CN1218930C - Process for preparing micropowdered salbutamol sulfate - Google Patents
Process for preparing micropowdered salbutamol sulfate Download PDFInfo
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- CN1218930C CN1218930C CN 03128673 CN03128673A CN1218930C CN 1218930 C CN1218930 C CN 1218930C CN 03128673 CN03128673 CN 03128673 CN 03128673 A CN03128673 A CN 03128673A CN 1218930 C CN1218930 C CN 1218930C
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Abstract
The present invention relates to a method for preparing micronization salbutamol sulfate, particularly to a method for preparing crystallization sulfuric acid salbutamol by using raw material solution containing salbutamol sulfate. The present invention adopts a rotating packed bed; raw material solution containing salbutamol sulfate and anti-solvent acetone respectively pass through a solution inlet of the rotating packed bed and a solution distribution machine, are mixed in a material feeding layer, and are recrystallized to obtain crystallization slurry of the salbutamol sulfate. The crystallization slurry obtained by the rotating packed bed is filtered, washed and dried to obtain crystallization finished product of the salbutamol sulfate. The range of the volume flow ratio of anti-solvent to the raw material containing salbutamol sulfate is from 7: 1 to 10: 1, and the crystallization temperature is at the normal temperature or below the normal temperature. The method obtains salbutamol sulfate crystal having the advantages of narrow granularity distribution and controllable average granularity, and easy to realize micronization industrial production of salbutamol sulfate medicine.
Description
Technical field
The present invention relates to prepare the method for crystalline sulfuric acid salbutamol, particularly use rotating packed bed prepared sizes narrowly distributing, the micronized salbutamol sulfate crystal that median size is controlled by the material solution of sulfur acid salbutamol.
Background technology
Salbutamol sulfate [1-(4-hydroxyl-3-hydroxymethyl phenyl)-2-(uncle's fourth amino) ethanol vitriol] is a kind of potent selectivity β
2-receptor stimulant.At present, because determined curative effect, the easy administration of salbutamol sulfate, become one of main medicine of the clinical respiratory tract diseases such as bronchospasm that are used for the treatment of asthmatic bronchitis, bronchial asthma and pulmonary emphysema patient.The salbutamol sulfate medicine uses with the form of aerosol, capsule, the diffusing sheet of slowly-releasing, sustained release pellet on market usually.
The preparation method of salbutamol sulfate routine is to be starting raw material with the hydroxy acetophenone, make salbutamol sulfate through nine steps such as chloromethylation, esterification, bromination, amination, hydrolysis, neutralization, catalytic hydrogenation, hydrogenolysis, salifies, total recovery is (Study on Synthesis of Albuterol Sulfate between 11-13%, the Chinese Medicine The Chemicals, 1995,5 (3), 215-217).In the process of preparation salbutamol sulfate, make salbutamol earlier, then it is obtained the ethanolic soln of salbutamol with anhydrous alcohol solution, usually the ethanolic soln of employing sulfuric acid and salbutamol carries out the pH value of acid-base reaction regulator solution, when the pH value reached 5.5-6.0, salbutamol sulfate just had crystallization to separate out.This crystallization processes process is usually carried out in conventional stirring tank, in order to make the ethanolic soln contain salbutamol fully contact with sulfuric acid, needs bigger power of agitator usually, otherwise will influence that crystallization is separated out and finally influence the yield of product.In addition, because aspects such as the separating out of nucleus, crystalline growth in the reaction, the crystallographic dimension difference that exists between each batch is big, the problem of poor reproducibility, unstable product quality.
