Patent Publication Number: US-2006008498-A1

Title: Nano-particle production

Description:
TECHNICAL FIELD  
      This description relates to the production of nano-particles.  
     BACKGROUND  
      The particle size of a compound often affects its physical and chemical properties, such as apparent solubility, color, wetting, suspension stability, compaction behavior, appearance, and tactility. These properties are important in many areas. For example, in the field of pharmaceutics, drug delivery, drug bioavailability, production processes, product properties, product stability, and physiological compatibility are closely related to the particle sizes of pharmaceutical compounds. When their particle sizes are reduced to smaller than 200 nano-meters (nm), many compounds display useful properties that are quite different from those of larger particles of the same compound. Nano-particles can be produced by, for example, expansion of a supercritical fluid and by supercritical fluid anti-solvent precipitation. 
    
    
     DESCRIPTION OF DRAWINGS  
       FIG. 1  shows a nano-particle generator.  
       FIG. 2  shows a powder feeder.  
       FIG. 3  shows a solid atomizer.  
       FIGS. 4 and 5  show cryogenic gas generators.  
       FIG. 6  shows a cryogenic jet mill.  
       FIG. 7  shows a cyclone collector. 
    
    
     SUMMARY OF INVENTION  
      In general, in one aspect, the invention features a method including processing larger particles of a material to generate smaller particles having at least one dimension smaller than 200 nm, at least a portion of the processing performed under a cryogenic condition and based on at least a physical property of the material under the cryogenic condition.  
      Implementations of the invention may include one or more of the following features.  
      The cryogenic condition includes a condition in which the temperature is less than −40° C. A physical property includes a greater tendency to crack under the cryogenic condition. The larger particles initially have at least one dimension larger than 100 μm. At least 5 percent of the larger particles are processed into smaller particles having at least one dimension smaller than 200 nm. At least 5 percent of the larger particles are processed into smaller particles having three dimensions smaller than 200 nm.  
      The processing includes milling the larger particles. The milling includes using a pressurized cryogenic gas to cause the particles to grind against or collide with one another. The cryogenic gas includes at least one of air, nitrogen, and inert gas. The inert gas includes helium.  
      The processing includes at least one treatment in addition to the milling, the additional treatment based on at least a physical property of the material under the cryogenic condition. The additional treatment includes imposing ultrasonic waves to the particles. The additional treatment includes imposing microwaves to the particles.  
      A physical property includes the material forming cracks when subject to ultrasonic vibrations under the cryogenic condition. The processing includes imposing ultrasonic waves on the particles. The material has a physical property such that the material forms cracks when the temperature of the material rises at least 20° C. per second from a first temperature under the cryogenic condition to a second temperature. The processing includes using microwaves to increase the temperature of the particles. The processing includes exposing the particles alternately to a cryogenic condition and a non-cryogenic condition.  
      The method includes generating a cryogenic gas to process the particles. Generating the cryogenic gas includes passing a gas through a passage that is cooled by liquid nitrogen, or passing a gas through liquid nitrogen. The passage includes a coil tube immersed in the liquid nitrogen. The gas includes at least one of air, nitrogen, and an inert gas. The inert gas includes helium. The cryogenic gas has a pressure at least 100 psi.  
      The method includes spraying a liquid from a higher pressure area to a lower pressure area to generate the larger particles. The method includes cooling the lower pressure area with cryogenic gas. The method includes generating the liquid by dissolving a material in a solvent. The solvent includes at least one of acetone, chloroform, alcohol, ether, petroleum ether, benzene, and water. The alcohol includes at least one of methanol, ethanol, and isopropyl alcohol. The material includes plastic.  
      The larger sized particles include herbs, calcium oxalate, calcium sulfate, calcium phosphate, silicon dioxide, cellulose and herbs, insulin, taxine, griseofulvin, albuterol sulfate, ibuprofene, lecithin, plastic, vitamins, iron oxide, or paclitaxcel. The material is in a solid state or a liquid state at 20° C.  
