U.S. patent application number 09/898104 was filed with the patent office on 2002-03-14 for biomedical assay device.
This patent application is currently assigned to Delsys Pharmaceutical Corporation. Invention is credited to Loewy, Zvi, Matthies, Dennis Lee.
Application Number | 20020031477 09/898104 |
Document ID | / |
Family ID | 24134605 |
Filed Date | 2002-03-14 |
United States Patent
Application |
20020031477 |
Kind Code |
A1 |
Loewy, Zvi ; et al. |
March 14, 2002 |
Biomedical assay device
Abstract
The present invention provides an integrated structural unit
that includes a diagnostic form that includes at least one active
ingredient that is present in an amount that advantageously does
not vary by more than about five percent from a predetermined
target amount. In one embodiment, the unit form comprises a
substrate, a deposit that is disposed on the substrate, and a
spreading layer that overlies the deposit and is used to retain and
spread a sample of liquid which is to be assayed. The deposit
comprises a powder, including the active ingredient(s). The
diagnostic form is created via a dry powder deposition apparatus
that electrostatically deposits the powder on the substrate
utilizing an electrostatic chuck and charged powder delivery
apparatus.
Inventors: |
Loewy, Zvi; (Fairlawn,
NJ) ; Matthies, Dennis Lee; (Princeton, NJ) |
Correspondence
Address: |
William Squire
Carella, Byrne, Bain, Gilfillan, Cecchi,
Stewart & Olstein
6 Becker Farm Road
Roseland
NJ
07068
US
|
Assignee: |
Delsys Pharmaceutical
Corporation
|
Family ID: |
24134605 |
Appl. No.: |
09/898104 |
Filed: |
July 3, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09898104 |
Jul 3, 2001 |
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09535522 |
Mar 24, 2000 |
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6287595 |
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09535522 |
Mar 24, 2000 |
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09095616 |
Jun 10, 1998 |
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6303143 |
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Current U.S.
Class: |
424/9.322 |
Current CPC
Class: |
G01N 33/521 20130101;
A61J 3/00 20130101; B05B 5/08 20130101; A61J 1/035 20130101; B65B
1/04 20130101; B65B 1/30 20130101; B65B 11/50 20130101; G01N
33/54386 20130101; A61K 9/70 20130101 |
Class at
Publication: |
424/9.322 |
International
Class: |
A61K 049/00 |
Claims
We claim:
1. A structural unit comprising an integrated diagnostic form, the
diagnostic form comprising: a polymeric substrate; an active
ingredient, electrostatically deposited on the surface of said
substrate; and a porous spreading layer electrostatically deposited
on the active ingredient, said spreading layer comprising particles
of controlled particle size, wherein said spreading layer serves to
retain and spread a sample of liquid which is to be diagnosed.
2. The structural unit of claim 1, wherein said active ingredient
is present in an amount that does not vary from a target amount by
more than about 5 weight percent.
3. The structural unit of claim 2, wherein said substrate comprises
a planar film.
4. The structural unit of claim 3, wherein the particles of the
spreading layer comprise latex beads with a diameter of from about
1 micron to about 200 microns.
5. The structural unit of claim 4, wherein the latex beads have a
diameter of from about 40 microns to about 200 microns.
6. The structural unit of claim 3, wherein the particles of the
spreading layer comprise cellulose acetate or inorganic particulate
materials.
7. The structural unit of claim 3, wherein the distance between the
particles in the spreading layer results in average pore sizes of
from about 1.5 microns to about 50 microns.
8. The structural unit of claim 7, wherein the average pore size is
from about 10 microns to about 30 microns.
9. The structural unit of claim 3, wherein the void volume in the
spreading layer is between from about 60% to about 90%.
10. The structural unit of claim 3, wherein the particles of the
spreading layer are deposited in a uniform layer with a thickness
of at least a monolayer.
11. The structural unit of claim 3, further comprising an
ingredient electrostatically deposited onto, or codeposited with,
the spreading layer, such ingredient selected from the group
consisting of surfactants, carriers, binders, buffering agents,
solvents, and reagents for detection.
Description
Field of the Invention
[0001] The present invention relates generally to unit dosage or
unit diagnostic forms and an apparatus and method for making such
unit forms.
Background of the Invention
[0002] In the pharmaceutical industry, pharmaceutical products
including diagnostic products comprise a container (e.g., a bottle,
a blister pack or other packaging) containing a plurality of "unit
dosage forms" or "unit diagnostic forms." Each of such unit forms
contains a pharmaceutically- or biologically-active ingredient or
ingredients and inert or inactive ingredient(s).
[0003] The pharmaceutically-active ingredient typically forms a
drug. The diagnostic form may comprise a reagent or the like for
use in diagnostic tests, and may be part of a set which includes
several different reagents or active ingredients. Moreover, the
diagnostic form may comprise an antibody, an antigen, or labeled
forms thereof and the like.
[0004] A pharmaceutically- or biologically-active ingredient for
use in a unit form may be supplied as a powder comprising a
plurality of active-ingredient particles. Such active-ingredient
particles are combined with inert or inactive ingredient particles
to form a plurality of "major particles." The major particles are
quite small, with dimensions on the order of microns. Such major
particles are typically combined with one another to create the
final unit dosage or diagnostic form (e.g., tablet, caplet, test
strip, capsule, etc.).
