Abstract:
The invention relates to methods and apparatuses for manipulating small amounts of solids. Specific embodiments of the invention are particularly suited for the automated transfer of small amounts of solids. In one embodiment, a uniform powder bed is lightly compressed into plugs of powder and dispensed. In another embodiment, the solid is placed in a liquid carrier to form a slurry, dispensed, and the liquid component is subsequently removed. In yet another embodiment, solids are manipulated using adhesive surfaces.

Description:
RELATED APPLICATIONS 
       [0001]    This application claims priority under 35 USC 119(e) to U.S. Provisional Application No. 60/423,377, filed Nov. 4, 2002, U.S. Provisional Application No. 60/424,001, filed Nov. 6, 2002, U.S. Provisional Application No. 60/430,089, filed Dec. 2, 2002, U.S. Provisional Application No. 60/449,554, filed Feb. 24, 2003 and U.S. Provisional Application No. 60/450,285, filed Feb. 27, 2003, all of which are incorporated herein by reference in their entireties. 
     
    
     TECHNICAL FIELD OF THE INVENTION 
       [0002]    The invention relates to methods and apparatuses for manipulating small amounts of solids. Specific embodiments of the invention are particularly suited for the automated transfer of small amounts of solids. 
       BACKGROUND OF THE INVENTION 
       [0003]    A variety of methods and devices exist for obtaining and dispensing small amounts of liquids that have found use in a variety of applications. However, few methods and devices exist for manipulating small amounts (e.g., less than about 25, 10, 5, or 1 mg) of solids (e.g., powders). In the laboratory, such small amounts of solids are often dispensed by hand using a highly accurate scale. Unfortunately, such methods are not amenable to the rapid or automated manipulation of compounds, as they are tedious, time consuming, and prone to error. 
         [0004]    Recently, methods and systems have been disclosed for the preparation and analysis of arrays of samples, each of which can contain very small amounts of one or more compounds. See e.g., International Publication WO01/51919, published on Jul. 19, 2001. In such applications, it is often desirable to rapidly and accurately measure and dispense small amounts of solids. In some circumstances, this can be done by dissolving a compound in a solvent to provide a solution of known concentration, dispensing controlled amounts of that solution using micropipettors, and then evaporating the solvent. In certain applications, however, it is necessary that a solid compound be manipulated in a manner that does not substantially affect its physical form. For example, if the crystallinity of a solid is important, it is desirable to measure and dispense the solid in a manner that does not affect its crystalline form (e.g., its crystal structure and habit). Similarly, if the amorphous nature (e.g., average particle size and distribution of particle sizes) of a solid is important, it is preferred that the methods and devices used to manipulate the solid do not substantially affect that quality. Physical characteristics such as these cannot be controlled using solution-based dispensing techniques. 
         [0005]    A need therefore exists for methods and devices that can be used to rapidly and accurately dispense small amounts of solids. A need also exists for methods and devices that can be used to manipulate solids without substantially affecting their form. 
       SUMMARY OF THE INVENTION 
       [0006]    This invention encompasses methods of manipulating (e.g., obtaining, transferring, dispensing, mixing and/or weighing) small amounts of solids (e.g., powders), and apparatuses that can be used in such methods. Particular embodiments of the invention are particularly useful in the high throughput preparation and screening of arrays of compounds and compositions. Specific embodiments of the invention do not substantially affect the form of the solid being manipulated. 
         [0007]    One embodiment of the invention encompasses methods and apparatuses for dispensing solids by producing plugs with a controlled amount of a solid material of interest. Specific plugs are formed in a way that does not substantially affect the form of the solid. 
         [0008]    Another embodiment of the invention encompasses methods and apparatuses for dispensing solids using slurries. Specific methods of this embodiment do not substantially affect the form of the solid. 
         [0009]    Another embodiment of the invention encompasses methods and apparatuses for manipulating solids, wherein particles of the solid are adhered non-electrostatically to an adhesive surface. Specific methods of this embodiment do not substantially affect the form of the solid. 
         [0010]    Another embodiment of the invention encompasses methods and apparatuses for transferring the solid content inside one container into another container. Specific methods of this embodiment do not substantially affect the form of the solid. 
         [0011]    Another embodiment of the invention encompasses methods and apparatuses for mixing small amounts of solid in a container. Specific methods of this embodiment do not substantially affect the form of the solid. 
         [0012]    Another embodiment of the invention encompasses methods and apparatuses for transferring and measuring the mass of small amounts of solid. Specific methods of this embodiment do not substantially affect the form of the solid. 
     
    
     
       BRIEF DESCRIPTION OF THE FIGURES  
         [0013]    Specific embodiments of the invention can be understood with reference to the attached figures, described below: 
           [0014]      FIG. 1  illustrates a method of forming a uniform powder bed that involves lifting a rotating pin from a packed powder bed. 
           [0015]      FIG. 2  illustrates a top view of a grille that is placed on top of the uniform powder bed that is produced via the method shown in  FIG. 1 . 
           [0016]      FIG. 3  illustrates a method of forming a uniform powder bed that involves sliding a plate off of a packed powder bed. 
           [0017]      FIG. 4  illustrates a top view of a grille that is placed on top of the uniform powder bed that is produced via the method shown in  FIG. 3 . 
           [0018]      FIG. 5  illustrates a method of creating and dispensing a plug of powder that involves inserting a tube completely through a powder bed, lifting, and then ejecting. 
           [0019]      FIG. 6  illustrates a method of creating and dispensing a plug of powder that involves inserting a tube completely through a powder bed, compressing the plug, lifting, and then ejecting. 
           [0020]      FIG. 7  illustrates a method of creating and dispensing a plug of powder that involves inserting a tube part way through a powder bed, lifting, and then ejecting. 
           [0021]      FIG. 8  illustrates a method of creating and dispensing a plug of powder that involves inserting a tube part way through a powder bed with the ejector piston held stationary at a predetermined height relative to the tube, lifting, and then ejecting. 
           [0022]      FIG. 9  illustrates a specific apparatus to punch and dispense plugs of solids which includes a punching assembly, x and y linear servos, a receiving plate, a source receptacle assembly, a wash station, a weigh station and a supporting base and frame. 
           [0023]      FIG. 10  illustrates a method of extruding powder from a source chamber into a dose chamber to create a plug of powder. 
           [0024]      FIG. 11  illustrates examples of trajectories for moving and filling the dose chamber above the powder surface. 
           [0025]      FIG. 12  illustrates a method of ejecting a plug of powder from the dose chamber into a receiving plate. 
           [0026]      FIG. 13  illustrates the front and side view of a specific apparatus to extrude plugs of powder which includes a dispensing assembly, x and y linear servos, a receiving plate, a weigh station and a supporting base and frame. 
           [0027]      FIG. 14  illustrates a method of preparing solids for extrusion. 
           [0028]      FIG. 15  illustrates the grid cutter utilized in the method shown in  FIG. 14 . 
           [0029]      FIG. 16  illustrates a method of extruding multiple plugs of powder and ejecting the plugs into a receiving plate. 
           [0030]      FIG. 17  illustrates a method of installing a slide plate to vary the thickness of the plugs of powder produced. 
           [0031]      FIG. 18  illustrates a method of extruding multiple plugs of powder of different thicknesses using more than one ejector pin. 
           [0032]      FIG. 19  illustrates the front and side view of a specific apparatus to extrude multiple plugs of powder which includes a dispensing assembly, x and y linear servos, a receiving plate, a weigh station and a supporting base and frame. 
           [0033]      FIG. 20  illustrates various arrangements of adhesive areas on a surface to manipulate solids. 
           [0034]      FIG. 21  illustrates a method of applying solids to the adhesive areas on a surface. 
           [0035]      FIG. 22  illustrates a method of mixing solids adhered to an adhesive area with a solvent, reagent or excipient suspended on a separate surface such that the resultant agglomeration can be easily dispensed into a container. 
           [0036]      FIG. 23  illustrates a method of transferring solids from one container into another container by turning the original container upside-down. 
           [0037]      FIG. 24  illustrates a method of increasing the throughput of the transfer process by incorporating a carousel with two or more stations. 
           [0038]      FIG. 25  illustrates a method of enhancing the release of solids from a container by applying external vibration to the swing arm or the container. 
           [0039]      FIG. 26  illustrates a method of preventing the premature release of solids from a container by incorporating a retractable seal on the container. 
           [0040]      FIG. 27  illustrates a method of transferring solids from one container into another by utilizing a container with a retractable bottom plate. 
           [0041]      FIG. 28  illustrates a method of transferring solids from one container into another by utilizing a container with a filter plate. 
           [0042]      FIG. 29  illustrates a method of transferring solids from one container into another by utilizing a container with an internal piston. 
           [0043]      FIG. 30  illustrates a method of placing a container holding solids into another container to achieve a two-dimensional array of containers. 
           [0044]      FIG. 31  illustrates a method of increasing the throughput of pick-and-placing containers by incorporating a carousel with two or more stations. 
           [0045]      FIG. 32  illustrates a method of mixing solids in a sealed container using turbulent gas jets. 
           [0046]      FIG. 33  illustrates a method of mixing solids in a sealed container using rotating wire. 
           [0047]      FIG. 34  illustrates a method of mixing solids in a sealed container using rotating blades. 
           [0048]      FIG. 35  illustrates a method of mixing solids in a sealed container by compressing the walls of the container. 
           [0049]      FIG. 36  illustrates a method of mixing solids by dispensing alternate layers of different solids into a container. 
           [0050]      FIG. 37  illustrates a method of weighing individual samples as part of a two-dimensional array of samples. 
           [0051]      FIG. 38  illustrates a method of dispensing and weighing a plug of powder using a coring device and an integrated mass sensor. 
           [0052]      FIG. 39  illustrates a typical frequency spectrum of the mechanical response of a coring tube that is used to identify its resonant frequency. 
           [0053]      FIG. 40  illustrates a typical shift in the frequency response of the coring tube when a mass is ejected from the tube. 
           [0054]      FIG. 41  illustrates a correlation between the measured frequency ratio and the amount of mass dispensed from a coring tube. 
           [0055]      FIG. 42  illustrates a method of dispensing and weighing a plug of powder using an electrode assembly and an integrated mass sensor. 
           [0056]      FIG. 43  illustrates a typical frequency spectrum of the mechanical response of an electrode assembly that is used to identify its resonant frequency. 
           [0057]      FIG. 44  illustrates a correlation between the measured frequency ratio and the amount of mass dispensed from an electrode assembly. 
