Bead manipulating chucks with bead size selector

Bead manipulating chucks for selective pick up and discharge of polymer beads for chemical synthesis or analysis, whereby bead collection zones are recessed from bead contact surfaces. The strong dependence of the electrostatic image force on bead overall diameters provides a mechanism that sharply selects bead sizes that are successfully attracted and retained by the bead manipulating chuck. In this way, the bead manipulating chuck acts as an electrical analog to a low pass filter, only attracting and retaining beads of an overall diameter lower than a selected value.

The present invention is directed to devices for electrostatically picking 
up and dispensing beads in a spatially resolved manner. Specifically, this 
disclosure describes electrostatic bead transporter chucks using specific 
geometries to serve as bead size discriminators and selectors. 
Electrostatic bead transporter chucks can be used to pick up, manipulate, 
transport, and then discharge or place beads or objects for use in 
creating pharmaceutical or chemical compositions, or in performing assays 
or chemical analysis. 
Bead transporter chucks act as clamps to hold or retain an object or 
objects. Bead transporter chucks provide superior performance for 
manipulating synthetic beads having, for example, typical diameters of 
100-300 microns, such as are used in chemical processes, such as 
combinatorial chemistry for solid phase synthesis, or in an assay using 
PCR (polymerase chain reaction) or other processes. In combinatorial 
chemistry, a multi-well array such as a microtiter plate allows screening 
or synthesis of many compounds simultaneously. 
For example, bead transporter chucks allow deposition of beads on an array 
in a manner that is faster and more reliable than by the use of 
micropipettes, which can be inefficient, tedious, and time consuming. 
Another application for bead transporter chucks is synthesis of 
pharmaceutical compositions, especially when used to combine compounds to 
form compositions to be packaged into administration forms for humans or 
animals. 
Beads containing one or more active ingredients can be deposited onto 
carriers or substrates to make pharmaceutical dosage forms. Such beads can 
take the form, for example, of [1] a powder, such as dry micronized forms 
made by air jet milling processes, where overall particle dimensions can 
be, for example, in the 1 to 10 micron range usefil for dry powder 
respiratory administration of medicaments, with 4-8 microns preferred, [2] 
microspheres; [3] extremely small structures, including fullerenes, 
chelates, or nanotubes; or [4] liposomes and fatty droplets formed from 
lipids or cell membranes. 
The use of bead transporter chucks provides a customized and precise method 
for formulating drug compositions. The transporter can be used when 
merging adjacent substrates carrying active ingredient to form multidosage 
packs, in which dosage can decrease or increase from one individual unit 
to the next, as in hormone-based (e.g., birth control) drugs or antibiotic 
remedies. Using an electrostatic bead transporter chuck, dosages can be 
easily established or determined by the number and/or type of beads 
dispensed onto each pharmaceutical carrier. Using bead transporter chucks 
to place active ingredients into pharmaceutical compositions can give high 
repeatability and is also advantageous when the active ingredients are not 
compatible, such as when the active ingredient is poorly soluble with the 
carrier, or where a formulation or carrier negatively affects the 
bioavailability of the active ingredient. 
Although emphasis is placed in this disclosure on electrostatic bead 
transporter chucks using electric fields for bead retention and/or 
release, the teachings given here can be applied to chucks using other 
phenomena, such as the use of compressed gas or vacuum or 
electrically/chemically switchable adhesives, in controlling beads. 
Electrostatic holding mechanisms, however, are far more benign to delicate 
bead structures than traditional mechanical techniques, particularly when 
manipulating biologically active compounds where crushing, contamination, 
or oxidative damage should minimized or eliminated. 
The present invention can also be used in conjunction with acoustic bead 
dispensers, where acoustic energy, provided by a speaker or piezoelectric 
device, is used to great advantage in bead control, that is, propelling 
and/or tribocharging beads prior to, and especially during, electrostatic 
manipulation. Tribocharging the beads, as known in the art, and described 
below, is efficient and less damaging to the beads than corona or plasma 
charging, which typically requires high applied voltages of around 5 kV. 
Often, the sonically vibrating membrane used in such an acoustic bead 
dispenser can itself be used to tribocharge the particles, eliminating the 
need to charge the beads prior to their entry into the acoustic dispenser. 
The use of acoustic dispensers allows polarity discrimination of beads, 
where wrongly charged beads are discouraged from being retained by the 
bead transporter chuck. 
In the course of using bead transporter chucks for creating pharmaceutical 
or chemical compositions, or in performing assays or chemical analysis, 
certain problems arise and certain requirements have been identified. 
Bead transporter chucks can offer precision in being able to have one, and 
only one bead attracted, transported, and discharged for each bead 
transporter chuck, or for each well, pixel, or individual spatial element 
of the bead transporter chuck. In many cases, each pixel can be considered 
a tiny bead transporter chuck that is selectively and independently 
controlled, such as planar chucks having individually addressable x and y 
coordinates. This includes individually addressable pixels for different 
(multiple) bead types. 
Beads manipulated by suitable bead transporter chucks are easily and 
controllably releasable, with wrongly charged beads (objects or beads 
having a charge of the opposite polarity desired) not occupying bead 
retaining or collection zones on the bead transporter chuck. Such bead 
transporter chucks function well for a wide range of bead diameters, 
including beads with general dimensions of 100 microns and up, and also 
including porous or hollow beads that have high charge/mass ratios. These 
bead transporter chucks also offer durability and re-usability, and good 
ease-of-use, including having selectively or wholly transparent elements 
for easy movement and alignment of the chuck with intended targets or 
carriers. 
However, when using bead transporter chucks for chemical analysis or 
synthesis, it is desirable to select a narrow range of eligibility for 
overall bead diameters or sizes to be attracted, retained, and selectively 
discharged by the bead transporter chuck. 
In preparing pharmaceutical compositions, for example, it is important to 
meet established standards. Section 501(b) of the United States Food, 
Drug, and Cosmetic Act (Title 21) deems an official drug to be adulterated 
if it fails to conform to compendial standards of quality, strength or 
purity. Standards and test methods have been established for such 
characteristics as potency, sterility, dissolution, weight variation and 
content uniformity. Favorable experience with these factors should be 
demonstrated for drug approval, and weight variation and content 
uniformity can be affected by the distribution of overall bead diameters 
used in synthesis, especially since the amount of active ingredient in 
beads is usually proportional to their surface areas or volumes, which are 
more drastically affected by variations in bead sizing. 
Methods for use of bead transporter chucks and acoustic bead dispensers are 
set forth in Sun, "Chucks and Methods for Positioning Multiple Objects on 
a Substrate," U.S. application Ser. No. 08/630,012, filed Apr. 09, 1996 
now U.S. Pat. No. 5,788,814; Sun et al., "Electrostatic Chucks," U.S. 
application Ser. No. 08/661,210 filed Jun. 10, 1996 now U.S. Pat. No. 
