " dissolving " is meant that medicine forms basic clear solutions in solvent.In the above-mentioned drug solution, medicine can any suitable concentration exist, as long as it can satisfy dissolved requirement.Among the present invention raw material medicine solution concentration be under the uniform temp saturated solution concentration 5% to 98%.
In the inventive method, employed anti-solvent is water, normal hexane, cyclohexane extraction, petroleum ether, diisopropyl ether, ether, heptane, octane or their mixture.
In the inventive method, the volume ratio of raw material medicine solution and anti-solvent is 1: 5 to 1: 30, and preferred 1: 10 to 1: 20, and obtain by the flow velocity of regulating two strands of materials, the flow velocity that two strands of materials enter microreactor was 1ml/min to 80ml/min.
In the inventive method, recrystallization temperature is-10 ℃ to 50 ℃, preferred 10 ℃ to 20 ℃.When the amount of anti-solvent during much larger than the amount of raw material medicine solution, the temperature of system can realize by the temperature of controlling anti-solvent.
The present invention prepares the equipment of micronized medicine, comprising:
(1) microreactor is used to carry out anti-solvent recrystallization process;
(2) raw material medicine solution storage bottles and an anti-solvent storage bottle;
(3) two constant-flux pumps, one of them constant-flux pump links to each other with the raw material medicine solution storage bottle with microreactor respectively, be used for carrying drug solution to microreactor, another constant-flux pump links to each other with anti-solvent storage bottle with microreactor respectively, is used for carrying anti-solvent to microreactor.
In the equipment of the present invention, employed microreactor is Y type or linear type, and the inner microchannel size that supplies fluid flow of microreactor is from the submicron to the submillimeter level, and cross sectional shape is a square or circular.Two bursts of chargings of solution and anti-solvent are by separately constant-flux pump control flow, carry out fully after converging, contact equably, can reach good microcosmic rapidly and mix, and collect slurry after the crystallization from the serosity outlet.Because the passage of microreactor is narrow, the equivalent diameter order of magnitude is a micron order, and its mass transfer characteristic makes reactant can mix in the Millisecond scope in microreactor, thereby has greatly strengthened mass transport process.
The medicine that the present invention can prepare is: (1) beclometasone, asthma class medicine; (2) azithromycin, antibiotics; (3) danazol, weak androgen is mainly used in the treatment endometriosis, but is not limited to said medicine.
Solution and anti-solvent can be fully, contact uniformly, and the microcosmic of having strengthened molecular level mixes, and overcome that solution contact inhomogeneous, inadequate problem in the stirred tank with anti-solvent, also avoided the local supersaturation of common appearance in the stirred tank simultaneously.And since the restriction of microreactor passage effectively limited the size of recrystallization particle, and improved the uniformity coefficient of particle size distribution.In addition, the amplification of microreactor is the stack of microchannel quantity only, has avoided the enlarge-effect of traditional amplification process.Its amplifying device had both had the stability of successive reaction, can regulate output neatly again, realized producing as required.
Among the present invention, microchannel size, shape and the angle etc. of charging rate by adjusting raw material medicine solution and anti-solvent and ratio, solution concentration, crystallization temperature, microreactor, can access mean diameter controlled, drug particles uniformly.Mean diameter micronized medicine granule controlled, narrow particle size distribution particularly.And resulting granules of the present invention is owing to there not being the problem that stirs the inhomogeneous relative granularity inequality that causes in traditional stirred tank, so can be used for tablet or capsule effectively in field of medicaments.With respect to prior art, for example, for tablet and capsule, because uniform particles, granularity is less, thus easy packaged preparation, and high bioavailability is arranged.
Description of drawings
Fig. 1 is the stereoscan photograph of the micronization beclometasone that makes of embodiment 1.
Fig. 2 is the stereoscan photograph of the micronization azithromycin that makes of embodiment 2.
Fig. 3 is the stereoscan photograph of the micronization danazol that makes of embodiment 3.