       
    
    
     DEFINITIONS 
       [0058]    As used herein and unless otherwise indicated, the term “controlled amount” refers to an amount of a compound that is weighed, aliquotted, or otherwise dispensed in a manner that attempts to control the amount of the compound. Preferably, a controlled amount of a compound differs from a target amount by less than about 30, 20, 10, 5, or 1 percent of the target amount. For example, if a target amount of 100 micrograms is specified for a particular application, a controlled amount for that application would be a mass that is between about 70 micrograms to about 130 micrograms, or about 80 micrograms to about 120 micrograms, or about 90 micrograms to about 110 micrograms, or about 95 micrograms to about 105 micrograms, or about 99 micrograms to about 101 micrograms. 
         [0059]    As used herein and unless otherwise indicated, the term “plug” is used to refer to an agglomeration of a solid or solids. Preferred plugs are not compressed, or are compressed under conditions that do not substantially affect the form of the solid or solids. 
         [0060]    As used herein and unless otherwise indicated, the terms “form” and “physical form,” when used to refer to a solid, mean the physical characteristics of the solid. Such characteristics include, but are not limited to, crystallinity or lack of crystallinity, appearance, texture, and color. For example, a solid may be in the form of a powder comprised of particles having a particular average size or size distribution, shape, or color. A solid may be amorphous, crystalline, or may comprise both amorphous and crystalline components. Further, the form of a crystalline solid includes, but is not limited to, its crystal structure and habit. 
         [0061]    As used herein and unless otherwise indicated, the phrase “without substantially affecting the form,” when used to refer to the effect of a method, process, or device on a compound, means that the method, process, or device does not materially change the physical form of a majority of the compound. For example, the phrase encompasses methods, processes, and devices that do not affect the form of about 70, 80, 90, 95, or 99 weight percent of a compound. The phrase also encompasses methods, processes, and devices that affect the average particle size or particle size distribution of a powder of a crystalline compound but that do not affect the crystal structure or habit of the crystalline compound. 
         [0062]    As used herein and unless otherwise indicated, the term “slurry” refers to a mixture of solid and liquid wherein a substantial portion of the solid (e.g., greater than about 70, 80, 90, 95, or 99 weight percent) is not dissolved in the liquid. 
         [0063]    As used herein and unless otherwise indicated, the term “tube” refers to a hollow instrument (e.g., a hollow needle) with an outer wall and a definable cross-sectional area (e.g, a cylinder, a square, or a hexagon) that can be inserted into a bed of powder. 
         [0064]    As used herein and unless otherwise indicated, the term “controlled distance” refers to a distance that does not differ substantially from a predetermined distance. Preferably, a controlled distance differs from a predetermined distance by less than about 10, 5, or 1 percent of the predetermined distance. For example, if one were to insert a tube 2 mm into a bed of powder, a controlled distance of insertion would preferably be from about 1.9 mm to about 2.1 mm, from 1.95 mm to about 2.05 mm, or from about 1.99 mm to about 2.01 mm. 
       DETAILED DESCRIPTION OF THE INVENTION  
       [0065]    This invention encompasses methods and apparatuses that can be used to accurately manipulate small amounts (e.g., less than about 25 mg, 10 mg, 5 mg, 1 mg, 750 micrograms, 500 micrograms, 350 micrograms, 250 micrograms, 175 micrograms, 100 micrograms, 75 micrograms, 50 micrograms, 25 micrograms, 15 micrograms, 10 micrograms, 7.5 micrograms, 5 micrograms, 3 micrograms, 1 micrograms, 900 ng, 750 ng, 500 ng, 350 ng, 250 ng, or 100 ng) of solids. Examples of solids include, but are not limited to pharmaceuticals, excipients, dietary substances, alternative medicines, nutraceuticals, agrochemicals, sensory compounds, the active components of industrial formulations, and the active components of consumer formulations. Solids can be amorphous, crystalline, or mixtures thereof. 
         [0066]    A first embodiment of the invention encompasses a method and apparatus for manipulating a solid in the form of a powder by compressing a controlled amount of powder into a plug. Preferably, the amount of compression is sufficient to provide a plug that can be manipulated to a desired degree but which is insufficient to substantially affect the physical form of the solid (e.g., by inducing a loss of crystallinity or polymorphism). 
         [0067]    A specific method of this embodiment comprises the steps of: (a) forming a bed of powder of predetermined mass and uniform height; (b) inserting a tube a controlled distance into the bed or completely through the bed to obtain a plug of powder, wherein the tube has an interior that accommodates a means of ejecting materials from within the tube; (c) optionally, compressing the powder within the tube; (d) removing the tube with the plug of powder from the bed; (e) moving the tube over a target location; and (f) ejecting the plug of powder. 
         [0068]    Another method of the first embodiment comprises the steps of: (a) forming a bed of powder of predetermined mass and uniform height; (b) inserting a grid with multiple hollow partitions with side walls of sufficient width, length (or diameter) and height to create a desired volume of space (e.g., a grid made of thin blades) a controlled distance into the bed or completely through the bed to obtain multiple plugs of powder; (c) optionally, compressing the powder within each partition of the grid; (d) moving the grid with the powder plugs over a target location; and (e) selectively ejecting a plug of powder into the target. 
         [0069]    Another method of the first embodiment comprises the steps of: (a) dispensing a predetermined mass of powder into a source chamber; (b) sealing the source chamber with a plate which holds a smaller chamber of variable depth; (c) applying pressure to the powder in the source chamber; (d) sliding the plate against the powder surface in a patterned motion that exposes the smaller chamber to the powder and fills it with powder; (e) releasing the pressure on the source powder; (f) moving the slide plate with its plug of powder away from the source chamber to a target location; and (g) ejecting the plug of powder from the cavity Another method of the first embodiment comprises the steps of: (a) dispensing a predetermined mass of powder into a source chamber; (b) sealing the chamber with a plate which contains a grid with multiple hollow partitions, with side walls of sufficient width, length (or diameter) and height to create a desired volume of space (e.g., a grid made of thin blades), centered above the source chamber and covered by another solid plate; (c) applying pressure to the powder in the source chamber such that the powder flows into the partitions of the grid; (d) releasing the pressure on the source powder; (e) moving the plate with its plugs of powder away from the source chamber to a target location; and (f) selectively ejecting a plug of powder from the cavity 
         [0070]    Another embodiment of the invention encompasses a method for manipulating a solid by producing a slurry, which comprises the steps of: (a) blending a controlled amount of the solid with a liquid to provide a slurry; (b) dispensing a controlled amount of the slurry; and (c) removing the liquid to provide an amount of the solid, wherein the amount of the solid is less than about 1 mg. In specific embodiments, the amount of the solid is less than about 25 mg, 10 mg, 5 mg, 1 mg, 750 micrograms, 500 micrograms, 350 micrograms, 250 micrograms, 175 micrograms, 100 micrograms, 75 micrograms, 50 micrograms, 25 micrograms, 15 micrograms, 10 micrograms, 7.5 micrograms, 5 micrograms, 3 micrograms, 1 micrograms, 900 ng, 750 ng, 500 ng, 350 ng, 250 ng, or 100 ng. The liquid vehicle can be selected such that it does not dissolve a substantial portion (e.g., which can be specified as less than 10 percent, 5 percent, 2.5 percent, 1 percent, 0.5 percent, 0.25 percent, 0.1 percent, 0.01 percent or 0.001 percent) of the solid to avoid affecting the solid form. 
         [0071]    Another embodiment of the invention encompasses a method and apparatus for manipulating a solid by using adhesive surfaces, which comprises contacting particles of the solid with a surface comprising a plurality of discrete adhesive areas separated by non-adhesive areas. In specific embodiments, the size of the adhesive areas are less than about 1 cm 2 , 50 mm 2 , 10 mm 2 , 1 mm 2 , or 0.5 mm 2 . As used herein and unless otherwise indicated, the terms “adhesive surface” and “adhesive area” encompass any surface or area on a surface to which a particular solid can adhere by, for example, chemisorption, chemical bonding interactions (e.g., hydrogen bonding and van der Waals interactions), or adsorption (e.g., as a result of vapor deposition). Adhesive surfaces may be a liquid, semi-solid, or solid. Specific adhesive surfaces may utilize conventional adhesives (e.g., glues or gummy or sticky materials). Suitable adhesives are well known to those of ordinary skill in the art. Examples of specific adhesive materials include, but are not limited to, pressure-sensitive adhesives (PSA&#39;s), silicones, and hydrogels. Certain pharmaceutically acceptable excipients may also be used as adhesives. In preferred methods of this embodiment, the form of the solid(s) being manipulated does not substantially change during manipulation. 
         [0072]    Another embodiment of the invention encompasses a method and apparatus for transferring the solids content inside one container (e.g., a tube or vial) into another container (e.g., a multi-well plate). A specific method of this embodiment comprises the steps of: (a) accelerating a container that holds a controlled amount of solids through an arc trajectory and (b) halting the motion of the container suddenly when it is located above the receiving container in a downward-facing position, thereby causing the solids to be expelled from the initial container and into the receiving container. Another embodiment comprises the steps of: (a) utilizing a container that holds a controlled amount of solids and that has bottom plate which is removable and (b) removing the bottom plate in order to release the solids into a receiving container positioned below the initial container. Another embodiment comprises the steps of: (a) utilizing a container that holds a controlled amount of solids and that has a gas-permeable bottom plate, (b) inverting the container while applying suction through the bottom plate to retain the solids, and (c) reversing the direction of the gas through the bottom plate to expel the solids into a receiving container positioned below the initial container. Another embodiment comprises the steps of: (a) utilizing a container that holds a controlled amount of solids and that has an internal piston, (b) inverting the container, and (c) actuating the piston through the container to eject the solids into a receiving container positioned below the initial container. Another embodiment comprises the steps of: (a) utilizing a container that holds a controlled amount of solids and (b) placing the container inside a well in a receiving plate that has a two-dimensional array of wells. 
         [0073]    Another embodiment of the invention encompasses a method and apparatus for mixing small amounts of solid inside a container (e.g., a tube, vial or a well in a multi-well plate). Mixing achieves intimate particulate contact between the solids such that resulting chemical or physical interactions can be analyzed. A specific method of this embodiment comprises applying gas jets through gas-permeable container walls to mix the contents inside the container. Another embodiment comprises vibrating or rotating the container in various directions, orientations, and speeds to mix its contents. Another embodiment comprises placing a mixing tool such as a bar, ball, blade, or wire inside the container and manipulating the mixing tool by means of an oscillating magnet or rotating drive shaft connected to the tool. Another embodiment comprises compressing the walls of the container to mix the contents of the container. Another embodiment comprises dispensing alternate layers of different solids into a container to achieve interparticle contact between different solids. 