5,858,099; Pletcher et al., "Method and Apparatus for Electrostatically 
Depositing a Medicament Powder Upon Predefined Regions of a Substrate," 
U.S. application Ser. No. 08/659,501, filed Jun. 06, 1996; and Sun et al., 
"Acoustic Dispenser," U.S. application Ser. No. 08/661,211 file Jun. 10, 
1996 now U.S. Pat. No. 5,753,302. 
Bead transporter chuck designs that use flat or undifferentiated bead 
contact surfaces and bead collection zones to pick up and discharge beads 
generally do not discriminate, or can only weakly discriminate, among bead 
sizes or diameters that have access to the bead contact surfaces. With 
little or no explicit or physical discrimination in bead size, a broad 
range of bead diameters can be attracted to and picked up by the bead 
transporter chuck. While bead size can, in principle, be controlled at 
other stages of a process, the present bead transporter can advantageously 
provide for size selectivity. Thus, for example, the bead transporter can 
provide for secondary quality control for bead size. 
Because of this wide distribution of overall bead diameters retained during 
operation of the chuck, the density of pixels or individual bead 
collection zones per unit area of the bead contact surface achieved in a 
chuck design can be low. If, for example, a bead transporter chuck design 
or configuration has pixels or individual bead collection zones placed too 
close together, then during operation of the chuck, some bead collection 
zones can remain vacant, as these zones are partially blocked by large 
beads retained in neighboring zones. Since a bead per bead collection zone 
is the goal, this is unacceptable. 
When using the bead transporter chuck to perform synthesis, a wide 
distribution in bead diameters--size distributions with .+-.30% standard 
deviations are not uncommon--makes close packing, such as hexagonal close 
packing, difficult to achieve. Hexagonal close packing can be important in 
the manufacture of pharmaceutical compositions, where high bead density 
per unit area can be desirable, as discussed below. 
Alternatively, when using the bead transporter chuck to perform assays, 
chemical analyses or other chemical processes, the distribution of overall 
bead diameters manipulated by the chuck can lead to even wider surface 
area and volume distributions that can render the assays or analysis 
qualitative, not quantitative. Even a 10% uncertainty in overall bead 
diameter can translate approximately to a 21% uncertainty in bead surface 
area, and a 33% uncertainty in bead volume or mass. 
Currently, separation by bead sizes is done by mechanical sieving, such as 
by using gravity fed physical sieves or meshes. A typical size 
distribution or range obtained using sieving is 20% of the average bead 
diameter (D.sub.average). One problem is that beads sorted in this way 
undergo physical rubbing and scraping, which can damage the beads. Another 
problem is that during sieving, beads get trapped in the sieve, mesh, or 
screen used. This clogging can be a serious problem, as beads trapped can 
be difficult to retrieve, or can emerge after bead damage or loss of 
active ingredient has occurred. 
It is therefore desirable to separate beads according to their overall 
diameter or size, using electrostatic techniques during the course of 
electrostatic bead transporter chuck operation. The higher the desired 
densities of bead collection zones per unit area on the bead contact 
surface, the more important bead size selection and discrimination becomes 
for achieving close packing. For certain chemical processes using the 
chucks, bead size selection is essential for quantitative results. 
SUMMARY OF THE INVENTION 
The problems of bead sizing are addressed in this invention by introducing 
bead manipulating chuck geometries that offer narrow specificity in 
overall bead sizes or diameters. Rather than use casually chosen 
geometries for the bead contact surface and bead collection zones, 
Applicant has discovered that sensitive physical mechanisms can be 
exploited that give a narrow bead diameter specificity. 
Bead manipulating chucks using geometries described herein can be used, in 
effect, as the electrical analogue to low pass filters to discriminate 
among bead sizes--that is, they can be used to attract, retain, and later 
discharge--in effect, select--only beads below a certain overall diameter. 
Samples can be generated possessing a narrow bead size range using 
successive iterations if necessary, creating bead classes that have tight 
size ranges or tolerances, making them acceptable candidates for creating 
or forming the active ingredients in administration forms. 
In one embodiment, a bead manipulating chuck for attracting beads to a bead 
collection zone on a bead contact surface, and for retaining and 
discharging beads from the bead collection zone, is disclosed whereby one 
or more bead electrodes are provided for selectively establishing a bead 
attracting field to a bead collection zone. The bead collection zone is 
recessed from the remainder of the bead contact surface, and configured 
and positioned with respect to the bead contact surface such that the 
resultant electrostatic image force generated between the bead and the 
surface of the bead electrode for a given bead charge is lower than that 
for beads of higher than a selected overall diameter. 
In another embodiment, the bead contact surface comprises a shield material 
on the bead contact surface, where the shield material is shaped and 
configured to allow beads to be influenced by the bead electrode and to 
allow the bead collection zone to be or remain recessed. Optionally, a 
dielectric can be positioned between the bead electrode and the bead 
contact surface. 
The bead manipulating chuck can have its bead electrode positioned for 
exposure to the bead contact surface, with or without the dielectric. The 
bead electrode can also comprise a bus electrode to serve as a connecting 
bus for the bead electrode. This allows two or more bead electrodes to be 
connected to the bus electrode and the bus electrode to be configured to 
allow x-y addressing of the bead electrodes to control individually and 
selectively two or more bead collection zones. 
Also disclosed are methods for using the bead manipulating chuck to 
attract, transport and dispense beads, and to perform bead size sorting.

DEFINITIONS 
The following definitions shall be employed throughout: 
"Bead" or "beads" refers to any material thing such as a particle, object, 
tablet or receptacle, capable of being manipulated. This includes spheres 
or beads made from polymer and reactive polymer masses, such as 
styrene-based polymers used in the Merrifield type of solid-phase 
synthesis. 
"Bead electrode" connotes any electrode meant to attract and retain 
materials things such as beads. Upon reducing or reversing of the 
electrical potential applied to it, a bead electrode can selectively allow 
discharge or release of a bead or beads retained. 
"Bead contact surface" includes all surfaces of the bead manipulating chuck 
that are accessible to bombardment, contact or exposure to beads, 
regardless of whether such access is physically encouraged or discouraged. 
However, when discussing specifically the bead collection zone (see 
definition below), the bead collection zone can then be described 
separately from the remainder of the bead contact surface. 
"Bead collection zones" includes surfaces of the bead contact surface at 
which bead attracting fields generated by bead electrodes attract and 
favor retention of a bead. In preferred embodiments of the invention, the 
bead collection zones are found at holes, apertures, or recessed areas of 
the bead contact surface, and these recessed areas are sized to favor 
retaining of beads of a selected size range or shape. 