With regard to the salbutamol sulfate product that the method for routine obtains, owing in crystallisation process, there is local supersaturation usually, cause the salbutamol sulfate crystallographic dimension inhomogeneous, size-grade distribution is wide, and crystal is mobile poor, the specific volume height.Therefore, the drug particles that obtains by conventional crystallization processes, preparation packing difficulty not only, and can influence human bioavailability.The salbutamol sulfate crystal that is obtained by conventional crystallization processes is big, can cause absorbing not exclusively.Bibliographical information (respiratory tract administration novel form-powder inhalation is arranged; foreign medical science pharmacy fascicle; 1996; 23 (1), 1-6), when being used for aerosol; particle diameter is at the easiest segmental bronchus that enters of medicine of 0.5-7 μ m; can bring into play the expansion bronchus effect fast, and the drug particles outside this particle size range or external by exhalation, perhaps being deposited on pars oralis pharyngis can not be well in segmental bronchus place performance curative effect through gastrointestinal absorption.In order to overcome the above problems, there is the investigator to attempt preparing salbutamol (that is: the medicine in early stage of salbutamol sulfate) (Supercritical antisolvent precipitation ofsalbutamol microparticles E.Reverchon with the supercutical fluid recrystallization method, G.Della Porta, P.PalladoPowder Technology 114 2001 17-22), its principle is that the dissolving because of SCF is expanded solvent volume when feeding supercutical fluid (SCF) in solvent, under the identical situation of temperature, pressure is high more, the volumetric expansion of solvent is just big more, dissolve each other until two-phase, become single-phase, changed the reactive force between solvent and solute simultaneously, reduced the dissolving power of solvent, made solute form supersaturation and precipitate and separate out.Though this method energy better controlled granular size, the granular size that makes is between 1-5 μ m, and its operating equipment is complicated, needs supercharging system and expander.After solution expansion, the particle precipitating, solvent separates with solid and can realize that process often adopts periodical operation or semi continuous operation by microwell plate filtration or direct extraction solvent, and the operating procedure more complicated is difficult to realize industrialization.
Anti-solvent recrystallization method, its principle is: another kind of to the very poor solvent of solute solvability (anti-solvent) by dissolving in solvent, reduce the dissolving power of former solvent, made solute form supersaturation and precipitate and separate out, thereby reached the purpose of purifying or forming subparticle.Present anti-solvent recrystallization method is used for liquid phase separation and purification more.Have not yet to see the report that anti-solvent recrystallization method is used to prepare salbutamol sulfate.
High-gravity technology is to utilize to produce the hypergravity environment more much bigger than earth gravity acceleration in rotary packed bed (RPB).Liquid in high dispersive, high turbulence, mix by force and mass transfer process and micro mixing have more greatly been strengthened under the news rapidly in the interface.Simultaneously, the characteristics that rotating packed bed has compact construction, takes up an area of little, serialization production, output is high.The applicant successfully is used to prepare ultrafine aluminium hydroxide (ZL 981263712), silicon-dioxide powdery (ZL001322753), calcium carbonate powder (ZL 001003550) etc. with rotary packed bed.But have not yet to see the rotary packed bed report that is used to prepare salbutamol sulfate.
Summary of the invention
The invention provides a kind of novel method for preparing the crystalline sulfuric acid salbutamol, and can obtain narrow particle size distribution, the controlled salbutamol sulfate crystal of median size.The present invention can realize salbutamol sulfate drug powder suitability for industrialized production.
Technical scheme of the present invention is as follows: adopt rotating packed bed, the material solution of sulfur acid salbutamol is contacted mixing through the fluid inlet and the liquid distributor of rotating packed bed respectively with anti-solvent in packing layer, carry out recrystallization and obtain the salbutamol sulfate slurry; To pass through filtration, washing, drying through the slurry that rotating packed bed obtains again, promptly obtain the salbutamol sulfate crystal product; Anti-solvent acetone, the volume flow ratio scope of the material solution of anti-solvent and sulfur acid salbutamol is 7: 1-10: 1; Crystallization range is at 0 ℃-normal temperature.
The 90%-98% of salbutamol sulfate saturation concentration under the preferred uniform temp of material solution concentration of sulfur acid salbutamol of the present invention.
The rotating speed of rotating packed bed of the present invention is 500-2500rpm, preferred 800-2000rpm.Be provided with two independently fluid passages in the liquid distributor of rotating packed bed, each fluid passage communicates with spray orifice on the liquid distributor outer wall respectively.Liquid distributor adopts the polytetrafluoroethylmaterial material thermal insulation material.
The solution of the sulfur acid salbutamol that the present invention adopts comprises the solution of the salbutamol sulfate that directly obtains from the method for synthetic salbutamol sulfate; Perhaps the salbutamol sulfate that will obtain is dissolved in the salbutamol sulfate solution in the solvent.Normally used solvent is water, water and ethanol, water and acetone or water and Virahol.Also can use known other solvent that can be used for dissolving salbutamol sulfate.So-called herein " dissolving " is that the salbutamol sulfate crystal forms basic clear soln in solvent.Micronization process with concentration be under the crystallization condition salbutamol sulfate in its solvent saturated concentration about 95% for good, also can salbutamol sulfate be extracted for the tail washings that contains salbutamol sulfate after the crystallization, can reuse with the method for recrystallization of the present invention.