         [0074]    Another embodiment of the invention encompasses a method and apparatus to manipulate and weigh small amounts of solids. Measuring the mass of a controlled amount of solids is a necessary step for various chemical assays including crystallization, dissolution, and stability analysis. A specific method of this embodiment comprises an apparatus that rapidly dispenses and weighs controlled amounts of solids in a two-dimensional array format with a conventional microbalance. Another method of this embodiment manipulates and measures the mass of a controlled amount of solids without using a conventional microbalance. The method comprises the steps of: (a) measuring a first mechanical resonant frequency of a transfer device, (b) adhering particles to the transfer device, (c) measuring a second mechanical resonant frequency of the transfer device, (d) determining the mass of the attached particles by comparing the first and second resonant frequencies, and (e) removing the particles from the transfer device. Another method of this embodiment comprises the steps of: (a) adhering particles to a transfer device, (b) measuring a first mechanical resonant frequency of the transfer device, (c) removing the particles from the transfer device, (d) measuring a second mechanical resonant frequency of the transfer device, and (e) determining the mass of the removed particles by comparing the first and second resonant frequencies. In addition, the ability to weigh the transferred solids, can be used to provide real-time feedback to the transfer device. Thus, the parameters that control the transfer device can be adjusted to transfer a desired amount of solids. 
         [0075]    Specific methods and apparatuses of the invention do not substantially affect the form of the solid being manipulated. Furthermore, specific methods and apparatuses can be readily adapted for use in the high-throughput preparation of arrays of samples. For example, embodiments of the invention can be incorporated into the methods and systems referred to as FAST® and CRYSTALMAX™. The methods and systems referred to as FAST® are described in U.S. patent application Ser. No. 09/628,667, filed Jul. 28, 2000, the entirety of which is incorporated herein by reference. The methods and systems referred to as CRYSTALMAX™ are described in U.S. patent application Ser. No. 09/756,092, filed Jan. 8, 2001, and International Publication WO01/51919, published on Jul. 19, 2001, both of which are incorporated herein by reference in their entireties. 
       EXAMPLES 
       [0076]    Certain embodiments of the invention, as well as certain novel and unexpected advantages of the invention, are illustrated by the following non-limiting examples. 
       Example 1 
     Manipulating Solids by Coring a Plug of Powder From a Powder Bed 
       [0077]    Solids, such as those in the form of a powder, can be manipulated using systems and methods described for the present invention. For example, solids in the form of fine powders comprising particles having an average size of less than about 200, 150, 100, 50, 10, 5, 1, 0.1, or 0.01 micrometers can be compressed and dispensed in controlled amounts as plugs without the use of solvents, high pressures, or temperatures that may affect the form of the solids. As will be apparent to those of skill in the art, the particular amount of pressure that can be used to provide such plugs will depend on the particular compound and its form. However, that amount is readily determined using little, if any, routine experimentation. Examples of such pressures include, but are not limited to, less than about 30, 20, 10, 5, or 2 psi. The use of such low pressures typically avoids physical form changes such as loss of crystallinity or conversion to a polymorphic form, which can occur under compression conditions used to make conventional tablets. 
         [0078]    In a specific embodiment of this method, a known mass of powder (e.g., less than about 1 gram, 500 mg, 100 mg, 25 mg, 1 mg, 500 micrograms, 250 micrograms, or 100 micrograms) is dispensed into a cylindrical cavity of predetermined diameter and depth. The powder is packed evenly across the base of the cavity using a rotating cylinder that applies a predetermined average pressure to the bed that is less than 30, 20, 10, 5, or 1 psi. Next, a hollow tube (e.g. a cylindrical needle with an inner diameter less than 0.01 mm, 0.1 mm, 0.5 mm, 1 mm, 2 mm, 3 mm, 5 mm or 10 mm) with a predetermined cross sectional area is used to core a plug of the powder. The tube, which can be of any shape so long as the volume of the resulting plug can be determined, is inserted a controlled distance into the powder bed to obtain a plug of predictable size. Preferably, the tube is inserted all the way through the powder bed. Reproducible packing inside the tube can result from specific ratios of height to diameter of the coring cavity, for example, a 1:1 height to diameter ratio is effective. The plug is then optionally compressed, as discussed below, and the tube, which still contains the plug, is removed from the powder bed and positioned over a receptacle (e.g., a tube, vial or a well in a multi-well plate). To prevent the bed from breaking apart during punching, a grill (i.e. a thin plate with an array of holes) that the tube can pass through may be placed over the bed prior to punching. The plug is then ejected from the tube using, for example, compressed gas, a liquid in which the solid is soluble, sparingly soluble, or insoluble, vibration of the tube, or mechanical means, such as a piston located within the tube. 
         [0079]      FIGS. 1A through 1D  illustrate a method and apparatus for uniform powder bed preparation. A predetermined weight of powder  200  is placed in a cavity (e.g., hollow cylinder)  204  in source receptacle assembly  205 , as shown in  FIG. 1A . Source receptacle assembly  205  comprises top block  208  with cavity  204  in its interior, strike plate  207 , and base  206 . Then, as shown in  FIG. 1B , rod  210  (preferably cylindrical) is inserted through cavity  204  and pressed into powder  200  with a predetermined force, which results in a powder bed pressure typically in the range of about 0.5 psi to about 30 psi. Cylindrical rod  210  is then rotated through an angle of typically 90 degrees in either direction with pressure applied. Cylindrical rod  210  is then rotated and pulled out (normally rotated and pulled out simultaneously) of cavity  204 . The result is powder bed  220  shown in  FIG. 1C  with a uniform thickness. Next, grille tube  227  of grille assembly  225  is inserted into cavity  204  so that grille plate  228  contacts the top of powder bed  220 , and so alignment pin  224  passes into alignment hole  202 , as shown in  FIG. 1D .  FIG. 1D  and  FIG. 2  shows a cross sectional side view and a top view, respectively, of grille assembly  225 , which comprises tube support  226 , thin walled tube  227 , grille plate  228  and alignment pin  224 . As shown in  FIG. 2 , grille plate  228  includes a closely packed array of equally sized holes  229  that cover the powder bed. 
         [0080]    Top block  208  and cylinder (or pin)  210  are preferably made from a corrosion resistant material that is harder than the powders that are processed. For many powders, a suitable material is unhardened stainless steel type 316. For very hard powders, a suitable material is case hardened stainless steel type 440C that is coated with a hard ceramic thin film, such as sapphire coating type MH provided by Surface Conversion Sciences Corporation in State College, Pa., USA. A suitable material for bottom plate  206  is unhardened stainless steel type 316, or a stainless steel grade with similar corrosion resistance. 
         [0081]    The material for strike plate  207  should be softer than the coring tool tip if the tip contacts it (e.g., when tip is inserted completely through the packed bed), so as not to blunt the tool. The strike plate should be chosen so that powder bed  220  will preferably cling to it when pin  210  is removed, while also allowing a punched plug to be cleanly lifted off. For a given powder, bed packing tests should be conducted with different strike plate materials to find one that meets these latter two criteria. Suitable strike plate materials for pharmaceutical powders include, but are not limited to: aluminum, copper, polycarbonate, acrylic, polyester, polystyrene, and PVC. To facilitate a clean release, a thin anti-stick material such as Teflon, UHMW, or wax paper can be adhered to pin face  211 . For a given powder, bed packing tests should be performed to determine if these materials cling to the powder enough to mix the powder when pin  210  is rotated and thus create an even pack, while at the same time cleanly releasing when pin  210  is pulled out. 
         [0082]    Suitable diameters for cavity  204  range from 2 mm to 50 mm depending on how much powder is available and how well it packs. Other sizes can also be used. Pinwall  212 , pinface  211 , and cavity wall  209  should preferably be ground and polished to a surface finish of 0.5 micrometers or less to minimize powder adhesion and thus waste. Pin  210  and cavity  204  preferably should be honed or ground to a roundness of under 7.5 micrometers and should be sized so the clearance between them is under 20 micrometers, to minimize intrusion of powder particles. Pin face  211  should deviate from a perfectly flat and perpendicular face by no more than 10 micrometers to produce a flat powder bed, and base  206  should be ground flat to within 10 micrometers. Strike plate  207  should be flat to within 10 micrometers in the region that contacts powder  200  to insure a flat powder bed. 
         [0083]    A suitable material for grille plate  228  is 0.2 mm thick full hard Invar, and a suitable method for cutting the outer contour and holes such as hole  229 , which typically range in diameter from 0.5 mm to 4 mm, is precision laser cutting which provides +/−5 micrometer accuracy. Custom laser cut Invar grille plates can be fabricated and supplied to these specifications by Photo Etch Technology Company, 71 Willie St, Lowell, Mass. 01854, USA. Suitable materials for thin walled tube  227  and tube support  226  are stainless steel type 316. Tube  227  preferably has a wall thickness of less than 0.4 mm to maximize the punched area. 
         [0084]      FIGS. 3A through 3D  illustrate another method and apparatus for uniform powder bed preparation. A predetermined weight of powder  240  is placed in cavity, typically hollow cylinder  249 , of source receptacle assembly  250 , as shown in  FIG. 3A . Source receptacle assembly  250  comprises block  251  with interior cavity  249 , cylinder  253 , strike plate  254 , and set screw  252 . As shown in  FIG. 3B , slide plate  260  is affixed on top of block  251  with screw  261 . Then a predetermined force which results in a powder bed pressure typically in the range of about 0.5 psi to about 30 psi is applied to cylinder  253 . Cylinder  253  is then rotated through an angle of typically 90 degrees in either direction with the pressure applied. Then, as shown in  FIG. 3C , set screw  252  is locked against cylinder  253 . Then, with screw  261  removed, slide plate  260  is lifted or slid off of powder bed surface  245  while remaining in sliding contact with block surface  255 . Next, as shown in  FIG. 3D , grille assembly  270  is placed on block surface  255  so that alignment pins  274  and  275  fit into holes  247  and  248  to provide alignment over powder bed  245 .  FIG. 3D  and  FIG. 4  show a cross sectional side view and a top view, respectively, of grille assembly  270 , which includes grille frame  272 , grille plate  271 , and alignment pins  274  and  275 . As shown in  FIG. 4 , grille plate  271  comprises a closely packed array of equally sized holes such as hole  273  that cover the powder bed area. 
         [0085]    Block  251 , cylinder  253 , and slide plate  260  are preferably made from a corrosion resistant material that is harder than the powders that are processed. For many powders, a suitable material is unhardened stainless steel type 316. For very hard powders, a suitable material is case hardened stainless steel type 440C that is coated with a hard ceramic thin film, such as sapphire coating type MH provided by Surface Conversion Sciences Corporation in State College, Pa., USA. 