"Conductor" and "electrode" shall include surfaces or sets of surfaces, 
continuous or non-continuous, that are capable of carrying electric 
current. 
"Dielectric" refers to any dielectric material, such as electric insulators 
in which an electric field can be sustained with a minimum power input; 
the term is applied generally such that solid metals, if manipulated to 
meet this definition, for example with a radio frequency applied voltage, 
can be considered dielectrics. This dielectric material need not be solid 
(e.g., it can be hollow) and it can be made up of substructures or 
different constituent dielectric subparts or material types. 
In the present context, "hexagonal close packing" refers to 2-dimensional 
packing structures where the location of bead collection zones in adjacent 
rows are offset to allow better use of the real estate on a bead contact 
surface than would occur if the bead collection zones were in register. 
The phrase does not imply that the bead collection zones or beads at these 
zones are in contact with one another. In some embodiments, it is 
preferred to keep an amount of shield material separating the bead 
collection zones. 
An "image force" is an attractive, electrostatic force resulting from a 
charged object such as a bead coming into the vicinity of a conductor, 
that undergoes a charge redistribution as a result of the proximate 
charged object to create the attractive force. 
"Reducing," such as in the context of reducing applied potentials to bead 
electrodes to allow bead discharge, shall include reduction and reversal 
of polarity of the applied potential, such as going from +500 V to -500 V 
or vice versa 
"Retention sufficient" force, such as image force, is a force sufficient to 
retain a bead at a bead collection zone under the operating conditions of 
a bead manipulating chuck. Such operating conditions can include vibrating 
or otherwise moving the bead manipulating chuck where appropriate for, or 
a consequence of, the process for which the chuck is used, or where 
vibration is applied to assure that weakly attracted beads are not be 
retained. 
"Shield material" refers to electrodes or other material that are used at 
the bead contact surface to shield (at least partially) a charged bead 
from being influenced by attraction fields emanating from a bead 
collection zone, and/or to define and shape (narrow) the local electric 
attraction field to encourage bead retention only in intended bead 
collection zones. 
Regarding electrode orientations, and surrounding dielectrics, the 
invention is sometimes defined using the terms "around," "between," and 
"surrounding," such as where shield electrode 10 is formed around, or 
surrounds, a bead collection zone. When electrodes, conductors, or 
dielectrics are found on different levels or layers of the bead 
manipulating chuck, "around" and "surround" are to be interpreted in view 
of the areas of the bead contact surface to which the electrode or 
structure in question will map to by projecting each point to the nearest 
point on the bead contact surface. 
It is also important to note that although the term electrostatic is used 
throughout this disclosure, no limitation is meant or intended in terms of 
time variations of charge on electrodes and conductors used in the present 
invention. Electrical currents can and will flow in the course of using 
the bead manipulating chucks as described, in order to apply and remove 
electric charge as required. Potentials refer to electric potentials or 
applied voltages. 
DETAILED DESCRIPTION OF THE INVENTION 
Referring to FlG. 1, a cross-sectional view of a portion of one bead 
manipulating chuck according to the present invention is shown. The figure 
shows the structures for a single bead collection zone. The lower portion 
of this figure shows shield material 10 which is applied to one face of 
dielectric layer D in a parallel plane using any number of techniques 
known in the att, such as laminating, powder deposition, vapor deposition 
or thin film deposition, such as magnetron sputtering or electron bean 
evaporation. Shield material 10 can be an electrode (i.e., conductor) or a 
dielectric, as discussed below. In certain embodiments, the shield 
material is preferably an electrode. 
As shown in the figure by way of example only, shield material 10 is 
affixed to dielectric layer D using an adhesive layer A, using any 
adhesive capable of forming a mechanical bond. Dielectrics can include, 
for example, commonly available materials such as Corning Pyrex 7740 glass 
(high melting point borosilicate glass, Corning Inc., Corning, N.Y.), for 
instance with a thickness of about 10 to about 50 microns. The shield 
material 10 is formed having apertures (as shown, by way of example). One 
such aperture allows for establishing a bead collection zone BCZ, at the 
face of dielectric layer D. Generally shield material 10, and exposed 
portions of dielectric layer D form a bead contact surface BCS that is 
accessible to bombardment, contact or exposure to beads, such as from a 
bead dispenser or container, not shown. The bead collection zone BCZ 
established is recessed from the remainder of bead contact surface BCS. In 
order to use applied voltages to establish an attraction field E.sub.a, 
which is illustrated pointing toward the bead collection zone BCZ, a bead 
electrode 9 is provided at the other face of dielectric layer D. 
Although the bead collection zone BCZ is shown as being flat, it can also 
be beveled, bowl-shaped, or have any other profile that can facilitate 
bead attraction, retention, and discharge. 
Electric fields in this and later figures are shown using the standard 
convention, indicating roughly the direction of the force on a positive 
test charge. For actual examples of applied voltages and bead manipulating 
chuck operation in this disclosure, a working convention is adopted that 
negatively charged beads are to be attracted and later discharged. When 
manipulating positively charged beads, however, one can simply reverse the 
applied voltages from those given in the discussion below. 
As shown, bead electrode 9 is not exposed to the bead contact surface BCS 
or the bead collection zone BCZ. The electric field, however, generated by 
a potential applied to bead electrode 9 can emanate through dielectric 
layer D. with the net electric field generated diminished by electric 
polarization in dielectric layer D, depending on its dielectric constant 
.epsilon., which can be anisotropic. See Classical Electrodynamics 2nd Ed, 
John David Jackson, .COPYRGT.1975, John Wiley & Sons, New York. 
A voltage can be applied to bead electrode 9 relative to shield material 10 
or relative to another surface in the bead dispenser or container to allow 
attraction of beads to the bead collection zone BCZ. Bead electrode 9 can 
serve to provide an attraction field for a plurality of bead collection 
zones, but only one bead collection zone is shown for illustration. 
To aid in visual confirmation of bead capture at the bead collection zone 
BCZ, a hole (not shown) can be provided through bead electrode 9 and 
dielectric layer D. For a transparent or translucent dielectric layer D, 
such a hole provides a visual or optical monitor sight to verify if a bead 
is being retained. This allows for automated verification of bead 
occupancy in the bead collection zone, using known sensors to determine 
the hole opacity in terms of percent light transmission. For example, the 
light transmitted through such a hole can be optically mapped onto an 
array detector such as a charge-coupled device (CCD), an intensified CCD 
array, a focal plane array, or photodiode array. The array detector can 
be, for example, a CCD (such as that available from DALSA, Inc. (Easton 
Conn.), Sarnoff Corporation (Princeton N.J.) or Princeton Instruments 
(Trenton N.J.); an intensified CCD array (such as that available from 
Princeton Instruments, Hamamatsu Corp. (Bridgewater, N.J.) or Photometrics 
Ltd. of Tucson, Ariz.); a focal plane array (such as that available from 
Scientific Imaging Technologies, Inc. (Beaverton, Oreg.), Eastman Kodak 
Co., Inc. (Rochester N.Y.) or Sarnoff Corp.); a photodiode array (such as 
that available from Reticon Corp. (Sunnyvale Calif.), Sensors Unlimited, 
Inc. (Princeton N.J.) or Hamamatsu); or a photodetector array (such as 
that available from FLIR Systems Inc. (Portland Oreg.), Loral Corp. (New 
York N.Y.) or Hughes Electronic Corp. (Los Angeles Calif.)). 