Fig. 4 is the stereoscan photograph of the micronization beclometasone that makes of embodiment 4.
The specific embodiment
Embodiment 1
The microreactor that adopts is a Y shape microreactor, the cross section of the passage of solution and two bursts of chargings of anti-solvent is a square, be of a size of 0.5mm * 1mm, the length of two passages is 20mm, angle is 60 °, and the cross section of serosity exit passageway is a square, is of a size of 1mm * 1mm, the passage length overall is 57.32nm, and channel center's distance of solution and two bursts of chargings of anti-solvent is 20mm.
Take by weighing beclometasone crude drug 1.5g, it is dissolved in is mixed with the beclometasone methanol solution 50ml that concentration is 0.03g/ml in the methanol, place the raw material medicine solution storage bottle, get the 1000ml deionized water in anti-solvent storage bottle, as anti-solvent.Substantially simultaneously enter in the microreactor through solution inlet and anti-colvent inlet beclometasone methanol solution and deionized water respectively by constant-flux pump, two fluid streams intersect in the crossing of microchannel, and mix fully rapidly, the products therefrom slurry is collected from discharging opening.The charging rate of beclometasone methanol solution and water is respectively 3ml/min and 60ml/min, and recrystallization temperature is 10 ℃.The slurry of collecting is filtered, washs, in 105 ℃ of vacuum drying ovens, be drying to obtain micronization beclometasone powder body then.As can be seen, the average minor axis of beclometasone is 1.14 μ m from stereoscan photograph shown in Figure 1, is distributed in 0.4-3.5 μ m.
Embodiment 2
The microreactor that adopts is identical with embodiment 1.
Take by weighing azithromycin crude drug 4.0g, it is dissolved in is mixed with the azithromycin alcoholic solution 50ml that concentration is 0.08g/ml in the dichloromethane, place the raw material medicine solution storage bottle, get the 500ml normal hexane in anti-solvent storage bottle, as anti-solvent.By constant-flux pump azithromycin alcoholic solution and deionized water are entered microreactor substantially simultaneously through solution inlet and anti-colvent inlet respectively, two fluid streams intersect in the crossing of microchannel, and mix fully rapidly, and the products therefrom slurry is collected from discharging opening.The charging rate of azithromycin solution and water is respectively 8ml/min and 80ml/min, and recrystallization temperature is 20 ℃.Recrystallization gained serosity at 20 ℃ of ageing 5-10min, is carried out sucking filtration, washing then, under 50-60 ℃ of condition, be drying to obtain the micro Azithromycin powder powder body.By scanning electron microscope observation, as shown in Figure 2, the spherical secondary agglomeration granule of gained azithromycin for assembling voluntarily by primary particle, the particle diameter of offspring is between 10-18 μ m, and this granule has good flowability and very high specific surface area.
Embodiment 3
The microreactor that adopts is identical with embodiment 1.
Take by weighing danazol crude drug 1.0g, it is dissolved in is mixed with the danazol alcoholic solution 50ml that concentration is 0.02g/ml in the ethanol, place the raw material medicine solution storage bottle, get the 500ml ether in anti-solvent storage bottle, as anti-solvent.By constant-flux pump danazol alcoholic solution and deionized water are entered microreactor substantially simultaneously through solution inlet and anti-colvent inlet respectively, two fluid streams intersect in the crossing of microchannel, and mix fully rapidly, and the products therefrom slurry is collected from discharging opening.The charging rate of danazol solution and water is respectively 7ml/min and 70ml/min, and recrystallization temperature is 20 ℃.The slurry of collecting is filtered, washs, is drying to obtain the micronization danazol powder under 60 ℃ of conditions.From stereoscan photograph shown in Figure 3 as can be seen, its average minor axis is about 800nm.