         [0086]    The material for strike plate  254  should be softer than the coring tool tip that will contact it, so as not to blunt the tool, and it should be chosen so that powder bed  245  will preferably cling to strike plate  254  when slide plate  260  is removed, while also allowing a punched plug to be cleanly lifted off. For a given powder, bed packing and punch tests must be conducted with different strike plate materials to find one that meets these latter two criteria. The embodiment shown in  FIGS. 3A to 3D  has the advantage over the embodiment shown in  FIGS. 1A to 1D  that the sliding action releases a cleaner powder bed surface with a greater variety of powders, including very sticky powders with a low pack density, than the pin lifting method does. Suitable materials for strike plate  254  for use with pharmaceutical powders include, but are not limited to, aluminum, copper, polycarbonate, acrylic, polyester, polystyrene, and PVC. Strike plate  254  is preferably adhered to cylinder  253  with a thin layer (less than 25 micrometers thick) of 5 minute or faster setting epoxy. To facilitate a clean release from powder bed  245 , a thin anti-stick material such as Teflon, UHMW, or wax paper can be adhered to slide plate surface  262 . Alternately, an assortment of slide plates can be provided with a variety of coatings on surface  262 . For a given powder, bed packing tests should be performed to determine if strike plate  254  and slide plate surface  262  cling to powder bed  245  enough so that when cylinder  253  is rotated the powder bed  245  is sheared and mixed thoroughly and thus is packed uniformly, while at the same time allowing for a clean release when slide plate  260  is slid off. 
         [0087]    Suitable diameters for cavity  249  range from 2 mm to 50 mm depending on how much powder is available and how well it packs. Other diameters can also be used. Cavity wall  256 , block face  255 , cylinder wall  257 , slide plate surface  262  and block face  255  preferably should be ground and polished to a surface finish of 0.5 micrometers or less to minimize powder adhesion and thus waste. Cylinder  253  and cavity  249  should be ground to a roundness of under 7.5 micrometers and should be sized so the clearance between them is under 20 micrometers. Cylinder face  258  should deviate from a perfectly flat and perpendicular face by no more than 10 micrometers, and slide plate surface  262  and block face  255  should be ground flat to within 5 micrometers. Strike plate  254  should be flat to within 10 micrometers. 
         [0088]    A suitable material for grille plate  271  is 0.2 mm thick full hard Invar, and a suitable method for cutting the outer contour and the holes such as hole  273 , which range in diameter from 0.5 mm to 4 mm, is precision laser cutting which provides +/−5 micrometer accuracy. Custom laser cut Invar grille plates can be fabricated to these specifications by Photo Etch Technology Company, 71 Willie St, Lowell, Mass. 01854, USA. A suitable material for grille frame  272  is stainless steel type 316. 
         [0089]      FIG. 5  illustrates a specific method of fabricating a plug from a uniform powder bed. Coring tool  305 , which comprises a tube  306  and means of ejecting the plug of powder, e.g. a piston  307 , is positioned above hole  301  in grille  302 . Next, as shown in view  310 , tube  306  is pushed partially through the powder bed or completely through powder bed  300  until it contacts strike plate  303  on base  304 . Next, coring tool  305  is lifted and moved to a target location, as shown in view  315 , and a plug  320  is ejected out of tube  306  via means of ejecting the plug of powder, e.g. a piston  307 , liquid, compressed gas, vibration, etc. This process can be performed without using grille  302 ; however, for some powders the bed can break apart and portions can stick to the sides of the coring tube, causing large plug mass variation. 
         [0090]    With the mass of the powder and the area of the cavity base predetermined, it is possible to calculate the average mass of powder per unit area, W. If, as in this example, the tube is circular and the tube is inserted all the way through the powder bed, then the mass of the plug is given by (1): 
         [0000]      Powder plug mass=π( d/ 2) 2    W   (1) 
         [0000]    where d is the inner diameter of the tube and W is the mass per unit area of the powder bed. Similar relationships for square, hexagonal, and other tube shapes are well known to those skilled in the art. Thus, controlling the shape or interior volume of the tube controls the mass of the plug. 
         [0091]    Plugs of powder may be lifted from the powder bed by simply removing the tube from the bed if the inner diameter of the tube is sufficiently small. For some solids and tube inner diameters, the plug may need to be compacted in order to adhere to the tube interior sufficiently to be lifted.  FIG. 6  illustrates a specific method of fabricating and lifting a compacted plug from a uniform powder bed. Coring tool  335 , which comprises a tube  336  and means of ejecting the plug of powder, e.g., a piston  337 , is positioned above hole  331  in grille  332 . As shown in the next view of coring tool  340 , tube  336  is pushed through powder bed  330  until it contacts strike plate  333  on base  334 . Next, as shown in view  345 , piston  337  is pushed into powder bed  330  with a force sufficient to create a pressure in the range of about 5 to about 5000 psi. Next, coring tool  335  is lifted and moved to a target location, and, as shown in view  350 , a compacted plug  355  is ejected out of tube  336  via means of ejecting the plug of powder, e.g., a piston or pin  337 . This process can be performed without using grille  332 , however for some powders the bed can break apart and portions can stick to the sides of the coring tube, causing large plug mass variation. 
         [0092]    Some powders will have properties that allow a plug with a controlled amount of mass to be produced from a thick bed that is punched multiple times in one place. This is desirable because it increases the number of punches that can be produced from a single packed bed.  FIG. 7  illustrates a specific method of fabricating a plug from a uniform powder bed that is taller than the plugs produced. Coring tool  365 , which comprises a tube  366  and means of ejecting the plug of powder, e.g., a piston or pin  367 , is positioned above hole  361  in grille  362 . As shown in the next view of coring tool  370 , tube  366  is pushed into powder bed  360  either with a predetermined force, or a predetermined distance. Next, coring tool  365  is lifted and moved to a target location, as shown in view  375 , and a plug  376  is ejected out of tube  366  via means of ejecting the plug of powder, e.g., a piston or pin  367 . This process can be performed without using grille  362 ; however, for some powders the bed can break apart and portions can stick to the sides of the coring tool, causing large plug mass variation. 
         [0093]      FIG. 8  illustrates another specific method of fabricating a plug from a uniform powder bed that is taller than the plugs produced. Coring tool  385 , which comprises a tube  386  and means of ejecting the plug of powder, e.g. a piston or pin  387 , is positioned above hole  381  in grille  382 . Pin  387  is held stationary to tube  386  so that the distance between piston face  388  and tube edge  389  remains at a fixed and specified value during punching. As shown in the next view of coring tool  390 , tube  386  is pushed into powder bed  380  either with a predetermined force, or a predetermined distance. Next, coring tool  385  is lifted and moved to a target location, and, as shown in view  395 , a plug  396  is ejected out of tube  386  via means of ejecting the plug of powder, e.g. a piston  387 . This process can be performed without using grille  382 ; however, for some powders the bed can break apart and portions can stick to the sides of the coring tool, causing large plug mass variation. 
         [0094]    Commercially available coring tools that are intended for tissue sampling purposes can be used as punching tools for the present invention. A supplier of suitable coring tools for the present invention is Fine Science Tools Inc., 202-277 Mountain Highway, North Vancouver, BC V7J 3P2, Canada, which supplies punching tools with inner tube diameters of 0.35 mm, 0.5 mm, 0.8 mm, 1 mm, 2 mm, 3 mm, and 5 mm. These coring tools include a hardened stainless steel tube and an ejector pin which fits with less than 10 micrometers of clearance. The outside wall of the tube and ejector pin is chrome plated to reduce surface energy so cored materials are less prone to stick. For creating plugs from very hard powders, a custom tungsten carbide tube and pin assembly is appropriate. A tungsten carbide tube and close fitting pin can be manufactured with sufficient precision by Bird Precision, One Spruce Street, Waltham, Mass., 02454-0569, USA. 
         [0095]      FIG. 9  depicts a specific apparatus for manipulating a solid according to the previously described methods. Punching assembly  420 , comprising tube actuator  425 , pin actuator  423 , coring tool  415 , and mounting plate  427 , is mounted to y linear actuator  460  and y guide rail  462 , which are mounted to x linear actuator  463 . Tube actuator  425  and pin actuator  423  together allow a plug to be punched, compressed if desired, and ejected. X linear actuator  463  and y linear actuator  460  has sufficient range to move coring tool  415  over four stations: receiving plate  410 , source receptacle assembly  405 , wash station  430 , and weigh station  440 , each with the following functions. Receiving plate  410  is where production plugs are dispensed; source receptacle assembly  405  is where plugs are punched; wash station  430  is where the tip of coring tool or tube  415  can be washed and dried; and weigh station  440  is where plugs can be weighed to characterize and monitor the dispense process. These components are supported by a machine base  470 , a receiving plate pedestal  472 , and actuator supports  471  and  473 . 
         [0096]    A suitable x linear actuator  463  is model ERB50-B02LA90-GSS600-A with a 600 mm stroke, a suitable y linear actuator  460  and guide rail  462  are models ERB32-B08LA90-FSS300-A and ERB32-IDLS-FSS300 model with 300 mm strokes, made by Parker Hannifin Corporation based in 6035 Parkland Boulevard Cleveland, Ohio 44124-4141, USA. A suitable product for x servo motor  464  and y servo motor  461  is motor model number NTE-207-CONS-000 by EMERSON, to be used in conjunction with servo drive model Ei-DN-20200-000, also manufactured by EMERSON (8000 West Florissant Avenue, St. Louis, Mo. 63136-8506, USA). Movement commands can be sent to the servo drives from a personal computer programmed with compatible driver software. Products that can be used for tube actuator  425  and pin actuator  423  are pneumatic actuator models MXS8-75A-F9PVL and MXS8-10A-F9PVL respectively, supplied by SMC Corporation of America, 3011 North Franklin Road, Indianapolis, Ind. 46226, USA. 
         [0097]    Wash station  430  comprises receptacle  433  with solvent reservoir  431  and drying hole  432 . Solvent reservoir  431  is filled with a solvent capable of dissolving powder  400 , and the bottom of drying hole  432  is connected to port  434  which is held under vacuum. Suitable solvents for typical powders include, but are not limited to, ethanol, methanol, acetone, ethyl acetate, dimethylsulfoxide, or methylene chloride. An appropriate material for wash receptacle  433  is TEFLON (DuPont) or UHMW polymer (Crown Plastics), which are inert to most useful solvents. To wash and dry, coring tool  415  is first inserted into solvent reservoir  431  for a fixed period of time, and then into drying hole  432  for a fixed period of time. To agitate fluid at the tip and thus speed up washing and drying, pin actuator  423  can be extended and retracted while being washed or dried. 