When grounded or biased to a polarity similar to the beads to be 
manipulated, shield material 10 can discourage beads from being attracted 
or retained at any locations on the bead contact surface BCS other than 
the intended bead collection zone BCZ. However, shield material 10 can 
comprise any nonconductive material such as an insulator or dielectric. 
In lieu of dielectric layer D, air or the ambient gas or vacuum can be used 
as a dielectric or insulator. In this case, insulated mechanical standoffs 
or other fasteners can be used to hold bead electrode 9 in the same plane 
as, but offset from, shield material 10. This would expose one or both of 
bead electrode 9 and shield material 10 directly to the bead contact 
surface. 
Fabrication techniques for forming conductive layers and electrodes in this 
disclosure can vary considerably, as any known technique satisfying modest 
electrical and mechanical requirements can be used. Nearly any metal can 
be used, for example, to form bead electrode 9 and shield material 10, 
which can comprise thermally or electromagnetically deposited metals such 
as indium tin oxide, brass, platinum, copper, or gold, of any usefull 
thickness, but preferably of about 1000 Angstroms to about 10 microns 
(100,000 Angstroms) in thickness. The same is true for dielectric layer D 
or laminates--the materials used can be of any type compatible with 
surrounding electrodes, and can have sufficient dielectric strength to 
withstand anticipated voltages applied. Such dielectrics include, for 
example, ceramic materials; silicon dioxide; alumina; polyimide resins and 
sheets or other suitable polymers; metallic oxides, such as aluminum oxide 
and titanium oxide; and titanates of calcium and magnesium. Dielectric 
layer 13 can range in thickness, for example, from about 10 Angstroms to 
about 1000 microns. Many of these fabrication methods do not require use 
of adhesive layer A. 
Now referring also to FIG. 2, a surface bottom view of the bead 
manipulating chuck of FIG. 1 is shown, with the shield material 10 now 
shown configured for sixteen pixels or bead collection zones, by way of 
sixteen apertures in shield material 10. Each bead collection zone thus 
produced exposes dielectric layer D to the bead contact surface, as shown. 
Spacing of the bead collection zones can vary, depending on the number and 
size of beads to be manipulated. For example, the entire surface of shield 
material 10 as shown, with all sixteen pixels or bead collection zones, 
can be a square of sides 49 mm in length; or it can be much smaller, say, 
5 mm square, or 1.0 mm square, for manipulating small beads for placement 
on a smaller substrate, such as a pill or capsule. Hexagonal close packing 
is preferred, as discussed below. 
The recesses in the bead contact surface are illustrated as circular in 
shape, as in a preferred aspect of the present invention. Other shapes, 
however, are useful, as indicated by empirical and geometric 
considerations, in a particular process. Oblong shaped recesses, for 
example, can be useful for oblong-shaped beads. 
Now referring also to FIG. 3, a cross-sectional view like that shown in 
FIG. 1 is given, with a bead (Bead) retained in the bead collection zone 
BCZ. For illustration purposes, the bead shown is of a particular size 
suitable for the bead manipulating chuck graphically shown. Specifically, 
the bead shown has a diameter at the upper end of the range of diameters 
that will allow the bead to touch the edge of the exposed portion of 
shield material 10 and dielectric layer D simultaneously. Due to geometric 
considerations, this corresponds to the maximum bead size for which the 
electrostatic image force does not drop significantly for a given bead 
charge q, as will be discussed. As discussed more fully above, the image 
force is an attractive electrostatic force tending to attract a charged 
bead due to charge redistributions in nearby conductors. In this case, the 
image force is typically that due to the charge of the bead and a charge 
redistribution or polarization in the bead electrode. 
The particular geometry shown by way of example allows for bead size 
discrimination, and we can approximate the discrimination characteristics 
by isolating geometries that contribute to a bead size selection process. 
Bead collection zone BCZ is shown having an overall diameter D.sub.zone, 
while dielectric layer D is shown having a thickness t.sub.D. The bead 
collection zone BCZ is recessed from the remainder of bead contact surface 
BCS, and to characterize this, note that as shown, t.sub.1 is the 
thickness of shield material 10, while t.sub.2 is the thickness of the 
adhesive layer A. 
These thicknesses, t.sub.1 and t.sub.2, add together to give an overall 
recession distance, T.sub.recession, of the bead collection zone BCZ 
relative to the bead contact surface BCS: 
EQU T.sub.recession =t.sub.1 +t.sub.2 (1) 
If bead collection zone BCZ is beveled, bowl-shaped, or has any non-flat 
profile to further favor retention of beads of a particular size, 
T.sub.recession can more generally be measured in other ways, such as by 
measuring the distance between the center of the bead collection zone BCZ 
and the plane of the exposed portion of the shield material 10 at the bead 
contact surface BCS. Since adhesive layer A is optional, T.sub.recession 
can consist simply of the thickness of shield material 10 alone, or of the 
thickness of the shield material and another intermediate layer. 
Now referring also to FIG. 4, a cross-sectional view similar to that of 
FIG. 3 is shown, but where the bead shown retained at the bead collection 
zone is larger than that of FIG. 3. Note t the larger bead shown here has 
a thin air gap of width t.sub.gap, as shown, between the bead top surface 
and dielectric layer D. This air gap can be a gap in air, or a gap in the 
ambient gas or vacuum environment in which the bead manipulating chuck 
operates. In the figure, the dielectric layer D is shown having a large 
thickness for illustration purposes; in practice, it can be quite thin, 
for example, about 10 to about 20 microns. This thinness accentuates the 
importance of the air gap, as will be seen below. 