      In general, in another aspect, the invention features a method that includes generating a cryogenic gas by passing a gas through a passage that is cooled by liquid having a temperature less than or equal to −40° C.  
      Implementations of the invention may include one or more of the following features.  
      The liquid has a temperature less than or equal to −100° C. The liquid includes liquid nitrogen. The passage includes a coil tube immersed in the liquid. The gas includes at least one of air, nitrogen, and an inert gas. The inert gas includes helium.  
      In general, in another aspect, the invention features a method that includes generating a cryogenic gas by passing a gas through liquid having a temperature less than or equal to −40° C.  
      Implementations of the invention may include one or more of the following features.  
      The liquid has a temperature less than or equal to −100° C. The liquid includes liquid nitrogen. The method includes removing oxygen in the gas by liquifying the oxygen in the liquid nitrogen. The gas includes at least one of air, nitrogen, and an inert gas. The inert gas includes helium.  
      In general, in another aspect, the invention features a method that includes generating small particles having three dimensions smaller than 200 nm, mixing the small particles with a liquid to generate a solution, and administering the solution to a human body through an intravenous injection.  
      Implementations of the invention may include one or more of the following features.  
      The small particles are generated according to a process in which at least a portion of the process is performed at a temperature less than or equal to −40° C. The process includes jet milling larger particles to generate the small particles. The small particles include a pharmaceutical agent.  
      In general, in another aspect, the invention features a method that includes generating droplets of a liquid containing a material that is dispersed in a dispersion medium, and cooling the droplets under a cryogenic condition to generate solid dispersion particles that contain the material.  
      Implementations of the invention may include one or more of the following features.  
      The cryogenic condition includes a condition in which a temperature is less than or equal to −40° C. Generating the droplets includes passing the liquid from a higher pressure region through an opening to a lower pressure region. Cooling the droplets under the cryogenic condition includes using a cryogenic gas to cool the droplets. At least a portion of the solid dispersion particles each contains a single molecule of the material.  
      In general, in another aspect, the invention features an apparatus that includes a jet mill to receive larger sized particles and a cryogenic gas to cause the larger sized particles to be milled into smaller sized particles, at least 5 percent of the smaller sized particles having three dimensions smaller than 200 nm.  
      Implementations of the invention may include one or more of the following features.  
      The apparatus includes a cryogenic gas generator to generate the cryogenic gas. The jet mill includes an insulated chamber to maintain a temperature equal to or below −40° C. The cryogenic gas has a temperature below or equal to −40° C.  
      The apparatus includes a collecting chamber to collect the smaller sized particles. The collecting chamber includes a low-pressure chamber having a pressure lower than 1 atm.  
      The apparatus includes an ultrasonic wave generator to direct ultrasonic waves toward the particles.  
      The apparatus includes a solid atomizer to generate the larger sized particles from the liquid. The solid atomizer includes a spray head to spray the liquid from a high pressure region to a low pressure region. The apparatus includes nozzles to inject cryogenic gas around the spray head to cool liquid droplets sprayed out of the spray head.  
      The apparatus includes a heater to heat the particles while the particles are being milled. The heater includes a microwave generator.  
      In general, in another aspect, the invention features an apparatus that includes a particle processor to receive larger particles and to process the larger particles into smaller particles having at least one dimension smaller than 200 nm, at least a portion of the particle processor being maintained under a cryogenic condition so that at least a portion of the processing of the larger particles is performed under the cryogenic condition.  
      Implementations of the invention may include one or more of the following features. The particle processor includes a jet mill to mill the larger particles under the cryogenic condition. The cryogenic condition includes a condition in which the temperature is less than or equal to −40° C.  
      In general, in another aspect, the invention features an apparatus that includes a container that contains a liquid maintained at a temperature less than or equal to −40° C., and a passage having at least a portion that is immersed in the liquid, the passage having a first opening to receive a gas having a temperature higher than −40° C., the passage having a second opening to output the gas after the gas passes the portion that is immersed in the liquid.  
      Implementations of the invention may include one or more of the following features. The liquid includes liquid nitrogen. The apparatus includes a source to generate the gas. The gas includes at least one of nitrogen, air, and an inert gas. The passage includes a coil tube.  