         [0098]    Weigh station  440  comprises microbalance  445  with weighing platform  444 , draft shield  441 , and weigh cup  442  to contain sample plugs  443 . To weigh a plug, coring tool  415  is moved over hole  446  and extended into weigh cup  442 , and a plug is ejected into the weigh cup. To allow the microbalance to settle to sufficient accuracy it may be necessary for all actuators to stop moving. The weigh station can be used to weigh a population of plugs to characterize a powder bed packed with predetermined conditions. To characterize a powder bed, typically 40 pellets are randomly sampled from the bed to obtain an average mass and a standard deviation. If the values are acceptable, subsequent beds are packed under the same conditions and production pellets are produced. A suitable microbalance for weighing plugs in the range from 1 microgram to 2 grams with an accuracy of +/−0.25 micrograms is microbalance model UMX2, manufactured by Mettler Toledo, GmbH, with corporate headquarters in Im Langacher, 8606 Greifensee, Switzerland. 
         [0099]    To punch a plug, tube actuator  425  is retracted, coring tool  415  is moved over a grille hole in source receptacle assembly  405 , tube actuator  425  is extended to push coring tool  415  through a grille hole into powder bed  400 , and then actuator  425  is retracted. To eject a plug, coring tool  415  is moved to a target location, tube actuator  425  is extended, pin actuator  423  is extended to eject a plug, then actuator  423  is retracted and actuator  425  is retracted. 
         [0100]    To reduce static electricity buildup ion blower  480  is mounted above coring tool  415  and blows ionized air onto the components below it. A suitable ion blower is model 4165 made by NRD LLC, 2937 Alt Blvd, PO Box 310, Grand Island, N.Y. 14072, USA. 
       Example 2 
     Manipulating Solids by Extruding a Plug of Powder 
       [0101]    This example illustrates an alternative method and apparatus to produce a plug of powder. The average particle size of the powder should be less than about 200, 100, 50, 10, 5, 1, 0.1, or 0.01 micrometers. This embodiment has two significant advantages over the method described in Example 1. It requires less time and labor since a uniform powder bed does not have to be prepared, and secondly, it requires less powder to create the same number of plugs. In other words, this embodiment may prove to be more efficient and less wasteful than coring a plug of powder. 
         [0102]    In a specific embodiment of this method and apparatus, plugs of powder are fabricated via the following process. First, as shown in  FIG. 10A , a known mass of powder  501  (e.g., less than about 1 gram, 500 mg, 100 mg, 25 mg, 1 mg, 500 micrograms, 250 micrograms, or 100 micrograms) is dispensed into a cylindrical source chamber  502  with source piston  503  located in a downward position. Source block  504  is then clamped to slide plate  506  by keeper plate  509 , as shown in  FIG. 10B . 
         [0103]    Next, as shown in  FIG. 10C , pneumatic cylinder  505 , or other means of moving the piston head closer to the slide plate  506 , presses source piston  503  with typically about 5 to about 50 psi of pressure and as such, powder  510  against slide plate  506 . Slide plate  506  is then moved so dose chamber  513  traverses over the powder surface  515 , for example, in a criss-cross trajectory  516  as shown in  FIG. 11A . Alternatively, other trajectories such as a spiral trajectory  517  as shown in  FIG. 11B  can be employed. As a guideline, the traversed distance should be greater than ten times the source chamber diameter, and the path should cover different portions of the source area  515  to achieve repeatable filling of dose chamber  513 . To improve the flow of powder  510  into the dose chamber  513 , the powder in the source chamber can be subjected to vibration or mixing. 
         [0104]    The size and mass of the plug can be changed by adjusting the height of the dose chamber  513  with micrometer device  508  shown in  FIG. 10B . Preferably, the ratio of the height to the diameter of dose chamber  513  is greater than 0.2 and less than 0.8, otherwise a different diameter dose chamber should be installed. 
         [0105]    After powder  510  fills dose chamber  513 , pressurized air to pneumatic cylinder  505  is switched off. Then, as shown in  FIG. 12A , slide plate  506  is moved relative to source block  504  so dose chamber  513  is positioned above target well  518 . Next, as shown in  FIG. 12B , pressurized air propels ejector pin  522  downwards and ejects plug  520  into target well  518 . Ejector piston  521  hits hard stop  523  and decelerates suddenly, thereby flinging powder off of ejector pin  522 . Ejector pin  522  is then retracted, slide plate  506  is moved back, and pressurized air is supplied to pneumatic cylinder  505  to press powder  510  again. The fill and eject processes are repeated until source powder height  524  (see  FIG. 12B ) reaches a minimum, typically 0.4 mm, at which point source chamber  502  is refilled. 
         [0106]    Slide plate  506 , ejector pin  512 , source block  504  and source piston  503  should be made from a hard, wear resistant material that provides a long wear life without lubrication. Suitable materials are tungsten carbide, zirconia, silicon carbide and alumina. If the device only needs to dispense soft powders, a less costly alternative is to use hardened 440C stainless steel coated with a hard ceramic thin film, such as sapphire coating type MH provided by Surface Conversion Sciences Corporation (State College, Pa.). Passive components of the dispense device are preferably made from corrosion resistant stainless steel, such as type 316. To create plugs that have a mass of 50 micrograms, a suitable dose chamber diameter is 0.5 mm, and a suitable source chamber diameter is 2 mm to 5 mm. Slide plate  506  should be 150 mm long or greater to allow a portion of it to remain clamped to source block  504  while allowing dose chamber  513  to reach all wells of an industry standard microtiter plate, which has a footprint of 85 mm by 127 mm. 
         [0107]    The mating faces of slide plate  506  and source block  504  should be ground to a flatness of 2 micrometers or better to minimize escape of powder particles. Dose chamber  513  and source chamber  502  should be honed to a roundness of under 2 micrometers, and ejector pin  512  and source piston  503  should be lapped to a roundness of under 2 micrometers, to allow a nominal radial clearance between the respective parts to be within 5 micrometers. Surfaces of ejector pin  512  and source piston  503  that contact powder should be ground flat to within 2 micrometers. Edges on dose chamber  513 , source chamber  502 , ejector pin  512  and source piston  503  should be left sharp to discourage particles from lodging between the sliding surfaces. To minimize wear, all faces in sliding contact should be polished to a surface finish of less than 0.2 micrometers. 
         [0108]      FIGS. 13A and 13B  show the front and side view, respectively, of a machine that incorporates dispense device  507  which can dispense into receiving plate  599  and into weigh cup  595  on microbalance  597 . Receiving plates can be an industry standard 96 well, 384 well, or 1536 well format, or a custom format. Receiving plate  599  is supported by pedestal  600  on machine base  601 . Slide plate  506  is moved relative to source block  504  by x linear actuator  592  and y linear actuator  589 . Suitable actuators are from the ROBO CYLINDER® series made by Intelligent Actuator, Inc., Japan. Pneumatic cylinder  603  connected to yoke  587  presses slide plate  506  against source block  504 . Yoke  587  has feet  584  made from ultrahigh molecular weight, polyethylene to minimize sliding friction. Pushrod  607  of servo  592  connects to shuttle frame  590 , which in turn is connected to servo body  589 , thereby allowing x and y movement of slide plate  506  relative to source block  504 . 
         [0109]    Linear actuator  582 , supported by columns  585  and  580 , moves dispense device  507  in the x direction to allow dispensing into receiving plate  599 . As shown in  FIG. 13B , dispense device  507  is supported by C-frame  591  which connects to carriages  605  and  606 . Slave linear guide  504  provides added support for C-frame  591 . Suitable linear actuators and supporting control hardware and software are made by Intelligent Actuator, Inc., Japan. 
         [0110]    Weigh station  583  shown in  FIG. 13A  allows plugs to be weighed for characterization and statistical tracking. Weigh station  583  comprises microbalance  597  with weighing platform  596 , weigh cup  595 , and draft shield  594 . Microbalance  597  is supported by granite pedestal  598 . A suitable microbalance is the UMX2 model made by Mettler Toledo, Switzerland. 
       Example 3 
     Manipulating Solids by Extruding Multiple Plugs of Powder Simultaneously 
       [0111]    This example is based on a similar method and apparatus as Example 2 except that it demonstrates a new method and apparatus for extruding multiple plugs of powder simultaneously. To begin,  FIG. 14A  shows that a known mass of powder  640  (e.g., less than about 1 gram, 500 mg, 100 mg, 25 mg, 1 mg, 500 micrograms, 250 micrograms, or 100 micrograms) is dispensed into a source chamber  642 . Then, in  FIG. 14B , assembly  648  comprising pneumatic cylinder  651  and source piston  649  is attached above source chamber  642 . At the base of source chamber  642  is slide plate  645  which is in between source block  641  and keeper  656 . Powder  640  is initially compressed inside source chamber  642  against slide plate  645  by supplying air to pneumatic cylinder  651  at typically about 5 to about 50 psi. 
         [0112]      FIG. 14B  also shows that source piston  649  has square cross section  665  sized to fit precisely into square source chamber  642  (round or other cross section shapes can also be used). Slide plate  645  includes multiple hollow partitions such as grid cutter  646  (See  FIG. 15 ), which comprises frame  708  holding a grid of thin blades such as  660  which form square partitions such as  675 .  FIG. 15  shows an isometric view of grid cutter  646 . Ejector pin  670  has a square cross section  674 , sized to fit precisely into grid partitions such as  675 . However, source chamber  642 , source piston  649 , ejector pin  670 , and partitions  675  in grid cutter  646  can be designed to have any arbitrary shape including, circular, rhombic, or hexagonal shape such that the parts fit appropriately within each other. 
         [0113]    After powder  655  is initially compressed to achieve a uniform packing density of powder in source chamber  642 , the pressurized air supply to port  664  (See  FIG. 16A ) of pneumatic cylinder  662  is released and slide plate  645  is moved directly below source chamber  642 . Then, as shown in  FIG. 16A , pressurized air is supplied to port  664  to press powder  668  through blades  660  of grid cutter  646 . Pressurized air to port  664  is then switched off, and slide plate  645  is moved so plug  673  is under ejector pin  670 , as shown in  FIG. 16B . Dispense device  659  is also moved so plug  673  is over target well  662 . Next, as shown in  FIG. 16C , pressurized air is supplied to port  676  and it propels ejector pin  670  down to eject powder plug  673  into target well  662 . Ejector piston  678  hits hard stop  677  and decelerates suddenly, thereby flinging virtually all powder off ejector pin  670 . Slide plate  645  is then translated incrementally so another partition is under ejector pin  670 , and the eject process is repeated. The extrude and eject processes are repeated until source powder height  650  reaches a value that is less than the slide plate thickness. The minimum source powder height can be detected with a standard hall effect sensor. 
