Generation of nanoparticles and microparticles of controllable size using acoustic and ultrasonic vibration

Abstract

The current invention, Supercritical Antisolvent Precipitation with Enhanced Mass Transfer (SAS-EM) provides a significantly improved method for the production of nano and micro-particles with a narrow size distribution. The processes of the invention utilize the properties of supercritical fluids and also the principles of virbrational atomization to provide an efficient technique for the effective nanonization or micronization of particles. Like the SAS technique, SAS-EM, also uses a supercritical fluid as the antisolvent, but in the present invention the dispersion jet is deflected by a vibrating surface that atomizes the jet into fine droplets. The vibrating surface also generates a vibrational flow field within the supercritical phase that enhances mass transfer through increased mixing. Sizes of the particles obtained by this technique are easily controlled by changing the vibration intensity of the deflecting surface, which in turn is controlled by adjusting the power input to the vibration source. A major advantage of the SAS-EM technique is that it can be successfully used to obtain nanoparticles of materials that usually yield fibers or large crystals in SAS method. Microencapsulation via coprecipitation of two or more materials can also be achieved using the SAS-EM technique.

What is claimed is:  
     
         1 . A method for generating a solid particle containing a compound of interest, the method comprising: 
 providing a reservoir containing a solution of the compound in a solvent;    providing an antisolvent in a contained space in fluid communication with the solution in the reservoir, wherein the antisolvent is selected such that the compound is less soluble in the antisolvent than in the solvent; and    applying focused acoustic energy to the reservoir so as to produce a droplet of the solution in the antisolvent in the contained space, whereby admixture of the solution droplet and the antisolvent results in the precipitation of the compound, forming a solid particle.    
     
     
         2 . The method of  claim 1 , wherein focused acoustic energy is applied to the reservoir at a plurality of loci so as to eject a plurality of droplets, whereby a plurality of solid particles is provided.  
     
     
         3 . The method of  claim 1 , wherein the solvent is aqueous.  
     
     
         4 . The method of  claim 1 , wherein the solvent is non-aqueous.  
     
     
         5 . The method of  claim 4 , wherein the solvent is organic.  
     
     
         6 . The method of  claim 1 , wherein the antisolvent is a supercritical fluid.  
     
     
         7 . The method of  claim 4 , wherein the antisolvent is a supercritical fluid.  
     
     
         8 . The method of  claim 5 , wherein the antisolvent is a supercritical fluid.  
     
     
         9 . The method of  claim 1 , wherein the antisolvent is gaseous.  
     
     
         10 . The method of  claim 1 , wherein the precipitation of the compound of interest comprises crystallization thereof.  
     
     
         11 . The method of  claim 1 , wherein the solution and the antisolvent are both present in the reservoir.  
     
     
         12 . The method of any one of claims  6 ,  7 ,  8 ,  9 ,  10  and  11 , wherein the antisolvent is selected from the group consisting of carbon dioxide, water, ammonia, nitrogen, nitrous oxide, methane, ethane, ethylene, propane, butane, n-pentane, benzene, methanol, ethanol, isopropanol, isobutanol, monofluoromethane, trifluoromethane, chlorotrifluoromethane, monofluoromethane, hexafluoroethane, 1,1-difluoroethylene, 1,2-difluoroethylene, toluene, pyridine, cyclohexane, m-cresol, decalin, cyclohexanol, 0-xylene, tetralin, aniline, acetylene, chlorotrifluorosilane, xenon, sulfur hexafluoride, propane and combinations thereof.  
     
     
         13 . The method of  claim 12 , wherein the antisolvent is carbon dioxide.  
     
     
         14 . The method of  claim 1 , wherein the solution droplet is ejected onto a surface of a substrate having the antisolvent thereon.  
     
     
         15 . The method of  claim 1 , wherein the solution is a saturated solution.  
     
     
         16 . The method of  claim 1 , wherein the compound of interest is hydrophilic, the solvent is hydrophilic, and the antisolvent is lipophilic.  
     
     
         17 . The method of  claim 1 , wherein the compound of interest is hydrophilic, the solvent is aqueous, and the antisolvent is lipidic.  
     