      In general, in another aspect, the invention features an apparatus that includes a container that is partially filled with a liquid maintained at a temperature less than or equal to −40° C.; a first passage having a first opening to receive a gas having a temperature higher than −40° C., the first passage having a second opening that is immersed in the liquid to output the gas into the liquid, the gas forming bubbles in the liquid that emerge from the liquid and enter a space in the container above the liquid; and a second passage to receive the gas in the open space.  
      Implementations of the invention may include one or more of the following features. The liquid includes liquid nitrogen. The apparatus includes a source to generate the gas. The gas includes at least one of nitrogen, air, and an inert gas.  
      In general, in another aspect, the invention features an apparatus that includes means for reducing the temperature of particles to a cryogenic condition, and means for processing the particles to generate smaller particles.  
      Implementations of the invention may include one or more of the following features. The means for reducing the temperature of particles includes a cryogenic gas generator to generate a gas having a temperature that is less than −40° C. The means for processing the particles includes a jet mill.  
      An advantage of using the invention to reduce the particle size of a material is that the solubility of the material can be increased. Increasing the solubility of a drug can enhance its bioavailability. Another advantage of using nano-particles is that, for some drugs, the nano-sized solid particles can be inhaled directly into the lung. The nano-sized particles can then pass through the membranes of the lung cells and enter the blood stream.  
     DETAILED DESCRIPTION  
      Nano-particles having dimensions smaller than 200 nm can be generated by processing a material under cryogenic conditions in which the temperature is equal to or lower than −40° C. Many materials become brittle when cooled to a temperature below −40° C. To form the nano-particles, larger particles (e.g., having all three dimensions greater than 1 μm) of a material are blown into a jet mill by pressurized cryogenic gas (e.g., nitrogen at a temperature below −40° C.) to cause the larger particles to collide with one another and to grind against the inner walls of the jet mill. Because of the brittleness of the larger particles at low temperature, the collision and the grinding (also called fluidized milling) produce particles having all three dimensions smaller than 200 nm.  
      Referring to  FIG. 1 , a nano-particle generator  100  includes a cascaded pair of jet mills  102  and  104  to generate nano-particles having dimensions smaller than 200 nm. One or both of the jet mills  102  and  104  process particles under cryogenic conditions. By using two jet mills, one cascaded after the other, the processed particles have smaller sizes, and the sizes of the particles have a more uniform distribution. The use of two separately controlled jet mills allows the particles to be processed under different conditions within a brief span of time, such as at different temperatures and pressure conditions. Pressurized cryogenic gas, generated by a high pressure cryogenic gas generator  112 , is injected through nozzles  110   a - 110   e  into the jet mill  102  to cause the particles to collide with one another and grind against the chamber walls to produce smaller particles. The gas injected into the second jet mill  104  can be cryogenic (e.g., equal to or lower than −40° C., similar to jet mill  102 ) or have a higher temperature.  
      The particles in the jet mills  102  and  104  can be treated under cryogenic conditions in different ways depending on the physical properties of the particles. Some materials are susceptible to cracking when bombarded with ultrasonic waves that have frequencies higher than 20 kHz. Some materials have high thermal expansion coefficients and are susceptible to cracking when subjected to abrupt temperature changes. When processing materials that are susceptible to ultrasonic vibrations, an ultrasonic wave generator  114  is turned on to generate ultrasonic waves that are directed toward the particles in the jet mill  102 . When processing materials that have large thermal expansion coefficients, a microwave generator  116  is turned on to generate microwaves to heat the particles rapidly, causing cracks or fissures due to rapid thermal expansion. The cracks or fissures caused by the ultrasonic waves or microwaves facilitate the breaking of particles during the jet milling process. Depending on the physical properties of the material being processed, either one or both, or none, of the ultrasonic wave generator  114  and the microwave generator  116  is used.  
      The particles processed in the jet mill  102  are received from a powder feeder  106  or a solid atomizer  108 . The powder feeder  106  is used when a material can be easily ground into nano-size from its powder form. The powder feeder  106  receives the material as a powder, and stirs the powder to prevent the small particles in the power from sticking to one another and to prevent formation of aggregates.  