In the method for the invention, the volume flow ratio of the solution of anti-solvent acetone and sulfur acid salbutamol is in 7: 1 to 10: 1 scopes.The throughput ratio of controlling two materials is the degree of supersaturation for system in the crystallization control process, thereby reaches crystallization control speed, crystalline particle is little and the purpose of crystallisation process yield.Because the amount of anti-solvent is far longer than the amount of the solution of sulfur acid salbutamol, the temperature that can control anti-solvent realizes that the crystallization control temperature is lower than normal temperature.Tc directly influences the supersolubility temperature of system, and when Tc was high, the degree of supersaturation of system was less, and when Tc was hanged down, the degree of supersaturation of system was higher.When degree of supersaturation is high, the crystalline nucleation rate is greater than its growth velocity in the system, the degree of supersaturation of wishing the hierarchy of control helps obtaining tiny crystal, so in a high scope, so just can reduce the system Tc by lowland as far as possible and realize.
The present invention carries out recrystallization with the stock liquid and the anti-solvent of sulfur acid salbutamol by rotating packed bed, thereby obtains the salbutamol sulfate crystal.According to crystallization method of the present invention, two strands of materials in rotating packed bed fully, uniform contact and fast microcosmic mix, overcome two bursts of inhomogeneous, inadequate problems of material contact in conventional stirring tank, also reduced the local oversaturated phenomenon that in conventional stirring tank, occurs usually simultaneously.Because the rotating packed bed that adopted compact construction, take up an area of little, continuous production, output is high, thereby help realizing suitability for industrialized production.
The rotating packed bed that the present invention adopts as shown in Figure 1, and common the same comprising of rotating packed bed: liquid distributor 1, packing layer 2, rotor 3, rotating shaft 4, sealing 5, shell 6.What the used rotating packed bed of the present invention was different with common rotating packed bed is to be provided with two independently fluid passage 1-1 and 1-2 in the liquid distributor 1, each fluid passage communicates with spray orifice 1-3 on liquid distributor 1 outer wall respectively, and the aperture of spray orifice and hole count can be determined according to the needs of two fluid streams throughput ratios, like this, two strands of liquid can enter packing layer 2 respectively with different flow, and realize mixing at packing layer 2.After rotating packed bed was opened, packing layer 2 rotated under the drive of rotor 3.The solution a of sulfur acid salbutamol and anti-solution b enter the fluid passage 1-1 and 1-2 of liquid distributor 1 from import respectively, and the spray orifice 1-3 on liquid distributor 1 sprays into packing layer 2 respectively; A contacts in packing layer 2 with b two liquid, crystallization.In crystallisation process, the slurry c that throws away through packing layer 2 leaves rotating packed bed through liquid exit.
The packing layer 2 of rotating packed bed used in the present invention is silk screen, porous plate, waved plate or structured packing.
The liquid distributor of rotating packed bed used in the present invention (for example: tetrafluoroethylene) adopts thermal insulation material, this is because solution enters the packing layer of rotating packed bed with anti-solvent with different temperature, the concentration of solution is often very near saturation concentration, when the temperature of anti-solvent is hanged down, liquid distributor adopt thermal insulation material can prevent solution and anti-solvent liquid distributor carry out heat exchange so that before entering packing layer the material solution of salbutamol sulfate separate out with regard to excessive crystal is arranged, influence crystal mass.
The rotating speed of the rotor of rotating packed bed used in the present invention is generally 500rpm to 2500rpm.The rotating speed of rotating packed bed is that the size of crystalline particle and size-grade distribution are had very big influence, when the rotating speed of rotating packed bed is high more, reinforcement for transmittance process and micro mixing is strong more, the easy more small-particle that obtains narrow diameter distribution, rotating speed is low more, this strengthening effect is just weak more, and resultant particulate size is just big more, and it is also wide more to distribute.But consider economy (for example energy consumption etc.) reason usually, so recrystallization process normally carries out in the speed range of preferred 800rpm to 2000rpm.The salbutamol sulfate crystalline median size size that the present invention can regulate gained by the rotating speed of regulating the rotating packed bed rotor obtains median size micronization salbutamol sulfate controlled, narrow particle size distribution crystal.
The present invention is under the hypergravity environment, can strengthen greatly transmittance process and micro mixing, molecular diffusion between different sized molecules and interphase mass transfer process be faster than under the normal gravity field all, produce the contact of flowing in the porous medium of liquid-liquid two-phase under the hypergravity environment bigger hundreds of times to thousand times than earth gravity field, great shear forces makes liquid tear into nano level film, silk and drip, produce huge and phase interface fast updating, microcosmic mixes and mass transfer process has obtained very big reinforcement.Nucleation process is carried out in the environment that microcosmic mixes, thereby make nucleation process controlled, narrow particle size distribution.These characteristics of high-gravity technology just in time can remedy the shortcoming of conventional crystallization processes.