[0005] There may be significant variation in the amount of
pharmaceutically- or biologically-active ingredient in one major
particle and the next. Since a large number of major particles are
required to create a final unit form, the aforedescribed
particle-to-particle variation may result in a substantial
variation in the amount of active ingredient between one unit form
and the next. Thus, any given final form may contain substantially
more or less than a desired amount of active ingredients.
[0006] Destructive analytical screening procedures are
conventionally performed to assess the amount of active
ingredient(s) in final unit forms. Since such procedures destroy
the unit forms, a statistical sampling is performed whereby a
relatively small number of forms per batch are actually sampled and
tested. Such screening procedures disadvantageously provide no
assurance that all forms in a given batch contain a desired amount
of the pharmaceutically- or biologically-active ingredients. In
fact, such statistical methods practically "guarantee" that a
statistically determinable percentage of the forms in each batch
will be out of specification.
[0007] As such, the art would benefit from a method and apparatus
that provides improved control over the active-ingredient content
of unit dosage and diagnostic forms.
SUMMARY OF THE INVENTION
[0008] In one embodiment, the present invention provides a product
comprising a plurality of pharmaceutical unit dosage forms or unit
diagnostic forms (collectively, "unit forms"). Each form includes
at least one active ingredient that is present in an amount that
advantageously does not vary by more than about five percent from a
predetermined target amount.
[0009] In one embodiment, the unit form comprises a substrate, an
active ingredient deposited thereon, and a cover layer that covers
the active ingredient and is joined (e.g., via welding, adhesives,
etc.) to the substrate in the proximity of the active
ingredient.
[0010] In the illustrated embodiments, the product is made via a
dry deposition apparatus that deposits powder/grains on the
substrate. In one embodiment, the apparatus comprises an
electrostatic chuck, a charged powder delivery apparatus, and an
optical detection system. The substrate is engaged to the
electrostatic chuck for the dry deposition of powder. The chuck has
at least one collection zone at which a powder-attracting
electrical field is developed. The charged powder-delivery
apparatus directs charged powder for electrostatic deposition to
the substrate at the collection zone(s). The optical detection
system quantifies the amount of powder deposited.
[0011] In some embodiments, the dry deposition apparatus also
includes an electronic processor for controlling depositions
responsive to sensor inputs. Such sensor inputs advantageously
include one or more deposition sensors that are disposed on or
adjacent to the electrostatic chuck and that provide data
pertaining to the amount of powder deposited. Responsive to sensor
data, the electronic processor adjusts deposition parameters, as
necessary. Controllable parameters include powder flux through the
powder-delivery apparatus and applied voltage at the collection
zone(s).
[0012] In still other embodiments, the present dry deposition
apparatus advantageously includes a variety of other elements that
are described in detail later in this Specification.
Brief Description of the Drawings
[0013] FIG. 1 is an isometric view of a strip package of
pharmaceutical unit dosage or diagnostic forms;
[0014] FIG. 1a is a plan schematic view of a system for making a
product according to one embodiment of the present invention;
[0015] FIG. 2 is a sectional elevation view of a portion of the
package of FIG. 1 showing one of the forms;
[0016] FIG. 3a is a sectional elevation view of a separated unit
form of the embodiment of FIGS. 1 and 2;
[0017] FIG. 3b is a side elevation view of a tablet form of the
present invention in a second embodiment;
[0018] FIG. 4 is a plan view of the embodiment of FIG. 3a;
[0019] FIG. 5 is a side elevation of a container package for the
unit forms of FIGS. 3a and 3b;
[0020] FIG. 6 is a fragmented isometric view of a package for the
strip unit forms of the embodiment of FIG. 1;
[0021] FIG. 7 is a schematic side elevation sectional view of a
robotically operated electrostatic chuck for carrying a substrate
forming the unit forms of an embodiment of the present
invention;
[0022] FIG. 8 is a side elevation sectional view of the chuck of
FIG. 7 taken along lines 7-7;
[0023] FIG. 9 is a plan view of a gasket employed in the embodiment
of FIGS. 7 and 8;
[0024] FIG. 10 is a side elevation sectional schematic view of the
formation of a package of the present invention at a lamination
station;
[0025] FIG. 11 is a plan view of a front surface the electrostatic
chuck of FIG. 7 without the gasket in place showing the surface of
the chuck showing through holes and collection zones for active
powder/grains;
[0026] FIG. 12 is a plan view of a rear surface of the chuck of
FIG. 11 showing addressing electrodes coupled to drive electronics
(not shown) for driving powder collection electrodes;
[0027] FIG. 13 is a plan view of the underside of the chuck
attached to a robotically operated receiving head;
[0028] FIG. 14 is a plan view of the receiving head without the
chuck installed;
[0029] FIGS. 15a, 15b and 15c are schematic sectional elevation
views of different embodiments of powder/grain attracting
electrodes that may be employed in the electrostatic chuck
embodiment of FIGS. 7, 8, 11, 12 and 13;
[0030] FIG. 16A is a schematic illustration of a diffuse reflection
system for characterizing the amount of deposited dry powders;
[0031] FIG. 16B is a schematic illustration of an optical
profilometry system for characterizing the amount of deposited dry
powder/grains;
[0032] FIG. 17 illustrates a substrate that can be measured with
both the optical profilometry and diffusion reflection systems of
FIGS. 16B and 16A respectively;
[0033] FIG. 18 is a graph useful for explaining the principles of
the present invention;
[0034] FIG. 19 is schematic plan view of a detection array at the
measurement station of the embodiment of FIG. 1a;
[0035] FIG. 20 is a schematic circuit diagram for providing an AC
bias charge and deposition sensing for a floating pad
electrode;
[0036] FIG. 21 is a waveform diagram useful for explaining the
principles of the diagram of FIG. 20; and
[0037] FIG. 22 is a schematic circuit diagram for providing an
alternative AC bias charge and deposition sensing.