      The solid atomizer  108  is used when the material can be intermixed with a liquid (or dissolved by a solvent) to form a liquid solution. The liquid solution is sprayed from a nozzle head into a chamber cooled by a cryogenic gas, causing the liquid to solidify and form solid dispersion particles. The process of forming solid dispersion particles will be described later. The cryogenic gas carries the solid particles into the jet mill  102 .  
      The particles that have been processed by the jet mills  102  and  104  are forwarded to a cyclone collector  118 , which has a low pressure chamber that allows water or solvent to evaporate and allows the nano-particles to fall into a collector  134  due to gravity.  
      The frequency of the sound waves generated by the ultrasonic wave generator  114  is adjustable. The frequency of the wave is selected based on the material to be processed. Different materials crack or fissure at different frequencies. The ultrasonic wave is sent to the chamber  120  through a waveguide  234 . More than one ultrasonic wave generator may be used.  
      Examples of materials that are susceptible to ultrasonic vibrations include calcium oxalate, calcium sulfate, calcium phosphate, and silicon dioxide.  
      The microwave generator  116  has an adjustable output power. The microwave generator  116  can be turned on continuously to quickly heat the particles (e.g., using a power so that the temperature of the particles increase at least 20° C. per second), which enter the grinding chamber  122  of the jet mill  104 . When the particles leave the grinding chamber  120  of the jet mill  102 , the particles have low temperatures (because the particles are cooled by the cryogenic gas). When the particles enter the grinding chamber of the jet mill  104 , the sudden increase in temperature may cause the particles to crack.  
      In one example, cryogenic gas is injected to the grinding chamber  122  of the jet mill  104  at ports  110   f  to  110   j  so that the grinding chamber  122  is maintained at a cryogenic temperature. The microwaves from the microwave generator  106  pass through a waveguide  235  and are directed to a feed port  129  of the grinding chamber  122 , so that the particles are heated by the microwaves as the particles enter the grinding chamber  122 . When the particles leave the region heated by the microwave, the particles are cooled by the cryogenic gas. The cold-hot-cold cyclic change of temperature produces cracks in the particles. More than one microwave generator may be used to provide heating of the particles at different regions of the grinding chamber  122 , producing multiple alternating hot and cold regions in the chamber  122 . In that case, as the particles pass through the grinding chamber  122 , the particles go through multiple cycles of thermal expansion and contraction, producing cracks in the particles in each cycle.  
      Examples of materials that crack when subjected to thermal treatment include cellulose and herbal medicines.  
      Referring to  FIG. 2 , the powder feeder  106  includes a receiving chamber  144  to hold solid particles before the particles are loaded into the jet mill  102 . Solid particles having diameters in the range of about 100 μm to 200 μm are poured into the receiving chamber  144  through a feed hopper  138 . Hammers  142  connected to a vertical rotating shaft  140  stir the solid particles to prevent the particles from aggregating. An outer jacket  146  containing liquid nitrogen surrounds the receiving chamber  144  to maintain the receiving chamber  144  at a cryogenic temperature. The particles exit the receiving chamber  144  through an opening  148  at the bottom of the powder feeder  106 .  
      Referring to  FIG. 3 , a solid atomizer  108  generates solid dispersion particles  152  by passing a pressurized liquid (not shown) through a spray head  150  that is positioned in a low-pressure chamber  164 . The pressurized liquid contains a material for which nano-particles are to be produced, and a dispersion medium (e.g., a solvent) that is used to disperse the material. The chamber  164  includes an inner region  166  (surrounded by a cylindrical wall  156 ) and an outer region  168 . A cryogenic gas distributor  160  ejects cryogenic gas through nozzles  154  that are positioned beside the spray head  150 . The cryogenic gas flows upward in the inner region  166  and downward in the outer region  168 , reducing the temperature of the low pressure chamber  164 . The cryogenic gas flows out of the solid atomizer  108  through an opening  170 .  