Embodiment 4
The microreactor that adopts is the linear microreactor, and the cross section of the passage of solution and two bursts of chargings of anti-solvent is a square, is of a size of 0.4mm * 0.4mm, and the passage length overall is 40mm, and the centre distance of two imports is 20mm.
Take by weighing beclometasone crude drug 1.5g, it is dissolved in is mixed with the beclometasone methanol solution 50ml that concentration is 0.03g/ml in the chloroform, place the raw material medicine solution storage bottle, get the 1000ml cyclohexane extraction in anti-solvent storage bottle, as anti-solvent.By constant-flux pump beclometasone methanol solution and deionized water are entered microreactor substantially simultaneously through solution inlet and anti-colvent inlet respectively, two fluid streams intersect in the crossing of microchannel, and mix fully rapidly, the products therefrom slurry is collected from discharging opening.The charging rate of beclometasone solution and water is respectively 3ml/min and 60ml/min, and recrystallization temperature is 10 ℃.The slurry of collecting is filtered, washs, in 105 ℃ of vacuum drying ovens, be drying to obtain micronization beclometasone powder body then.As can be seen, the average minor axis of beclometasone is 1.07 μ m from stereoscan photograph shown in Figure 4, is distributed in 0.3-2.7 μ m.
Claims (3)
1. a method for preparing micronized medicine comprises the steps:
(1) crude drug is dissolved in the certain density raw material medicine solution of preparation in the organic solvent; The volume ratio of raw material medicine solution and anti-solvent is 1:5 to 1:30; The concentration of raw material medicine solution be under the uniform temp saturated solution concentration 5% to 98%;
(2) make raw material medicine solution and anti-solvent enter microreactor simultaneously through solution inlet and anti-colvent inlet respectively, intersect and mix fully the anti-solvent recrystallization process of carrying out in the crossing of microreactor by constant-flux pump; The flow velocity that raw material medicine solution and anti-solvent enter microreactor is 1ml/min to 80ml/min; Recrystallization temperature is-10 ℃ to 50 ℃;
(3) slurry that recrystallization is obtained filter, wash, drying, promptly get micronized medicine.
2. method according to claim 1 is characterized in that: organic solvent is methanol, ethanol, acetone, isopropyl alcohol, propylene glycol, glycerol, n-butyl alcohol, the tert-butyl alcohol, amylalcohol, capryl alcohol, dichloromethane, chloroform.
3. method according to claim 1 is characterized in that: anti-solvent is water, normal hexane, cyclohexane extraction, petroleum ether, diisopropyl ether, ether, heptane, octane.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101849910A (en) * | 2010-05-18 | 2010-10-06 | 重庆华邦制药股份有限公司 | Preparation method of betamethasone dipropionate micro-particle |
| CN108024963A (en) * | 2015-07-23 | 2018-05-11 | 拉曼·梅塔 | On-mechanical technique for digoxin micronizing |
| CN108157584A (en) * | 2018-03-26 | 2018-06-15 | 东北农业大学 | A kind of Isolation and the method for preparing high nutrition albumen particle and products thereof |
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2008
- 2008-10-10 CN CNA200810223969XA patent/CN101390838A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101849910A (en) * | 2010-05-18 | 2010-10-06 | 重庆华邦制药股份有限公司 | Preparation method of betamethasone dipropionate micro-particle |
| CN101849910B (en) * | 2010-05-18 | 2012-02-22 | 重庆华邦制药股份有限公司 | Preparation method of betamethasone dipropionate micro-particle |
| CN108024963A (en) * | 2015-07-23 | 2018-05-11 | 拉曼·梅塔 | On-mechanical technique for digoxin micronizing |
| AU2016296162B2 (en) * | 2015-07-23 | 2021-03-18 | Raman Mehta | Non-mechanical process for the micronization of digoxin |
| CN108157584A (en) * | 2018-03-26 | 2018-06-15 | 东北农业大学 | A kind of Isolation and the method for preparing high nutrition albumen particle and products thereof |
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Open date: 20090325 |