     
         18 . The method of  claim 1 , wherein the compound of interest is lipophilic, the solvent is lipophilic, and the antisolvent is hydrophilic.  
     
     
         19 . The method of  claim 1 , wherein the size of the particle is in the range of approximately 0.1 nm to about 5 μm.  
     
     
         20 . The method of  claim 19 , wherein the size of the particle is in the range of approximately 5 nm to about 2.5 μm.  
     
     
         21 . The method of  claim 1 , wherein the compound of interest is metallic.  
     
     
         22 . The method of  claim 1 , wherein the solution comprises two or more compounds of interest.  
     
     
         23 . The method as  claim 1 , wherein the solution further comprises a biodegradable polymer.  
     
     
         24 . The method of  claim 1 , wherein the compound of interest has a lipophilic group, the solvent is lipophilic, and the antisolvent is lipophilic.  
     
     
         25 . The method of  claim 1 , wherein the compound of interest has a hydrophilic group, the solvent is hydrophilic, and the antisolvent is hydrophilic.  
     
     
         26 . The method of  claim 1 , wherein the compound of interest has a hydrophilic group, the solvent is hydrophilic and CO 2  philic, and the antisolvent is CO 2 .  
     
     
         27 . A method for generating a plurality of particles containing a compound of interest, the method comprising: 
 providing a plurality of reservoirs each containing a solution of the compound in a solvent;    providing an antisolvent in a contained space in fluid communication with the solution in each reservoir, wherein the antisolvent is selected such that the compound is less soluble in the antisolvent than in the solvent; and    applying focused acoustic energy to each reservoir so as to produce droplets of the solution into the antisolvent in the contained space, whereby admixture of the solution droplets and the antisolvent results in the precipitation of the compound, forming solid particles.    
     
     
         28 . The method of  claim 27 , wherein the focused acoustic energy is applied to each reservoir simultaneously using a plurality of acoustic ejection devices.  
     
     
         29 . The method of  claim 27 , wherein the focused acoustic energy is applied to each reservoir in succession using a single acoustic ejection device.  
     
     
         30 . A device for making solid particles of a compound of interest, comprising: a reservoir containing a solution of the compound in a solvent; an antisolvent in a contained space in fluid communication with the solution in the reservoir such that droplets ejected from the solution are directed into the antisolvent, wherein the antisolvent is selected such that the compound is less soluble in the antisolvent than in the solvent; an acoustic ejector comprising an acoustic radiation generator for generating acoustic radiation and a focusing means for focusing the acoustic radiation at a focal point within the solution in the reservoir so as to eject a droplet therefrom; and a means for positioning the ejector in acoustic coupling relationship to the reservoir.  
     
     
         31 . The device of  claim 30 , comprising a single acoustic ejector.  
     
     
         32 . The device of  claim 30 , comprising a plurality of acoustic ejectors positioned to direct focused acoustic energy to a plurality of loci within the solution so as to eject a plurality of droplets, whereby a plurality of solid particles is provided.  
     
     
         33 . The device of  claim 30 , further comprising a means for maintaining the solvent in the reservoir at a constant temperature.  
     
     
         34 . The device of  claim 30 , wherein the acoustic coupling relationship between the ejector and the solution in the reservoir is established by providing an acoustically conductive medium between the ejector and the reservoir.  
     
     
         35 . The device of  claim 30 , wherein acoustic coupling between the ejector and the fluid in each reservoir is established at a predetermined distance between the ejector and each reservoir.  
     
     
         36 . The device of  claim 30 , wherein the solvent is aqueous.  
     
     
         37 . The device of  claim 30 , wherein the solvent is non-aqueous.  
     
     
         38 . The device of  claim 37 , wherein the solvent is organic.  
     
     
         39 . The device of  claim 30 , wherein the antisolvent is a supercritical fluid.  
     
     
         40 . The device of  claim 37 , wherein the anti solvent is a supercritical fluid.  
     
     
         41 . The device of  claim 38 , wherein the anti solvent is a supercritical fluid.  
     