      The spray head  150  is connected to a source of the pressurized liquid, which can be an emulsion (e.g., guaiacol carbonate chloroform solution in water), or a solution that contains the material dissolved in a solvent (e.g., griseomycin ethanol solution). In one example, the liquid has a high pressure of 1000 pounds-per-square-inch (psi) while inside the spray head  150 . When the liquid is sprayed into the inner chamber  166 , the material is finely dispersed in small droplets of the liquid at the molecular or colloidal level. Before the small droplets congregate to form larger droplets, the small droplets are cooled abruptly by the cryogenic gas and become frozen, preventing crystallization of the material. Because the material in the small droplet is frozen before it crystallizes, each of the particles  152  can contain one or more individual molecules of the material. The three dimensional structures of the molecules of the material are preserved in the solid dispersion particles  152 . The solid dispersion particles  152  are drawn by the flow of the cryogenic gas from the inner region  166  to the outer region  168  and out of the solid atomizer through the opening  170 .  
      Because the material is frozen before it crystallizes, the material in the solid dispersion particles  152  has reduced structural strength, and has a greater tendency to crack under the cryogenic condition. After the solid dispersion particles  152  are processed by the jet mills  102  and  104 , and enter the cyclone collector  118 , the dispersion medium (or solvent) sublimes and exits the exhaust ports  232 . At least a portion of the nano-particles that are processed by the jet mills  102  and  104  will maintain the three dimensional structures of the molecules of the material. This is useful when the material contains, e.g., drugs (such as insulin), polymers, proteins, or peptides. For example, preserving the three dimensional structures of drug molecules will enhance their bioavailability.  
      Table 1 lists examples of materials and solvents that can form solutions suitable for generating solid dispersion particles  152  by the solid atomizer  108 .  
                           TABLE 1                                   Material   Solvent                          Insulin   Water           Taxine   Ethanol                      
 
       FIG. 4  shows an example of a high pressure cryogenic gas generator  180 , which includes a coil tube  184  immersed in a tank of liquid nitrogen  182  maintained at about −196° C. Pressurized nitrogen gas from a nitrogen gas source (not shown) enters the cryogenic gas generator  180  through an inlet  186 , passes through the coil tube  184 , and is cooled to a low temperature by the liquid nitrogen  182 . The amount of nitrogen gas flowing through the coil tube  184  is controlled by a control valve  188 . A temperature gauge  192  and a pressure gauge  194  monitor the temperature and pressure, respectively, of the nitrogen gas before it enters the coil tube  184 . The liquid nitrogen  182  is stored in a thermally insulated tank  208  that has a safety valve  196  to release nitrogen gas to prevent pressure buildup. A temperature gauge  200  and a pressure gauge  202  monitor the temperature and pressure, respectively, of the nitrogen gas leaving the coil tube  184 . The pressurized cryogenic gas leaves the cryogenic gas generator  180  through an outlet  206 , which is connected to the gas inlets of the jet mills  102  and  104 . A control valve  204  controls the amount of nitrogen gas that enters the jet mills.  
      Heat exchangers  190  and  198  allow adjustment of the temperature of the pressurized cryogenic nitrogen gas. Different materials may require use of cryogenic gas at different temperatures during the jet milling process. Table 2 lists suitable temperatures for the cryogenic gas for different materials.  
                           TABLE 2                                   Material   Temperature of cryogenic gas                          Griseofulvin   −140° C.           Albuterol Sulfate   −100° C.           Ibuprofene   −120° C.           Lecithin   −100° C.                      
 
       FIG. 5  shows an alternative example of a high pressure cryogenic gas generator  210 , in which pressurized nitrogen gas is diffused into the liquid nitrogen  182 . The pressurized nitrogen gas passes through a passage  216  that extends into the liquid nitrogen  182 . The passage  216  is connected to a gas diffuser  214 , which has openings to allow the pressurized nitrogen gas to enter the liquid nitrogen  182 . The nitrogen gas, after being diffused into the liquid nitrogen  182 , rises to the top of the liquid nitrogen  182  and exits the tank  208  through an outlet  218 . The nitrogen gas that exits through outlet  218  is cooled to near the temperature of the liquid nitrogen  182 , which is about −198° C.  