It is important to note that particle charging--whether by triboelectric 
and contact transfer, corona charging, thermionic and field emission 
charging or other method typically occurs essentially at the particle 
surfaces. These surface effects are well known, and are aided by electric 
polarization, that is, induced surface charge in response to an applied 
electric field. Polarization is ubiquitous in nature. A charged rod, for 
example, will attract uncharged bits of paper due to polarization (charge 
redistribution) in the paper. In attracting and manipulating beads, image 
charges, and electric polarization play a role. To attract and retain 
beads, the total electrical force F.sub.elec generated in the electric 
field E inside a bead source such as a dispenser or container should be 
equal to, or greater than, the force F.sub.grav of gravity: 
EQU F.sub.elec =Eq.gtoreq.F.sub.grav =mg (2) 
Using this invention, a cutoff in electrostatic image force, F.sub.image, 
begins for increasing bead size, roughly after a maximum bead size is 
reached as indicated in FIG. 3, where the bead size is such that the bead 
can just touch both dielectric layer D and shield material 10 at the same 
time. For larger bead sizes than this, a gap (t.sub.gap) occurs. Bead 
collection zone BCZ has a radius 
EQU R.sub.zone =D.sub.zone /2 (3) 
while the charged bead to be attracted, retained, and later discharged has 
a radius 
EQU r.sub.bead =d.sub.bead /2 (4) 
The maximum bead size for which t.sub.gap is zero can by geometric 
considerations and Pythagoras' Theorem be evaluated simply: 
EQU (r.sub.bead).sup..LAMBDA.2 =(R.sub.zone).sup..LAMBDA.2 +(r.sub.bead 
-T.sub.recession).sup..LAMBDA.2 (5) 
which yields 
EQU r.sub.bead =(T.sub.recession.sup..LAMBDA.2 
+R.sup..LAMBDA.2)/(2T.sub.recession) and (6) 
EQU R.sub.zone =[2r.sub.bead T.sub.recession -T.sub.recession.sup..LAMBDA.2 
].sup..LAMBDA.1/2 (7) 
Although a particular bead size cannot touch dielectric layer D, the bead 
will still be held by the electrostatic image force and be retained or 
lowered to some extent This can be experimentally determined, and a simple 
model will illustrate here. Using similar geometric considerations, 
t.sub.gap can be calculated by: 
EQU t.sub.gap =T.sub.recession +[r.sub.bead.sup..LAMBDA.2 
-R.sub.zone.sup..LAMBDA.2 ].sup..LAMBDA.1/2 -r.sub.bead (8) 
Further increases in bead size beyond the critical or maximum bead size 
result in a gap (t.sub.gap) and a sharp reduction in resultant holding 
forces for the charged bead. In the vicinity of the bead collection zone 
BCZ, surface charge shifting (polarization) on the bead plays a large 
role. As the bead approaches the bead collection zone BCZ, and bead 
electrode 9, an image charge of increasing magnitude will accumulate on 
the lower surface of electrode 9. In the vicinity of bead collection zone 
BCZ, the electrostatic image force, F.sub.image, due to this image charge 
is in practice more significant than the force F.sub.elec given above. As 
a gap of thickness t.sub.gap widens, the overall distance between the 
surface charge on the charged bead and the corresponding image charge on 
the lower surface of bead electrode 9 increases. This lowers the 
electrostatic image force, as electric fields by their nature attenuate in 
an inverse square relationship. We can use the following rough model to 
illustrate the dependence of the electrostatic image force on the bead 
size, for a given charge q on a bead. We can roughly approximate the 
critical dependence of the electrostatic image force F.sub.image on 
t.sub.gap and other factors using the electrostatic image force equation, 
which written for the bead as follows: 
##EQU1## 
in the denominate to .epsilon..sub.0 so is the vacuum permittivity; 
.epsilon. is the overall dielectric constant of dielectric layer D; 
(.pi.d.sup..LAMBDA.3 /6) is the bead volume; .rho. is the bead mass 
density in kg/m.sup.3 ; and g is the acceleration due to gravity. This 
gives the electrostatic image force on a bead occupying the bead 
collection zone in units of g. This rough model assumes that the air gap 
of width t.sub.gap and adhesive layer A have the same dielectric constant 
as the dielectric layer D. This is generally an acceptable assumption, 
since the dielectric constant .epsilon. is not responsible for the 
critical dependence of the image charge-induced holding force on bead 
size. 
Without being bound by a particular theory, in certain embodiments it is 
believed that the weaker image force applicable to over-sized beads will 
be sufficient to provide a statistical period of release of these beads 
from bead collection zones, so that beads that of the desired size have an 
opportunity to fill these bead collection zones (and be retained more 
strongly). This steady-states release of over-sized beads allows for size 
selectivity to proceed in essentially one step. This selectivity can be 
exemplified if one makes the simplifying assumption that the process is 
stepwise. Thus, viewed as a stepwise process, if 40% of bead collection 
zones are initially filled with larger beads, and then the over-sized 
beads are released, when these 40% are re-filled with, for example, the 
same ratio, only 16% will be filled with over-sized beads. Three 
iterations leaves only 6.4% filled with over-sized beads, and five 
iterations results in only 1% filled with over-sized beads. 
Alternatively, because the image force can predominate over the attractive 
force due to a potential applied the bead electrode, physical motion such 
as vibration can be used to displace weakly retained beads, thereby 
providing openings for smaller sized beads to fill a given bead collection 
zone. Once an appropriately size bead fills a bead collection zone, the 
stronger image force retaining the bead reduces that beads tendency to 
vacate the bead collection zone. 
In certain aspects of the invention, it may be desirable to adjust the 
potential applied to the bead electrode to further favor release of 
over-sized bead. Thus, in one aspect of the invention, the potential 
applied to the bead electrode can be reduced or terminated after beads are 
initially attracted to the bead collection zones. For example, the bead 
electrode can be grounded. The force tending to retain the beads will be 
lowered for all beads that are of greater diameter than that intended to 
be attracted to the bead manipulating chuck, since the retentive image 
force will be sharply smaller for these larger beads. Accordingly, an 
iterative cycling of potential applied to the bead electrode can (a) 
attract beads, (b) release over-sized beads, (c) again attract beads to 
bead collection zones vacated in step (b), (d) over-sized beads are again 
released, and so forth. 
As discussed more fully below, the bead manipulating chucks of the 
invention can be used in sizing procedures. For instance, a first bead 
manipulating chuck can be used to remove from a collection of beads 
individual beads that are smaller than desired, yielding a second 
collection of beads. Then another bead manipulating chuck can be used to 
collect a narrowly sized collection of beads, with over-sized beads are 
left in the second collection. 
An example of the resulting bead diameter specificity is shown in FIG. 5, 
which shows a Cartesian graphical relationship between individual bead 
overall diameter, in meters, and the resultant electrostatic image force 
produced by a bead manipulating chuck according to the present invention, 
in units of g, the acceleration due to gravity. For this plot, the 
diameter of the bead collection zone, D.sub.zone is 225 microns; the 
charge on the bead is 10.sup..LAMBDA.-12 Coulomb; the thickness t.sub.D of 
the dielectric layer D is 13 microns, with the dielectric layer having a 
simple isotropic dielectric constant .epsilon. of 3.5; the thickness 
t.sub.1 of the shield material 10 is 70 microns; and the thickness t.sub.D 
of the adhesive layer A is 25.4 microns, giving a total recession of the 
bead collection zone, T.sub.recession, of 95.4 microns. The assumed 
density of the beads is 1000 kg/m.sup.3. Making certain idealized 
assumptions with these values, the maximum bead size for which t.sub.gap 
is zero, and for which the electrostatic image force is undiminished, is 
228.07 microns. This target maximum bead size can be termed r.sub.bt (bead 
target). 