Method of the present invention comprises the operational condition such as temperature, throughput ratio of rotating speed, solution and the anti-solvent of rotating packed bed, the salbutamol sulfate crystal that obtains having required micronized narrow size distribution by adjusting.The particle size distribution that the present invention obtains is narrow, can reach 90% particle in the particle size range of the same order of magnitude, and plane of crystal is bright and clean.Use electron microscope observation, do not have to find the frequent brilliant knurl that occurs in the crystal of ordinary method preparation.The salbutamol sulfate crystal color and luster that the present invention obtains is pure white, uniform particles, good fluidity.
The salbutamol sulfate crystal that obtains by above-mentioned crystallization can obtain the finished product salbutamol sulfate further according to for example post-processing step of washing, drying etc. that comprises known to a person of ordinary skill in the art.With the S3500N type scanning electron microscopic observation that HIT produces, the rhabdolith of the narrow diameter distribution of minor axis in the 1-5 mu m range.The present invention can adopt the operate continuously method that salbutamol sulfate is carried out micronization, significantly shortens the recrystallization time, obtains narrow particle size distribution, the controlled micronization salbutamol sulfate crystal of mean particle size, has industrial prospect.
The present invention has overcome in the prior art usually because of stirring the problem of the inhomogeneous granularity inequality that produces.So in field of medicaments, can be used in effectively in aerosol or the capsule.For example, in aerosol, can not use or few just can obtain uniform stable suspension with suspending agent.Because uniform particles, so packing is used for capsule preparations easily.After the micronization, the dissolution rate of medicine also can be improved to a certain extent.The micronization salbutamol sulfate crystal of the present invention's preparation, according to Chinese Pharmacopoeia version two ministerial standards check in 2000, every conclusion all meets the pharmacopeia regulation.
Description of drawings
Fig. 1 is at rotating packed bed structural representation used in the present invention.
Fig. 2 is the electromicroscopic photograph of the salbutamol sulfate that obtains of the embodiment of the invention 1.
Fig. 3 is the salbutamol sulfate crystalline electromicroscopic photograph that Comparative Examples 2 obtains according to ordinary method.
Fig. 4 is the electromicroscopic photograph of salbutamol sulfate raw material medicine.
Embodiment
Embodiment 1
Adopt commercially available salbutamol sulfate raw material medicine, shown in electromicroscopic photograph among Fig. 4, salbutamol sulfate raw material medicine is that minor axis is at 5-20 μ m, the uneven rod-shpaed particle of globule size.Salbutamol sulfate raw material medicine is dissolved in the water, be mixed with concentration and be 0.25g/ml (be salbutamol sulfate under this temperature condition in water saturated concentration about 95%) salbutamol sulfate stock liquid A.Adopting liquid-liquid rotating packed bed, is 30 hertz by adjusting frequency modulation meter, determines that the rotating packed bed revolution is about 1800rpm, adopts the circular hole liquid distributor, and the low consumption of the liquid spray orifice that enters salbutamol sulfate crystallization stock liquid a is Φ 0.5 * 9; The big liquid measure spray orifice that enters anti-solvent b (acetone) is Φ 1.44 * 9.Adopting the anti-solvent b and the ratio of the flow of salbutamol sulfate stock liquid a is 10: 1 (volume), and anti-solvent b flow is 1.2m
3/ hr, salbutamol sulfate stock liquid a flow is 0.12m
3/ hr.Tc is 13.2 ℃.As shown in Figure 1, salbutamol sulfate stock liquid a sprays into rotating packed bed by fluid inlet through the low consumption of the liquid spray orifice, anti-solvent b sprays into rotating bed by fluid inlet through big liquid measure spray orifice, two strands of materials are dispersed into fine liquid drops, liquid film, contact, mix at packing layer 2, tangentially get rid of, flow out rotating packed bed to the rotating packed bed exocoel.Slurry C with obtaining passes through centrifuging again, and with acetone (or other suitable organic solvent) washing, the crystal that obtains is dry under 40-50 ℃, gets product.By SEM observation, as shown in Figure 2, product pellet is even, the average rhabdolith of minor axis about 1.4 μ m.The particle diameter that at least 90% particle is wherein arranged is at 1.0-2.0 μ m.
Embodiment 2
Operating parameters is identical with embodiment 1, and only different is that the change Tc is 22 ℃, and by SEM observation, it is similar with embodiment 1 to obtain the product pattern, but crystalline minor axis median size is about 2 μ m.The particle diameter that at least 80% particle is wherein arranged is at 1.0-4.0 μ m.