      An advantage of diffusing nitrogen gas through the liquid nitrogen  182  is that the nitrogen gas exiting through outlet  218  contains little or no water vapor. Traces of water, if any, become ice and remain in the tank of liquid nitrogen  182 . This reduces the amount of moisture in the particles in the jet mills  102  and  104 . Another advantage is that the nitrogen gas exiting through the outlet  218  contains little or no oxygen. Oxygen has a boiling point of −183° C., so any oxygen that passes the liquid nitrogen  182  is liquefied at the temperature of −196° C. This reduces the likelihood of oxidation of the particles in the jet mills.  
      Referring to  FIG. 6 , the jet mill  102  includes a loop-shaped grinding chamber  120 . Particles enter the chamber  120  through a feed port  124 , which is coupled to the powder feeder  106  or the solid atomizer  108 . Pressurized cryogenic gas is injected into the chamber  120  through nozzles  110   a,    110   b,    110   c,    110   d,  and  110   e  to force the particles to intermix, collide with one another, and grind against the walls of the chamber  120 , thereby producing smaller particles. The nozzle 110 a  is a pusher nozzle. Cryogenic gas rushing out of the nozzle  110   a  creates a suction force that pulls the particles into the feed port  124  from the powder feeder  106  or solid atomizer  108 .  
      The cryogenic gas nozzles  110   a  to  110   e  are connected to the outlet  206  of the pressurized cryogenic gas generator  180  or  210 . The nozzles are oriented so that the particles are blown in one direction (e.g., clockwise in the example shown in  FIG. 6 ) in the grinding chamber  120 . A larger portion of the nitrogen gas travels along a direction  220  and exits the chamber  120  through an outlet extension port  126 . In  FIG. 6 , one end  221  of the outlet extension port  126  extends in a direction parallel to the plane of the figure and connects to the chamber  120 . Another end  223  of the port  126  extends in a direction perpendicular to the plane of  FIG. 6 , and is coupled to a connector tube  128  ( FIG. 1 ), which in turn is coupled to the feeding port  129  of the jet mill  104 . The cross section of the end  223  is on a plane that is different from the plane of the cross section of the grinding chamber  120 .  
      A smaller portion of the nitrogen gas travels along a direction  222  and loops around the chamber  120  again. The nitrogen gas carries the particles with it, so that a larger portion of the particles travel along the direction  220  and exit the chamber  120  through the outlet extension port  126 . A smaller portion of the particles travel along the direction  222  and loop around the chamber again, going through another grinding cycle. The chamber  120  is insulated to maintain the nitrogen gas at a cryogenic temperature.  
      Jet mill  104  has a configuration similar to the jet mill  102 . Cryogenic gas enters the chamber  104  through inlets  110   f,    110   g,    110   h,    110   i,  and  110   j  (see  FIG. 1 ). The particles are jet milled in the grinding chamber  122 , similar to the jet milling process in the jet mill  102 . The chamber  122  has an outlet extension port  130  that is coupled to the cyclone collector  118  through a connecting tube  240 .  
      The particles that enter the feeding port  124  of the jet mill  102  can have dimensions in the range of about 100 μm to 200 μm, and the particles that exit the outlet extending port  130  of the jet mill  104  (referred to as the “final particles”) can have dimensions smaller than 1 μm. The dimensions of the final particles can be adjusted by varying the temperature and pressure of the gas injected into the grinding chambers of the jet mills  102  and  104 . In one example, more than half of the final particles have dimensions smaller than 200 nm.  
      Referring to  FIG. 7 , the cyclone collector  118  includes a pressure reduction chamber  224  that is connected to the connecting tube  240 . The pressure reduction chamber  224  allows the pressure of the nitrogen gas to be reduced prior to entering a cyclone chamber  226 . The cyclone chamber  226  is kept at normal atmospheric pressure or at a low pressure, so that any water or solvent in the particles is evaporated due to the sudden decrease in pressure. The particles settle down ( 231 ) at a particle collector  134  due to gravity.  