As can be seen, the value of the gap thickness t.sub.gap has an unusual and 
unexpected dependence on the electrostatic image force generated by a 
charged bead residing at bead collection zone BCZ. This is due to the 
unusual dependence of the gap thickness t.sub.gap on the bead overall size 
r.sub.bead, and the size of the bead collection zone, R.sub.zone, as given 
above. 
The result is that the recessed bead collection zone BCZ allows that only 
beads which will physically fit there without being pushed out of the bead 
collection zone by interference with the shield material 10 will 
experience a non-diminished electrostatic image force. One can see the 
electrostatic image force drop drastically as the bead size increases. As 
shown in the plot, using the example given above, starting with bead sizes 
for which t.sub.gap is zero, a ninety percent reduction in the 
electrostatic image force occurs for a nine percent increase in bead 
overall diameter. The thinner the thickness t.sub.D of dielectric layer D, 
the greater the enhancement of this effect. 
Those of ordinary skill will recognize that the above calculations provide 
guiding principles, but are based on underlying assumptions which in 
practice can be applicable to varying degrees. Thus, empirical results 
will be influenced by factors such as the degree to which beads vary from 
spherical shape, the degree to which the beads can deform, the solvent 
content of the beads, and the like. 
Available bead compositions are well known in the arr, and are typically 
polymer-based, such as divinylbenzene copolymer, polystyrene; polyethylene 
glycol; or polyethylene glycol graft polystyrene, such as supplied under 
the trade name PEG-PS by PerSeptive Biosystems of Framingham, Mass.; or 
cross-linked polyethylene glycol resin, as supplied by Rapp Polymer GmbH 
of Germany. Beads can be dry, or can have adsorbed a solvent such as an 
aqueous solution, or a fine powder. Beads can also be, for example, dry 
paint or phosphor particles, or any other powders that can be 
triboelectrically charged. 
Beads can be charged prior to their application to the bead manipulating 
chuck, for example, using plasma charging, or by the use of tribocharging 
(rubbing or contact charging), or other charging methods, as known in the 
art. Materials that can be used for tribocharging include 
polytetrafluoroethylene (TEFLON.RTM.), and polymers of 
chlorotrifluorethylene, chlorinated propylene, vinyl chloride, chlorinated 
ether, 4-chlorostyrene, 4-chloro4-methoxy-styrene, sulfone, 
epichlorhydrin, styrene, ethylene, carbonate, ethylene vinyl acetate, 
methyl methacrylate, vinyl acetate, vinyl butyral, 2-vinyl pyridine 
styrene, nylon and ethylene oxide. See, for example, "Triboelectrification 
of Polymers" in K. C. Frisch and A. Patsis, Electrical Properties of 
Polymers (Technonmic Publications, Westport, Conn.), which is hereby 
incorporated by reference in its entirety. Also see Handbook of 
Electrostatic Processes, Jen-shih Chang, Arnold J. Kelly, and Joseph M. 
Crowley, eds., Marcel Dekker, Inc., New York, .COPYRGT.1995. For example, 
polytetrafluoroethylene and polyethylene and other materials that become 
negatively charged tend to create a positive charge on the beads. Nylon 
and other materials that become positively charged will tend to create a 
negative charge on the beads. When using mechanical shaking to tribocharge 
beads, it is preferred that the ratio of the amount or mass of 
tribocharging material used to charge the beads to the amount or mass of 
beads is such that the respective total surface areas of the tribocharging 
material and the beads are about equal. 
Now referring to FIG. 6, a cross-sectional view of part of a bead 
manipulating chuck structurally similar to that shown in FIGS. 1, 2, 3, 
and 4, is given, showing structures that form three bead collection zones, 
and including a bead dispenser mesh and grid, shown symbolically. At the 
lower end of this figure is a bead dispenser grid (GRID) shown at a 
distance D from the bead contact surface BCS. Just under the bead 
dispenser grid is bead dispenser mesh (MESH). In this example, charged 
beads must pass through the bead dispenser mesh and grid prior to 
contacting the bead manipulating chuck However, beads can be introduced 
into the space between the bead dispenser mesh and grid, or in the space 
between the grid and the bead manipulating chuck. When conductive, the 
grid and mesh can also serve as driving electrodes to electrically propel 
charged beads toward the bead contact surface of the bead manipulating 
chuck. Any number of mesh types can be used, such as a #270 mesh (Newark 
Wire Cloth Co. Newark N.J.) for particles about 4-6 microns diameter; or a 
#200 mesh for particles of greater than about 6 microns diameter. The bead 
manipulating chuck structure shown is as above, with bead electrode 9 
influencing the three bead collection zones shown. The grid can, for 
example, be a coarse grid having 2 mm diameter holes. 
Various size beads are shown for illustration. For attracting and retaining 
negatively charged beads, for example, one can apply a negative bias to 
the bead dispenser mesh and/or grid, and a positive bias to the bead 
electrode 9, while a grounded shield material 10 (which enhances user 
safety at the bead contact surface) or a negatively biased shield material 
10 helps guide beads to their intended destinations at the bead collection 
zones BCZ. Electric attraction field E.sub.a as shown reflects any 
attractive potential applied to bead electrode 9. 
Generally, there is a discrimination field due to any applied voltage 
V.sub.p applied between the bead dispenser grid and the bead manipulating 
chuck, generally at the bead electrode 9. As an example of bead 
manipulating chuck operation, bead electrode 9 can be biased at +2000 
volts, the bead dispenser grid at -2533 volts, and the bead dispenser mesh 
at -3800 volts, and the shield material 10 grounded (set to 0 volts), for 
manipulating negatively charged beads. This gives an applied voltage 
V.sub.p of 4533 volts total across distance D, and a discrimination field 
roughly equal to V.sub.p /D. This will function in sorting out beads 
according to polarity and charge/mass ratio, with beads of a certain 
charge/mass ratio and correct polarity being encouraged to seat themselves 
at the bead collection zones. The bead dispenser mesh can be located at a 
distance of 3/8" (9.5 mmn) under the bead dispenser grid. Acoustic 
stimulation or other means can be used to propel beads through the bead 
dispenser mesh toward the grid and bead manipulating chuck. Such a 
propelling mechanism can be helpful, since image forces can cause charged 
beads to adhere to conductors. The grid functions to strongly discourage 
positively charged beads from entering the space between the bead 
dispenser grid and the bead manipulating chuck, for even if a positively 
charged bead emerges above the bead dispenser mesh due to its own high 
velocity, the field gradient between the mesh and the grid will further 
discourage its passage through the grid. For the purpose of so 
discouraging transit of beads of an inappropriate charge, the electric 
field between the bead dispenser mesh and grid can be made greater than 
that between the dispenser grid and the bead manipulating chuck. The 
relative field values of interest vary with the distance D selected, and 
with the voltages applied to the mesh, grid and bead electrode 9. Such a 
differential in electric field values is useful when acoustic or other 
means are used to propel beads towards the chuck. 