         [0114]    For this embodiment shown in  FIGS. 16A through 16C , the average packing density of powder  668  and the thickness of slide plate  645  determine the average mass of plugs produced. The average packing density of powder  668  is estimated by measuring rod height  647  ( FIG. 14B ) which determines powder height  650 , as shown in FIGS.  14 B and  16 A-C. For example, the average packing density is equal to the mass of powder  668  divided by the powder height  650  and the base area of source chamber  642 . Thus, the average mass of powder plug  673  is equal to the packing density times the thickness of slide plate  645  and base area of partition  675 . An assortment of slide plates with different thicknesses is made available to provide an average plug mass that is acceptably close to a target value. As a non-limiting example to install a new slide plate  657 ,  FIG. 17  shows dispense device  659  inverted and keeper  656  is removed and reattached. Alternatively, another embodiment is shown in  FIGS. 18A and 18B  where the height of each partition  746  in grid cutter  749  is controlled by independent micrometers  753  and  754  connected to individual ejector pins  742 . 
         [0115]    Slide plate  645 , ejector pin  670 , source block  641  and source piston  649  should be made from a hard, wear resistant material that provides a long wear life without lubrication. Non-limiting suitable materials include tungsten carbide, zirconia, silicon carbide or alumina. If only soft powders are being deposited, a less costly alternative is to use hardened 440C stainless steel coated with a hard ceramic thin film, such as sapphire coating type MH provided by Surface Conversion Sciences Corporation (State College, Pa.). The structural components of the dispense device are preferably made from a corrosion resistant stainless steel, such as type 316. Grid cutter insert  646  is preferably made from a tungsten carbide plate whose faces are ground and polished. The partitions can be cut by plunge or wire electrical discharge machining. 
         [0116]    Determining the various parameters necessary to make plugs of specific masses can be done using techniques and materials well known in the art. For example, to create plugs that have a mass of approximately 50 micrograms, a suitable thickness for slide plate  645  and cutter insert  646  is 0.4 mm, and a suitable partition dimension is 0.4 mm wide by 0.4 mm long. A suitable cutter wall thickness is 75 micrometers. The mating faces of slide plate  645 , source block  641 , and keeper  656  should be ground to a flatness of 2 micrometers or better to minimize escape of powder particles. Source chamber  642  walls should be lapped to an accuracy of under 2 micrometers, and ejector pin  670  and source piston  649  walls should be lapped to an accuracy of under 2 micrometers. The nominal clearance between square ejector pin  670  and a grid cutter partition such as  675  should be 10 micrometers or less. Ejector pin  670  and source piston  649  faces that contact powder  640  should be ground flat to within 2 micrometers. The edges on grid cutter  646 , ejector pin  670 , source chamber  642 , and source piston  649  should be left sharp to discourage particles from lodging between the sliding surfaces. To minimize wear, all of the faces in sliding contact should be polished to a surface finish of less than 0.2 micrometers. 
         [0117]      FIGS. 19A and 19B  show a machine that incorporates dispense device  659 , which can dispense into receiving plate  728  and into weigh cup  715  on microbalance  717 . Receiving plates can be an industry standard 96 well, 384 well, or 1536 well format, or a custom format. Receiving plate  728  is supported by pedestal  719  on machine base  718 . 
         [0000]    Slide plate  645  is moved in both x and y directions relative to source block  641  by x servo  709  (See  FIG. 19A ) and y servo  732  (See  FIG. 19B ). Suitable servos are the ROBO CYLINDER® series made by Intelligent Actuator, Inc., Japan. Part  712  couples the x and y servos to slide plate  645 . Clamping pneumatic cylinders  709  and  710  force keeper  656  to hold slide plate  645  against source block  641 . 
         [0118]    X linear actuator  725  and y linear actuator  721  move dispense device  659  relative to machine base  718 . Slave z linear guide  729  and y linear guide  721  provide added stiffness to the support of dispense device  659 . Suitable linear actuators and supporting control hardware and software are made by Intelligent Actuator, Inc., Japan. 
         [0119]    Weigh station  713  allows plugs to be weighed for characterization and statistical tracking. As shown in  FIG. 19A , it comprises microbalance  717 , weigh cup  715  on weighing platform  716 , and draft shield  714 . A suitable microbalance is the UMX2 model made by Mettler Toledo, Switzerland. 
       Example 4 
     Manipulating Solids by Producing a Slurry Suspension 
       [0120]    The physical characteristics of some solids make them more amenable to manipulation using a carrier. Consequently, this invention encompasses a method of manipulating solids that utilizes slurries. In this method, a solid or mixture of solids is combined with a liquid vehicle to form a slurry mixture, which is dispensed by using standard liquid handling devices (e.g., pipettes). The liquid vehicle is then removed (e.g., by evaporation, filtration, or sedimentation) to provide the solids. Long drying times and low drying temperatures are preferably used to promote crystal formation. Advantageously, a liquid vehicle can be selected such that it allows the ready manipulation of a given solid but does not dissolve a substantial portion of solid. By avoiding the formation of a solution into which the solid is dissolved, the method allows the manipulation of controlled amounts of solids without substantially affecting their solid forms. 
         [0121]    The selection of a liquid vehicle that can be used to provide a slurry of a solid that is easy to manipulate (e.g., prepare, handle, and/or dispense) can be done with little or no routine experimentation. Preferred liquid vehicles are readily removed (e.g., evaporated) and do not chemically react with the solid. The solid or solids being manipulated are also insoluble or have a low solubility (e.g., less than about 10 mg/mL, 1 mg/mL, 0.1 mg/mL, 0.01 mg/mL or 0.001 mg/mL ) in preferred liquid vehicles. In a specific method, the liquid vehicle comprises a wetting agent and water. The purpose of the wetting agent is to lower the surface tension of the water. Examples of wetting agents include, but are not limited to, alcohols such as isopropyl alcohol and methanol, sodium lauryl sulfate, polyvinylpyrrolidone (PVP), and TWEEN®. 
         [0122]    In a specific method, samples of the slurry suspension are collected into vials for high-performance liquid chromatography (HPLC) analysis during the dispensing step. These vials are used to validate how much solid was actually transferred during each dispense. In a specific method, solid-state analysis is performed after the liquid vehicle is removed (e.g., vacuum or evaporated) to verify that the solid has not substantially changed in form. Examples of techniques that can be used for this determination include, but are not limited to, NMR spectroscopy (e.g.,  1 H and  13 C NMR), Raman spectroscopy (e.g., resonance Raman spectroscopy), X-ray spectroscopy, powder X-ray diffraction, absorption and emission spectroscopy (e.g., infrared, visible, and ultraviolet absorption and emission), birefringence, differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). 
       Example 5 
     Manipulating Solids by Using Adhesive Surfaces 
       [0123]    In another embodiment of the invention, solids (e.g., powders) are manipulated using an adhesive surface to which a controlled amount of solid can be adhered. Particular methods of this embodiment utilize a surface comprised of two or more adhesive areas separated by non-adhesive areas (i.e., areas to which a given solid will not adhere or will adhere more weakly than it does to an adhesive area). Preferably, the adhesive areas are of approximately the same size and shape. Examples of specific sizes of adhesive areas include, but are not limited to, less than about 5 cm 2 , 2.5 cm 2 , 1 cm 2 , 50 mm 2 , 10 mm 2 , 1 mm 2 , and 0.5 mm 2 . 
         [0124]    Adhesive areas can be formed in a variety of ways. Examples include, but are not limited to, adhering an adhesive to a non-adhesive backing, overlaying an adhesive backing with a non-adhesive mask, and treating regions of a non-adhesive backing with chemicals, radiation, plasma, or other means sufficient to render those regions adhesive. Such methods are well known in the art. See, e.g., U.S. Pat. Nos. 6,284,329, 6,221,268, and 6,096,156, each of which is incorporated herein by reference. 
         [0125]      FIG. 20  provides various non-exhaustive illustrations of possible adhesive patch arrangements, which include arrays  815 , strips  820 , and wafers  825 . The surface area of the adhesive and particle size of the powder will affect the amount of solid attached to a specific area  825 . The pattern can be a familiar array of shapes, such as an array of circles, squares, lines, or other structures arranged in a pattern such as a grid or a spiral. Suitable backing materials can be stiff (e.g., made of glass or plastic) or flexible (e.g., plastic carrier film). 
         [0126]    The patterned surface is preferably de-ionized using an ion-gun to reduce non-specific and undesirable electrostatic interactions that can affect powder adhesion. Powder is then applied to the surface by, for example, pushing the surface into a powder bed, dipping the surface into a powder, spreading the powder across the surface and tapping off the excess, or sprinkling the powder over the surface and tapping off the excess. If any powder remains electrostatically adhered to undesired sections of the surface, an ion air-gun can be used to gently blow it off of the surface.  FIG. 21  illustrates an example of this embodiment, wherein sticky adhesive patches  805  on a de-ionized substrate  800  are contacted with a bed of powder  810 . In one embodiment, less than about 1 mg of powder is adhered to an adhesive area. In another embodiment, less than about 0.5 or 0.25 mg of powder is adhered to an adhesive area. 
         [0127]    After the solid preferentially adheres to the adhesive areas, the solid is removed from the substrate and transferred to a container or receptacle for further utilization (e.g., study, or experimentation). In a specific method, the solid is dissolved in a solvent and the resulting solution is transferred to the receptacle. Preferably, the adhesive (if one is used) is not soluble or is only sparingly soluble in the solvent. In another method, the solid is transferred using a liquid or gel in which the solid is insoluble or only sparingly soluble, but to which it adheres or in which it is trapped with enough affinity to facilitate its removal from the adhesive area. An example of such a liquid is polyethylene glycol (PEG). 
         [0128]      FIG. 22  illustrates a way by which a solid adhered to an adhesive area on a substrate or backing can be dispensed into a container (e.g., a well in a multi-well plate). According to this particular method, a reagent, solvent, or excipient  920  adhered or otherwise suspended on a backing is contacted with solid  925  adhered to a strip or array of adhesive areas  915  to provide a mixture  930 . The reagent, solvent, or excipient is selected such that the resulting mixture will not remain adhered to the strip or array  915  and will form an easily dislodged or displaced agglomeration  905 . The agglomeration can thus be readily dispensed into a suitable container  910  using, for example, a centrifuge, vibration, vacuum, or simply gravitational force. Preferred reagents do not react with, or substantially affect the form of, the solid being manipulated, and do not dissolve the adhesive. The reagent can optionally be removed using a variety of techniques such as, but not limited to, evaporation, filtration, and sedimentation. 
         [0129]    Depending on the particular use to which the solid is put, it may or may not need to be removed from the adhesive area to which it is adhered. In one embodiment of the invention, the solid is utilized (e.g., studied) while still adhered to an adhesive area on a backing. For example, a variety of experiments can be conducted in series or in parallel directly on a sheet or strip of solid samples, such as those shown in  FIG. 20 . 