Embodiment 3
Operating parameters is identical with embodiment 1, and only different is that change rotating bed rotating speed is 1140rpm, and by SEM observation, it is similar with embodiment 1 to obtain the product pattern, but crystalline minor axis median size is about 4 μ m.The particle diameter that at least 90% particle is wherein arranged is at 3.0-5.0 μ m.
Embodiment 4
Operating parameters is identical with embodiment 1, and the volume flow ratio that only different is changes anti-solvent and salbutamol sulfate crystallization stock liquid is 8: 1, observes by SEM, and it is similar with embodiment 1 to obtain the product pattern, but crystalline minor axis median size is about 2.5 μ m.The particle diameter that at least 90% particle is wherein arranged is at 1.0-3.0 μ m.
Embodiment 5
Operating parameters is identical with embodiment 1, and the rotating speed of only different is rotating bed is 1500rpm, and the crystal grain of gained is observed by SEM, and the average minor axis of particulate is 2.3 μ m, and the particle minor axis more than at least 80% is at 2-3 μ m.
Comparative Examples 1
Adopt conventional method in stirring tank, to carry out, 20 ℃ of temperature, anti-solvent acetone is 10: 1 (compare with embodiment 2, temperature is lower slightly, volume flow ratio is identical) with the husky volume flow ratio of deciding amine alcohol of sulfuric acid, mixing speed 500, the salbutamol sulfate concentration of aqueous solution is 95% of a saturation concentration,, the gained crystal grain is observed by SEM, the small-particle of minor axis less than 1 μ m arranged, the macrobead of minor axis greater than 5 μ m also arranged, and median size is at 3 μ m, and 60% particle minor axis is between 3-5 μ m.
Comparative Examples 2
Operating parameters is identical with Comparative Examples 1, and only the volume ratio of anti-solvent and solution is 8: 1, and the gained crystal grain is observed by SEM, electromicroscopic photograph as shown in Figure 3, the particulate size is inhomogeneous, and average minor axis is 5 μ m, 70% particulate minor axis is at 4-7 μ m.
Claims (3)
1. method for preparing the micronization salbutamol sulfate is carried out recrystallization with material solution and anti-solvent and is obtained slurry; Through filtration, washing, drying, promptly obtain the material crystal finished product; Anti-solvent acetone, crystallization range is at 0 ℃-normal temperature, it is characterized in that: adopt rotating packed bed, the rotating speed of rotating packed bed is 500-2500r/min, be provided with two independently fluid passages in the liquid distributor of rotating packed bed, each fluid passage communicates with spray orifice on the liquid distributor outer wall respectively, the material solution concentration of sulfur acid salbutamol is the 90%-98% of salbutamol sulfate saturation concentration under the uniform temp, and the volume flow ratio scope of the material solution of anti-solvent and sulfur acid salbutamol is 7: 1-10: 1; The material solution of sulfur acid salbutamol is contacted mixing through the fluid inlet and the liquid distributor of rotating packed bed respectively with anti-solvent in packing layer, carry out recrystallization and obtain the salbutamol sulfate slurry; Finally obtain the salbutamol sulfate crystal product.
2. method according to claim 1 is characterized in that: the rotating speed of rotating packed bed is 800-2000r/min.
3. method according to claim 1 is characterized in that: liquid distributor adopts the tetrafluoroethylene thermal insulation material.
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| CN 03128673 CN1218930C (en) | 2003-04-29 | 2003-04-29 | Process for preparing micropowdered salbutamol sulfate |
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| CN 03128673 CN1218930C (en) | 2003-04-29 | 2003-04-29 | Process for preparing micropowdered salbutamol sulfate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100448447C (en) * | 2007-03-08 | 2009-01-07 | 北京化工大学 | Preparation of superfine prednisolone powder |
| CN101721312B (en) * | 2008-10-10 | 2013-05-29 | 北京化工大学 | Method and device for preparing medicament particles with nano-micro structure |
| CN101513394B (en) * | 2009-03-30 | 2011-04-27 | 浙江新和成股份有限公司 | Continuous preparation method for nanometer dispersed vitamin A microcapsule |
| CN105001100A (en) * | 2015-06-11 | 2015-10-28 | 山西云鹏制药有限公司 | Method for refining salbutamol sulfate |
| CN114195608B (en) * | 2021-11-08 | 2023-03-31 | 北京化工大学 | Purification method of Suzuki reaction monomer |
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