     
         42 . The device of  claim 30 , wherein the antisolvent is gaseous.  
     
     
         43 . The device of  claim 30 , wherein the solution and the antisolvent are both present in the reservoir.  
     
     
         44 . The device of any one of claims  30  through  43 , wherein the antisolvent is selected from the group consisting of carbon dioxide, water, ammonia, nitrogen, nitrous oxide, methane, ethane, ethylene, propane, butane, n-pentane, benzene, methanol, ethanol, isopropanol, isobutanol, monofluoromethane, trifluoromethane, chlorotrifluoromethane, monofluoromethane, hexafluoroethane, 1,1-difluoroethylene, 1,2-difluoroethylene, toluene, pyridine, cyclohexane, m-cresol, decalin, cyclohexanol, 0-xylene, tetralin, aniline, acetylene, chlorotrifluorosilane, xenon, sulfur hexafluoride, propane and combinations thereof.  
     
     
         45 . The device of  claim 41 , wherein the antisolvent is carbon dioxide.  
     
     
         46 . The device of  claim 30 , wherein the solution is a saturated solution.  
     
     
         47 . The device of  claim 30 , wherein the compound of interest is hydrophilic, the solvent is hydrophilic, and the antisolvent is lipophilic.  
     
     
         48 . The device of  claim 30 , wherein the compound of interest is hydrophilic, the solvent is aqueous, and the antisolvent is lipidic.  
     
     
         49 . The device of  claim 30 , wherein the compound of interest is lipophilic, the solvent is lipophilic, and the antisolvent is hydrophilic.  
     
     
         50 . The device of  claim 30 , wherein the compound of interest is metallic.  
     
     
         51 . The device of  claim 30 , wherein the solution comprises two or more compounds of interest.  
     
     
         52 . The device as  claim 30 , wherein the solution further comprises a biodegradable polymer.  
     
     
         53 . A device for making solid particles of a compound of interest, comprising: a plurality of reservoirs each containing a solution of the compound in a solvent; an antisolvent in a contained space above and in fluid communication with the solution in each reservoir such that droplets ejected from the solution are directed into the antisolvent, wherein the antisolvent is selected such that the compound is less soluble therein than in the solvent; an acoustic ejector comprising an acoustic radiation generator for generating acoustic radiation and a focusing means for focusing the acoustic radiation at a focal point within the solution in the reservoir so as to eject a droplet therefrom; and a means for positioning the ejector in acoustic coupling relationship to the reservoir.  
     
     
         54 . The device of  claim 53 , comprising a single acoustic ejector.  
     
     
         55 . The device of  claim 53 , comprising a plurality of acoustic ejectors positioned to direct focused acoustic energy to each reservoir so as to eject a plurality of droplets therefrom.  
     
     
         56 . The device of  claim 53 , wherein each of the reservoirs is removable from the device.  
     
     
         57 . The device of  claim 53 , wherein the reservoirs are individual wells in a well plate.  
     
     
         58 . The device of  claim 53 , wherein the reservoirs are substantially acoustically indistinguishable.  
     
     
         59 . The device of  claim 53 , comprising at least about 10,000 reservoirs.  
     
     
         60 . The device of  claim 59 , comprising at least about 100,000 reservoirs.  
     
     
         61 . The device of  claim 60 , comprising in the range of about 100,000 to about 4,000,000 reservoirs.  
     
     
         62 . The device of  claim 53 , wherein each reservoir is adapted to contain no more than about 100 nanoliters of fluid.  
     
     
         63 . The device of  claim 53 , wherein each reservoir is adapted to contain no more than about 10 nanoliters of fluid.  
     
     
         64 . The device of  claim 53 , further comprising means for maintaining the solvent in each reservoir at a constant temperature.  
     
     
         65 . The device of  claim 53 , wherein the acoustic coupling relationship between the ejector and the fluid in each reservoir is established by providing an acoustically conductive medium between the ejector and each reservoir.  
     
     
         66 . The device of  claim 53 , wherein acoustic coupling between the ejector and the fluid in each reservoir is established at a predetermined distance between the ejector and each reservoir.