There is also electric polarization in the beads moving about the space 
between the bead dispenser grid and the bead manipulating chuck, giving 
rise to a polarization field. We can sum this field and the discrimination 
field, and refer to them simply as the polarization and discrimination 
field, E.sub.p ; a sample rough field line is shown, labeled, "E.sub.p." 
The polarization and discrimination field, E.sub.p, is mostly determined by 
the applied voltage V.sub.p between the bead dispenser grid and the bead 
manipulating chuck across an overall distance D shown in FIG. 6, 
EQU E.sub.p .apprxeq.V.sub.p /D. (10) 
E.sub.p is generally--but does not have to be--set to be less than that 
required to lift the beads in the absence of an attraction field from any 
of the bead electrodes: [Steve, please confirm] 
EQU E.sub.p .gtoreq.g/(q/m). (11) 
The field E.sub.p across a the distance D shown is gradual; as mentioned 
above, the electrostatic image force dominates in the vicinity of the bead 
collection zone BCZ. Of course, the shield material 10 can also generate 
an image charge in response to a charged bead in the vicinity, but it is 
believed that the mobility of this image force allows the beads to move 
(e.g., roll) to the bead collection zones. Empirical results indicate that 
the charge on beads is not rapidly dissipated through contact with 
conductive shield material. 
Using the bead manipulating chuck configuration as given in FIG. 6, and 
using the above potentials applied to bead electrode 9, shield material 
10, the bead dispenser grid and mesh, the critical dependence of the 
electrostatic image force on the overall bead diameter can be 
experimentally verified. One can use a 16 pixel chuck such as shown in 
FIG. 2 having a bead collection zone BCZ of diameter D.sub.zone equal to 
225 microns; a thickness t.sub.D of the dielectric layer D of 25.4 
microns, with the dielectric layer having a simple isotropic dielectric 
constant .epsilon. of 2.0; a thickness t.sub.1 of the shield material 10 
of 35 microns; and a thickness t.sub.2 of the adhesive layer A of 25.4 
microns, giving a total recession of the bead collection zone, 
T.sub.recession, of 60.4 microns; a grid, as shown, with 2 nmm diameter 
openings; a #270 fmeness mesh, as shown, and at a distance of 3/8" (9.5 
mm) below the grid. A bead distribution is introduced into the bead 
dispenser, consisting of about 12 mg of 250-300 micron diameter 
polystyrene beads; about 57 mg of 170-220 micron diameter Merrifield 
beads, about 520 mg of 300-350 micron diameter polystyrene beads. 
Using these values in the model given above for the electrostatic image 
force generated as a function of the gap width t.sub.gap, the 
electrostatic image force F.sub.image drops from 100 percent to 25 percent 
as the bead overall diameter goes from 269.9 microns to 309.9 microns. The 
model therefore indicates that the Merrifield beads, with diameters in the 
170-220 micron range, should be picked up and retained by the bead 
manipulating chuck, while most of the 300-350 micron diameter polystyrene 
beads will not, even though they are far more plentiful in the mixture. 
Four trials are undertaken, with deposition times of 5 seconds. During all 
four trials, none of the 300-350 micron polystyrene beads are captured by 
the chuck; one 250-300 micron diameter polystyrene bead is captured; and 
all other beads captured are the Merrifield beads having the 170-220 
micron diameters. 
It should be noted that with the electrostatic bead manipulating chuck 
operating in this way, it is essentially analogous to an electrical low 
pass filter--allowing attraction, retention, and later discharge of beads 
that have overall diameters below the critical or maximum value for which 
t.sub.gap above is zero. 
Overall, bead manipulating chucks according to this invention use field 
guidance so that only around a bead collection zone and bead electrode 9 
will the electric fields be strong enough to raise a bead from the bead 
dispenser or bead dispenser mesh and subsequently guide it toward the bead 
collection zone and optionally, bead hole 69. Once a bead lands there, it 
weakens and shields the electric field in the vicinity and no other beads 
are encouraged to arrive there. 
In the course of using the bead manipulating chucks of this invention, a 
number of operating modes can be used. For bead pickup or retention, a 
bead electrode, either exposed or unexposed to the bead contact surface, 
is electrically biased to attract beads, while the mesh of the bead 
dispenser or other conductive surface can be biased with the opposite 
polarity. Any number of bead electrodes 9 can be used, and they can be 
individually and separately connected by known means to facilitate 
individual and selective addressing in two dimensions. 
During bead pickup, the shield material 10 of the embodiments described in 
FIGS. 1-4 can be held at ground potential, or it can be biased to a charge 
polarity similar to that of the desired beads. The shield material 10 then 
becomes a repulsive field conductor. 
However, even when grounded and not acting in an explicitly repulsive 
manner, shield materials are useful, helping to define and shape the 
attraction field E.sub.a set up by the bead electrodes, particularly 
because the attraction field would otherwise be shaped instead by any 
dielectric material used surrounding the bead electrode, such as 
dielectric layer D. Shield material 10 can be allowed to "float," not 
biased or grounded. Generally however, grounded or not, good results are 
obtained when the shield materials are grounded, or when biased at a 
voltage between that applied to the bead electrode(s) 9 and that applied 
to the bead dispenser mesh (MESH). 
Once attracted and retained, beads on the bead manipulating chuck are 
optionally transported to a substrate, microtiter plate, processing 
equipment or other destination by moving the entire bead manipulating 
chuck, or alternatively, the target substrates or plates or processing 
equipment are brought to the chuck. Beads can then be released or 
discharged in a controlled manner when any or all of the applied voltages, 
such as those given above, are reversed or set to zero. For example, for 
bead release, the bead electrode 9 can be shorted out or grounded (0 
volts), or have an opposite voltage applied. Optionally, when shield 
material 10 is used, it can be biased to be repulsive to beads during bead 
discharge. An acoustic releasing mechanism or process can be used to aid 
in bead discharge and placement. 
When using bead manipulating chucks according to the present invention, the 
temperature is preferably between about -50.degree. C. and about 
200.degree. C., and more preferably between about 22.degree. C. and about 
60.degree. C. Relative humidity can be 0-100 percent, so long as 
condensation does not occur; more preferably the relative humidity is 
about 30 percent. 