         [0130]    In a specific method, solid-state analysis is performed to verify that the solid has not substantially changed in form during transfer. Examples of techniques that can be used for this determination include, but are not limited to, NMR spectroscopy (e.g.  1 H or  13 C NMR), Raman spectroscopy (e.g., resonance Raman spectroscopy), X-ray spectroscopy, powder X-ray diffraction, absorption and emission spectroscopy (e.g., infrared, visible, and ultraviolet absorption and emission), birefringence, differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). 
       Example 6 
     Transferring Solids from One Container into Another Container 
       [0131]    During the process of manipulating small amounts of solid, it may be necessary to transfer the solid content inside one container into a different container. For example, weighing small amounts of solid on a precision microbalance (e.g., the Sartorius SC2 Ultra Micro) requires a low-mass container (e.g., less than 2 g) in order to achieve sufficient mass resolution (e.g., 0.1 microgram readability). However, further processing of those solids may require a higher-strength container or a two-dimensional array format, both of which would exceed the mass limit of such a microbalance. For such applications and others, various methods and apparatuses for transferring solids from one container into another container are described below. 
         [0132]    In a specific method and apparatus, the container that originally holds the solids  1000  is a conventional open-faced vessel  1001  that can be weighed by a microbalance  1005  as shown in  FIG. 23A . The solids  1000  are transferred into a different container, such as a well in a multi-well plate, by employing a pneumatic clamp  1002  that is attached to a swing arm  1003  and grips the vessel  1001 .  FIG. 23B  shows a top view of the clamp  1002  and swing arm  1003  of the embodiment. As illustrated in  FIG. 23C , the swing arm  1003  accelerates the vessel  1001  through an arc trajectory and impacts a hard stop  1004  which causes the solids  1000  to exit the open-faced vessel  1001  and enter a target well  1006  in a multi-well plate  1007 . The position of the target well  1006  is located by a pair of x and y linear actuators  1008  to be directly below the stopped-position of the vessel  1001 . 
         [0133]    To increase the process throughput of the swing-arm embodiment, a carousel  1009  can be incorporated, as shown in  FIG. 24 . The carousel  1009  rotates two or more vessels  1001  between the microbalance  1005  for weighing and the position of the pneumatic clamp  1002  for transfer. As a result, transfer and weighing can occur simultaneously. 
         [0134]    To enhance the release of solids from the vessel  1001  in the swing-arm embodiment, a vibrating actuator  1010  can be incorporated to apply repeated taps either to the swing arm  1003  as shown in  FIG. 25A , or directly to the vessel  1001  as shown in  FIG. 25B . The frequency of the vibration would typically be between about 1 Hz and about 50 kHz. To prevent pre-mature release of the solids  1000  from the vessel during the swinging motion, a retractable shield  1011  can be placed over the open-faced vessel  1001  as shown in  FIG. 26A , and retracted just prior to dispense as shown in  FIG. 26B . 
         [0135]    An example of an alternative method and apparatus to transfer solid content from one container to another utilizes a container  1012  that can be weighed by a microbalance  1005  as shown in  FIG. 27 . The container  1012  incorporates a retractable bottom plate  1013  that can be removed to release the solids  1000  into a receiving container  1014 . To enhance the solids release from the container  1012 , the container can be shaken or impacted with an actuator, or a pulse of gas can be applied through the container. 
         [0136]    Another example of a method and apparatus to transfer solids content from one container to another comprises a container  1015  that can be weighed by a microbalance  1005  as shown in  FIG. 28A . The container  1015  incorporates a gas permeable bottom plate  1016 . To transfer the solids content  1000 , vacuum pressure is applied through the bottom plate  1016 , the container  1015  is inverted, and then, the vacuum pressure is removed or positive pressure is applied through the bottom plate to release the solids  1000  into the receiving container  1017 , as shown in  FIG. 28A . To enhance the solids release from container  1015 , a receiving container  1018  can incorporate its own gas permeable bottom plate  1019  which allows a continuous current of gas to run through both containers, as shown in  FIG. 28B . 
         [0137]    In some cases, the solids content of a container may be strongly adhered to the container walls and require a release force greater than gravity, low-pressure gas, or inertial vibration. In such cases, an example of a method and apparatus to transfer the solids content from one container to another is illustrated in  FIG. 29 . The solid-containing container  1020  can be weighed by a microbalance  1005  and is designed to allow an internal piston  1021  to slide through the container. The container  1020  is inverted and a pin  1022  is used to push the internal piston  1021  and solids content  1023  through the container  1020  and into a receiving container  1024 . 
         [0138]    In a separate method and apparatus, the solids are not removed from their original container during transfer to expedite the process. As shown in  FIG. 30 , the solid  1000  is transferred into a two-dimensional array format by utilizing a vessel  1025  that can be weighed by a microbalance  1005  and that fits inside a well  1026  in a receiving plate  1027  that has a two-dimensional array of wells. The vessel  1025  is manipulated by a robot arm or a pneumatic gripper  1028  mounted to x-linear stage  1029  and z-linear stage  1030 . The receiving plate  1027  sits on a y-linear stage  1031 . For certain applications, the vessel is designed to fit completely inside the well such that the receiving plate can be sealed with a conventional plate seal (e.g., a pressure-adhesive film, heat-activated film, or rubber capmat) for further processing of the solids. As shown in  FIG. 31 , the throughput of this transfer process can be enhanced by incorporating a carousel  1032  that allows vessels to be weighed and transferred simultaneously. 
       Example 7 
     Mixing Small Amounts of Solids 
       [0139]    In applications such as high-throughput preformulation screening of drug compounds, it is necessary to mix small amounts of different powders, with the total sample volume typically less than 1 mg. Mixing achieves intimate particulate contact between compounds such that any resulting chemical or physical interactions can be analyzed. Several methods and apparatuses to mix small amounts of solids are described here. 
         [0140]    In a specific method and apparatus as shown in  FIG. 32A , the solids  1100  (e.g., powders) are contained in a conventional multi-well plate  1101  with filter-bottom wells (e.g. Unifilter™ plate by Whatman, Clifton, N.J.). The top of the microplate is sealed with a lid  1102  that seals each well independently from each other (e.g. Capmats by Whatman). The lid is pierced to inject gas into a well. One well can be mixed at a time, or several wells in parallel, or all the wells in the plate can be mixed simultaneously. By directing a jet of gas  1103  into each well, turbulent air flow is created and the powders are forced to mix. The filter at the bottom of each well allows the gas to escape while retaining the powders. Alternatively, it is also possible to seal the top of a multi-well plate  1101  with a filter plate  1104 , so that short bursts of gas  1105  can be cycled back and forth, across each well to mix the solids  1100 , without piercing the plate  1104  as shown in  FIG. 32B . 
         [0141]    In a separate method and apparatus, the powders are contained in a commercial microplate or individual vials carried in a block. The vials are sealed with screw, snap, or crimp caps and clamped down to the carrier block, or each well in the microplate is sealed with a lid. After sealing the powder receptacles, the powders are mixed by shaking or vibrating the microplate or carrier block at high or low frequency for a period of time. The microplate or carrier block can also be rotated around different axes to achieve powder mixing. To enhance mixing, a small magnetic stirrer or spherical ball coated with a chemically-inert material can be placed into each well or vial. After sealing the powder receptacles, the powders are mixed by either shaking the microplate/carrier block which causes the internal ball to mix the powders, or by shaking the magnetic stirrer with an oscillating magnet. 
         [0142]    A similar method and apparatus for mixing involves using a pierceable seal  1106  on top of microplate  1107  or vial and inserting a flexible wire  1109  into each receptacle, as shown in  FIG. 33 . The wire  1109  can be sheathed in a stationary housing  1108  while a motor spins the wire  1109  to mix the powders  1100 . Various designs of stirrer blades  1110  and blade motions  1111  can be utilized to mix the powders, as shown in  FIG. 34 . After mixing, the stirrer wire  1109  or blade  1110  can be removed from the receptacle and cleaned. If the powder level in each receptacle is shallow enough, it is possible to mix the powders without sealing the receptacle. One well or vial can be mixed at a time, or several wells or vials can be mixed simultaneously. 
         [0143]      FIG. 35  shows another example of mixing where the powder  1100  is contained in compressible vials  1112  or a microplate fabricated with compressible wells  1113 . For example, the vials or wells can be fabricated from an elastic material such as silicone rubber or they can be fabricated with collapsible plastic bellows. The vials are sealed with a flexible or gas-permeable cap  1114 , while the top surface of the microplate is sealed with a filter plate  1115  to allow air to escape. The vials or wells are squeezed repeatedly in the same or different directions to mix the powders. 
         [0144]    In another example, instead of employing an active means of mixing compounds, it is possible to achieve particulate contact between different compounds by layering the powder dispensed inside each receptacle  1119 , as shown in  FIG. 36 . This method would allow an active ingredient  1116  to interact with excipient  1117  and a different excipient  1118 . 
       Example 8 
     Dispensing and Weighing Solids in a Two-Dimensional Array Format with a Conventional Microbalance 
       [0145]    Previously described in this invention are examples of methods and apparatuses to manipulate small amounts of powder. For applications such as high-throughput screening of drug compound stability, it is often desirable to dispense as well as weigh controlled amounts of solids rapidly and accurately without substantially affecting their form. Weighing small amounts (e.g., amounts less than about 5 mg, 2.5 mg, 1 mg, 750 micrograms, 500 micrograms, 250 micrograms, 100 micrograms, 50 micrograms, 25 micrograms, 10 micrograms, 5 micrograms, or 1 microgram) of solid on a conventional microbalance (e.g., SC2 Ultra Micro by Sartorius) restricts the total mass weighed (e.g., less than 2 g) in order to achieve sufficient mass resolution (e.g., 0.1 microgram readability). In other words, during mass measurement on a microbalance, the solids should be contained by a lightweight container. However, further processing of those solids may require them to be in a two-dimensional array format, such as a multi-well plate which is too massive for a precision microbalance. 
         [0146]      FIG. 37  illustrates a method and apparatus that enables a controlled amount of solid  1200  to be dispensed by a dispensing device  1205  directly into a two-dimensional array format and weighed by a precision microbalance  1207 . The apparatus comprises a cradle  1203  that supports a tray  1204  that has a two-dimensional array of through-holes. Each through-hole supports a low-mass container  1201  such that the container can slide in and out of the hole easily. The cradle  1203  is attached to a vertical actuator  1211  which is mounted to an x-linear actuator  1209  and a y-linear actuator  1210 . The x and y actuators position the tray  1204  such that a desired container  1202  is directly above the weigh platform  1206  of the microbalance  1207 . Then, the vertical actuator lowers the tray  1204  such that the desired container  1202  is supported by the weigh platform  1206  and no longer in contact with the tray  1204 . As result, a controlled amount of solid  1200  can be dispensed into the desired container  1202  and weighed individually by the microbalance  1207  while it is part of a two-dimensional array. After the desired container  1202  is weighed, it is removed from the microbalance  1207  by employing the vertical actuator  1211  to lift the tray  1204  such that the container  1202  is supported by the tray again. 