      The cyclone collection  118  includes a filter chamber  230  that is separated from the cyclone chamber  226  by a filter  228 . The filter chamber  230  has exhaust ports  232  that allow the nitrogen to diffuse into the atmosphere. The filter  228  prevents the nano-particles from leaving the cyclone chamber  226  through the exhaust ports  232 .  
      Examples of materials that can be processed by the nano-particle generator  100  to produce particles having dimensions smaller than 200 nm include calcium oxalate, calcium sulfate, calcium phosphate, silicon dioxide, cellulose and herbs, insulin, taxine, griseofulvin, albuterol sulfate, ibuprofene, lecithin, plastic, vitamins, iron oxide, paclitaxcel, and so forth.  
      The nano-particle generator  100  is useful in many areas. For example, the nano-particle generator  100  can be used to prepare drugs for intravenous injection. Drugs are usually dissolved in solvents to form solutions that are administered to patients through intravenous injections. Some drugs can be dissolved in water for injection (WFI, purified water that is suitable for injection), while some drugs have to be dissolved in pharmaceutical solvents (such as glycerin, ethanol, propylene glycol, or a mixture of these solvents). For drugs that cannot be dissolved in water, aqueous suspensions containing the drugs can not be safely administered to a patient intravenously because the un-dissolved drug particles are too large, and may block micro vessels or cause thrombosis. Although the drugs may be dissolved in pharmaceutical solvents, injecting pharmaceutical solvents into the body often create undesirable side effects. By using the nano-particle generator  100  to process the drugs to generate particles having sizes smaller than 200 nm, aqueous suspensions containing the nano-sized drug particles can be safely administered to the patient through intravenous injection, as the drug nano-particles can smoothly pass micro vessels. This provides a new approach to pharmaceutical dosage form, reducing the need for pharmaceutical solvents in intravenous injections.  
      Although some examples have been discussed above, other implementations and applications are also within the scope of the following claims. For example, the nano-particle generator  100  includes two cascaded jet mills  102  and  104 . For some materials, one jet mill  102  may be sufficient to produce nano-sized particles. More than two jet mills can be cascaded. The grinding chamber  120  and  122  can have different shapes. The ultrasonic wave generator  114  and the microwave generator  116  may both be coupled to the same jet mill  102  and/or  104 . The ultrasonic wave generator  114  and the microwave generator  116  are optional.  
      The cryogenic gas that is injected into the grinding chambers  102  and  104  can be different from a nitrogen gas. For example, air or an inert gases can be used. An example of an inert gas is helium. A mixture of inert gases may be used.  
      The example described above uses a jet mill to process the particles under a cryogenic condition to generate nano-particles that have all three dimensions smaller than, e.g., 200 nm. A material can also be processed under a cryogenic condition to generate particles that have one dimension smaller than 200 nm, while the other two dimensions are larger than 200 nm (e.g., the particles may have a thin and flat shape). A material can also be processed under a cryogenic condition to generate particles that have two dimensions smaller than 200 nm, while the third dimensions is larger than 200 nm (e.g., the particles can have a needle shape). For example, ultrasound may be imposed on the material under a cryogenic condition so that the material crack into thin-flat shaped or needle-shaped particles based on its crystalline structure.  
      When a material is processed under a cryogenic condition, whether using a jet mill or another processing tool, the particle size of the final product may not be completely uniform, and may have a range of distribution. In one example, the particles processed by the nano-particle generator  100  and collected at the collector  134  may have sizes in a range between 50 nm to 300 nm, with more than 50% of the particles having sizes in a range between 100 nm to 200 nm. In another example, at least 5% of the particles processed under the cryogenic condition have dimensions less than 200 nm. The distribution of sizes of the particles can be adjusted by adjusting the temperature and pressure of the cryogenic gas injected into the grinding chambers, and/or by adjusting the power of the ultrasonic waves and microwaves imposed on the particles, and/or by increasing or decreasing the number of jet mills that are cascaded one after another.