There can be multiple bead collection zones for each independently 
controlled bead electrode 9. The dielectric layers used can increase 
safety, and electrical isolation between electrodes and conductors. The 
dielectric layers also reduce fields produced by applied voltages and 
allow retention of beads containing a higher net charge. In addition, the 
dielectric layers also provide structural rigidity and strength to the 
bead manipulating chuck. 
Bead electrodes 9 can comprise any number of separately addressable pixels 
or elements in two directions x and y, each having separately controlled 
bead collection zones. Any number of well known means and structures are 
used to facilitate addressing as is known in the electrical and electronic 
arts. In this way, combinatorial synthesis or analysis can be simplified 
as discussed above. In using the bead manipulating chucks, one can expose 
the bead contact surface of such a chuck to beads; selectively apply 
voltages, such as the voltages given above, for each x-y addressable well, 
pixel, or individual spatial element of the chuck, to attract and retain 
beads selectively at each bead collection zone; then release the beads 
onto a desired destination aligned with the bead manipulating chuck by 
selectively reversing or reducing voltages associated with each bead 
collection zone as required. 
It is also possible that beads attracted by the chuck can become substrates 
for known processes, such as, for example, coating processes including 
processes that apply pharmaceutically active compounds. In one preferred 
aspect, such processed beads are large diameter beads of large overall 
size, say about 3 mm in diameter. Processed beads include oblong shapes, 
made of water soluble film, such as hydroxypropyl methyl cellulose resin. 
See U.S. patent application Ser. No. 08/471,889, "Methods and Apparatus 
for Electronically Depositing a Medicament Powder Upon Predefined Regions 
of a Substrate." filed Jun. 6, 1995 now U.S. Pat. No. 5,714,007, and 
continuation-in-part thereof filed Jun. 6, 1996, Ser. No. 08/659,501, 
which documents are incorporated herein by reference in their entirety. 
Electrostatic chucks can be scaled up for large scale continuous 
manufacturing, such as using a sheet of an edible substrate for use with 
tablets, for example, or a sheet of an inhaler substrate. For example, 
hydroxypropyl methyl cellulose can be used as substrate, such as Edisol M 
Film M-900 or EM 1100 available from Polymer Films Inc. (Rockville Conn.). 
Using an exposed bead electrode 9 the chuck can maintain the charge of a 
pharmaceutical substrate that would otherwise lose its charge. Generally, 
sizing of bead diameters can range from less than about one micron to 
about 1000 microns or larger, about 150 microns is fairly typical. 
With bead size selection now governed by physical design and geometries of 
the bead manipulating chuck, beads can through use of the chuck be sorted 
into groups or lots, which can be of tighter width or diameter tolerances 
than are possible through conventional sieving. This allows meeting, for 
example, a minimum 5 percent content uniformity, which degree of 
uniformity can be important for dosage form approvals. 
Specifically, multiple bead manipulating chucks, each having progressively 
smaller diameter bead collection zones (D.sub.zone), can be used serially 
to eliminate all beads above a certain diameter value. For example, a 
first bead manipulating chuck can be used to capture only beads above 
roughly 280 microns diameter, these retained beads in turn can be 
discharged and delivered to a second bead manipulating chuck whose 
geometries allow capture of only beads below roughly 260 microns; upon 
discharge, these beads in turn can delivered to a chuck set up to capture 
only beads below 240 microns, etc. Then optionally, the resulting beads 
from such a group or lot narrowing process can be delivered to a bead 
manipulating chuck for elimination of all beads below a certain diameter. 
For example, the resulting beads can be delivered to a bead manipulating 
chuck that favors beads of 180 microns and smaller. Beads then captured 
can then be discarded, so as to create a class of beads between 180 and 
240 microns. The process can be refined so that beads in the 220 micron 
range and smaller can be discarded; at that point, the remaining beads 
should be in the 220-240 micron range. 
By this kind of serial capture and release of desired beads with 
successively smaller preferred bead diameters, followed by a winnowing of 
beads smaller than desired by using bead manipulating chucks to discard 
small beads, lots or groups of beads having narrow size ranges of a few 
percent can be realized. Using the invention, one can practice size 
selection using just using two bead manipulating chucks--one to select 
beads of a size under, say by way of example 220 microns--and another to 
discard resulting beads whose size is under, say, 210 microns. 
Bead manipulating chucks of this invention can be fabricated, for example, 
using flexible circuit board manufacturing technology, giving a bead 
collection zone diameter D.sub.zone having manufacturing tolerances of, 
for example, 10 microns or better. In an alternative example, using well 
known semiconductor processing fabrication techniques, bead collection 
zone diameter (D.sub.zone) tolerances of 1 micron or less are achieved. 
To further decrease the net variation in bead widths in a group of beads, 
and to insure in turn that net overall variation in bead surface areas and 
volumes are narrower, the number of beads used in making a single capsule 
or tablet, or in filling a single array in a micro-titer plate, for 
example, can be increased. By using a large sample of beads to make a 
human drug administration form, the standard deviation of bead overall 
width from the mean, D.sub.average, through the use of bead manipulating 
chucks, will drop as the square root of the sample size. Using single 
beads to make tablets, for example, where the beads have a standard 
deviation in overall width or size of 5 percent, gives a standard 
deviation in bead volume of about 16 percent. If, however, 10,000 beads 
are used to make each tablet, this standard deviation is lowered by a 
factor of 100, to 0.16 percent, which is outstanding by present drug 
preparation standards. 
The locations of all pixels or bead collection zones BCZ on the bead 
contact surface are ideally arranged in a "hexagonal close pack" 
structure, as illustrated in FIG. 7, which shows shield material 10 and 
dielectric layer D for an embodiment of the invention. This configuration 
gives the highest density of beads per unit area of the bead contact 
surface to allow as many beads as possible to be manipulated at a time. 
Specifically, the center-to-center distance of the bead collection zones 
BCZs on the bead contact surface is preferably about 1.5 times the 
diameter of the mean bead diameter. This packing further enhances 
selectivity of the bead manipulating chuck at the high end of the 
distribution of bead diameters to be attracted and retained. The exact 
center-to-center bead packing ratio is best determined experimentally. For 
example, a 5 cm.times.5 cm size bead manipulating chuck can selectively 
pick up and discriminate among available bead diameters of beads 
contacting or approaching the bead contact surface, with a capacity for 
about 32,000 bead collection zones that can attract, retain and later 
discharge beads of 200 micron average overall diameters. 
Obviously, many modifications and variations of the present invention are 
possible in light of the above teaching. It is therefore to be understood, 
that within the scope of the appended claims, the invention can be 
practiced otherwise than as specifically described or suggested here.