       Example 9 
     Dispensing and Weighing Solids with an Integrated Mass Sensor 
       [0147]    Previously described in this invention are the limitations of weighing small amounts (e.g., amounts less than about 5 mg, 2.5 mg, 1 mg, 750 micrograms, 500 micrograms, 250 micrograms, 100 micrograms, 50 micrograms, 25 micrograms, 10 micrograms, 5 micrograms, or 1 microgram) of solid particles with a conventional microbalance (e.g., SC2 Ultra Micro by Sartorius). The current example describes novel methods and apparatuses that can dispense and weigh solids without a conventional microbalance. A transfer device is used to capture and dispense a controlled amount of solid. Transfer devices of the present invention can comprise a coring tool as described in Example 1, micromechanical tweezers, or microelectrodes that attract particles using electric or magnetic fields. A mass sensor is designed to quantify the mass of the captured solids by measuring the mechanical response of the transfer device before and after the solids are captured. Similarly, the mass sensor can quantify the mass of dispensed solids by measuring the mechanical response of the transfer device before and after the solids are dispensed. 
         [0148]    In general, the mechanical response of a structure to an applied input force exhibits a unique resonant frequency that is a function of its stiffness and mass. Therefore, the loading or unloading of solids onto a transfer device produces a proportional change in the resonant frequency of the device. As a result, the mass of the solids can be calculated from the measured shift in resonant frequency, assuming that the stiffness of the device does not change and that the solids are securely attached to the device. To increase the sensitivity of this measurement, the transfer device is preferably stiff and lightweight. Specific transfer devices of the invention are very small, and can be made using microfabrication techniques. 
         [0149]    To generate a mechanical response from transfer device, a transient force is applied to the transfer device, preferably at a location away from the attached solids. This is done using any of a variety of motion transducers known in the art, such as a piezoelectric actuator, solenoid shaker, impact hammer, acoustic speaker, electrostatic comb drive, or similar means. Different excitation signals can be applied to the motion transducer, such as a sweeping sine wave, impulse, step, or noise inputs to cause the transfer device to resonate. 
         [0150]    The mechanical response of the transfer device to the excitation is measured using any of a variety of instruments known in the art, such as a capacitance sensor, accelerometer, phase Doppler velocimeter, piezoelectric sensor, strain gauge, or similar means. Preferably, the sampling frequency of the motion sensor is at least two times faster than the resonant frequency of the transfer device to prevent aliasing. The motion sensor provides an analog voltage signal that corresponds to the movement of the transfer device. Commercial data-acquisition hardware and software is used to record and analyze the transient signal data to obtain a frequency spectrum of the transfer device&#39;s mechanical response. The frequency at which the device displays the maximum amplitude of vibration is its resonant frequency. If a piezoelectric transducer is used to impart motion to the transfer device, the resonant frequency of the piezoelectric transducer itself can be correlated to the added mass of attached particles. This can be accomplished with an oscillator circuit that takes advantage of the electrical impedance of resonance inherent to piezoelectric transducers. 
         [0151]      FIG. 38  provides a general illustration of a particular embodiment of the invention, wherein a coring tool is utilized as the transfer device. The coring tool  1301  is a thin-walled stainless steel tube (25.5 standard gauge hypodermic tube, 9 mm in length). The coring tool  1301  contains an internal piston  1302  that is a stainless steel rod (0.34 mm in diameter, 10 mm in length) that slides through the tube to eject a plug  1303  of powder. The coring tool  1301  is securely mounted onto a fixture  1304  that is connected to a set of x-  1310 , y-  1311 , and z-  1312  linear actuators. The actuators manipulate the coring tool in and out of a powder bed  1313  to extract a plug of powder. Further details of the coring method and apparatus are given in Example 1. 
         [0152]    In the embodiment shown in  FIG. 38 , a piezoelectric ceramic actuator  1305  (Piezo Systems, Cambridge, Mass., Part No. T220/A4-203Y) is affixed between the coring tube  1301  and the fixture  1304 . When the internal piston  1302  is withdrawn from the tube  1301 , a swept-sine voltage signal, 2 V peak-to-peak between 6.3 kHz and 7.1 kHz, is generated by a function generator  1308  (Model 33120A, Agilent, Palo Alto, Calif.) and applied to the piezoelectric actuator which causes the tube to vibrate. The displacement of the coring tube  1301  in the direction perpendicular to its length is measured with a laser displacement sensor  1309  (e.g., Model LC-2420 by Keyence Corp of America, Woodcliffe, N.J.). For each measurement, 12 consecutive frequency spectra are acquired using commercial data-acquisition hardware (Model #PCI-6052E DAQ board, National Instruments, Austin, Tex.) and customized software (LabVIEW™ Sound and Vibration Toolset, National Instruments, Austin, Tex.). The spectra are averaged linearly with 25% overlap to reduce spectral noise.  FIG. 39  shows a typical frequency response of the coring tube when it is empty. The peak  1315  in the spectrum indicates that the resonant frequency of the tube is about 6.8 kHz. 
         [0153]    When the transfer device, or in this case the coring tube  1301 , captures a small amount of solid or releases a small amount of solid, its resonant frequency will shift from its original value. For example,  FIG. 40  shows a 140 Hz increase in the resonant frequency of a coring tube when a solid pellet weighing 62.2 micrograms is dispensed by the coring tube. Therefore, two frequency measurements are made to resolve the mass of the amount added or subtracted from the transfer device. In this embodiment, the relationship between the shift in resonant frequency and the amount of mass dispensed by the coring tube is determined by a calibration procedure. During calibration, the shift in resonant frequency is measured for several different samples whose masses are determined off-line by a conventional microbalance. For the system described in  FIG. 38 , linear regression by least-squares fitting was performed on the calibration data to determine the following correlation (2): 
         [0000]        m= 3040×( f   0   −f   m )/ f   0 −0.66  (2) 
         [0000]    where m is the dispensed mass expressed in micrograms, and f m  and f 0  are the resonant frequencies of coring tube expressed in Hertz, before and after the mass is dispensed, respectively.  FIG. 41  illustrates strong agreement between the calibration curve and experimental data from weighed quantities of pharmaceutical powder, such as acetaminophen and naproxen, ranging from 26 micrograms to 38 micrograms. 
         [0154]      FIG. 42  illustrates another embodiment of the invention, wherein the transfer device is an electrode assembly  1306  that attracts dielectric particles  1316  to its tip surface by imposing a non-uniform electric field near the particles. This phenomenon is scientifically referred to as dielectrophoresis and does not require particles to be charged in order to manipulate them. In dielectrophoresis, when the permittivity of a dielectric particle is greater than that of its surrounding medium, a non-uniform electric field causes uncharged dielectric particles to move towards regions of stronger electric field intensity, regardless of the polarity of the field. 
         [0155]    There are various means by which a non-uniform electric field can be generated. Configurations suitable for use in the invention will be readily apparent to those of ordinary skill in the art. Examples of suitable configurations include, but are not limited to, concentric electrodes, parallel electrodes, and interdigitated electrodes. Increasing the number of electrodes or the perimeter of an electrode will tend to increase the amount of solid attached to it, since the electric field is usually greatest at the boundary or edge of an electrode. 
         [0156]    Depending on the complex permittivity of the particles and the surrounding medium, the strength of the electric field necessary to attract and hold the particles will also depend on their size and nature. However, electric fields used in typical embodiments of the invention range in strengths from about 10 5  V/m to about 10 8  V/m, from about 10 6  V/m to about 10 7  V/m, or from about 2×10 6  V/m to about 5×10 6  V/m. Specific transfer devices and methods of their manufacture and use that may be used in methods and devices of the invention are disclosed in U.S. patent application Ser. No. 09/976,835, filed Oct. 12, 2001, the entirety of which is incorporated herein by reference. 
         [0157]    In the particular embodiment shown in  FIG. 42 , an assembly  1306  of two concentric metal electrodes (FHC Inc., Bowdoinham, Me., Part No. CBHFM75) is used as the transfer device. A high voltage power supply  1314  (Trek Inc., Medina, N.Y., Model No. 623B) applies positive voltage to the inner electrode while the outer electrode is grounded to create a non-uniform electric field at the tip of the assembly. The electrode assembly is supported by a fixture  1307  which is mounted to a set of x, y, and z linear actuators. The actuators manipulate the electrode assembly toward a powder bed  1315  to extract a controlled amount of dielectric powder  1316 . 
         [0158]    Referring to  FIG. 42 , the mechanical response of the transfer device is generated using a thin piezoelectric ceramic actuator  1305  (Piezo Systems, Cambridge, Mass., Part No. T220/A4-203Y) affixed between the base of the electrode assembly and the fixture. A swept-sine voltage signal, 1 V peak-to-peak between 3.6 kHz and 4.0 kHz, is generated by a function generator  1308  (Model 33120A, Agilent, Palo Alto, Calif.) and applied to the piezoelectric actuator to excite the electrode assembly. The displacement on the electrode assembly in the direction perpendicular to its length is measured with a laser displacement sensor  1309  (Keyence Corp., Woodcliff Lake, N.J., Model No. LC2420A). Here, a small piece of specular material  1317  (3M Radiant mirror film) is epoxied on the tip of the transfer device to aid in the measurement. 
         [0159]    For each measurement, 10 consecutive frequency spectra are acquired using a commercial dynamic signal analyzer (Hewlett Packard, Model 35660A) and averaged linearly with 50% overlap to reduce spectral noise.  FIG. 43  shows a typical frequency response of the electrode assembly. The peak  1318  in the spectrum indicates that the resonant frequency of the electrode assembly is about 3.7 kHz. In this embodiment, the relationship between the shift in resonant frequency and the amount of mass captured by the electrode assembly is determined by a calibration procedure. During calibration, the shift in resonant frequency is measured for several different samples whose masses are determined off-line by a conventional microbalance. For the system described in  FIG. 42 , linear regression by least-squares fitting was performed on the calibration data to determine the following correlation (3): 
         [0000]        m= 6968×( f   0   −f   m )/ f   0 −0.0586  (3) 
         [0000]    where m is the captured mass expressed in micrograms, and f 0  and f m  are the resonant frequencies of electrode assembly expressed in Hertz, before and after the mass is captured, respectively.  FIG. 44  illustrates good agreement between the calibration curve and experimental data from weighed quantities of pharmaceutical powder, such as aspirin and avicel, ranging from 17 micrograms to 90 micrograms. 
         [0160]    While the invention has been described with respect to particular embodiments, it will be apparent to those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention as recited by the appended claims.