Detailed Description
[0038] In FIGS. 1 and 2, package 2 comprises a strip 3 of an array
of product forms 5. The strip 3 is formed from larger strips as
explained in more detail below. The package 2 further comprises a
cover substrate 4 and a base substrate 6. The cover substrate 4 is
a planar flexible film sheet as described below and includes an
array of semi-spherical bubbles or depressions 8 arranged in
columns and rows. The package 2 may comprise an array of three by
five unit pharmaceutical or diagnostic dosage forms by way of
example. More or fewer may be provided as desired. The base
substrate 6 is a planar film sheet. The dry powder active
ingredient 10 in the form of powder/grains is deposited between the
substrates 4 and 6 in each depression 8 as will be described below.
The unit product forms 5 are created by heat or ultrasonic annular
welds 7 formed about the depressions 8. The welds may also be
formed by a suitable adhesive or the like.
[0039] In the description that follows, the term unit
pharmaceutical or diagnostic dosage form includes a separate
discrete active ingredient or ingredients whether or not on a
discrete separate substrate, whether or not the substrate is
edible, that may be used as a dosage for pharmaceutical purposes or
as an element(s) for diagnostic purposes, whether or not
encapsulated, capable of being packaged or otherwise available for
end use as a unit.
[0040] The term dry deposited refers to a material deposited
without a liquid vehicle.
[0041] Grains are, for the purposes of this application, either
aggregates of molecules or particles, typically of at least about 3
nm average diameter, preferably at least about 500 nm or 800 nm
average diameter, and are preferably from about 100 nm to about 5
mm diameter, for example, about 100 nm to about 500 nm. Grains are,
for example, particles of a powder, or polymer structure that can
be referred to as "beads." Beads can be coated, have adsorbed
molecules, have entrapped molecules, or otherwise carry other
substances.
[0042] The active ingredient 10 may be a pharmaceutical product,
i.e., a drug, or a diagnostic product useful for biological
diagnostic laboratory or medical related purposes, for example.
[0043] In FIGS. 3a and 4, a second embodiment of the product form
may comprise discrete capsules 12. The capsules 12 are created by
severing the individual product forms from the strip forming the
package 2.
[0044] In FIG. 3b, the product form may comprise a tablet 14. The
tablet 14 comprises an active ingredient 16 deposited in
powder/grain form on an edible inert substrate 18. Reference is
made to the aforementioned patents for more detail regarding the
formation of such tablets.
[0045] In FIG. 5, a bottle 20 forms a container for the capsules 12
or tablets 14. In FIG. 6, a box or similar packaging device houses
the strips 3.
[0046] The substrates 4 and 6 are preferably films typically
flexible planar thermoplastic material having a thickness for
example of about 0.001 inches (0.0254 mm). Suitable plastic
substrate materials include polyvinylacetate,
hydroxypropylmethylcellulose and polyethylene oxide films.
[0047] In FIG. 1a, system 24 for fabricating the unit
pharmaceutical or diagnostic dosage forms 5 comprises a robotic
platform 26 in which the product forms 5 are created in which dry
powder/grains are deposited on the substrates. The platform 26 is
in an environmental enclosure comprising thermoplastic, e.g.,
acrylic, sheet walls 28 and including a ceiling (not shown).
[0048] The platform 26 comprises substrate input/output stations
30a, 30b and 30c at which framed substrate assemblies 32 and 34 are
stored for later use or processing. The platform 26 includes
alignment station 44, measurement station 48 employing dose
measurement apparatus 50, deposition station 52, and lamination
station 54.
[0049] The framed substrate assembly 32 at stations 30b and 30c
comprises a rectangular cover substrate 36 having an eight by
twelve array of depressions 8, for example. Assembly 32 includes a
metal frame (not shown), e.g., sheet aluminum, to which the
substrate is secured. The frame includes guide holes (not shown).
The guide holes mate with guide pins (not shown) at the
input/output stations 30b and 30c, FIG. 1a, the robot head (not
shown) of robot 56 at lamination station 54. The substrates 36 form
the cover 4, FIG. 1.
[0050] The substrates 34 at station 30a each form the base 6, FIG.
1. The substrate of assembly 34 differs from the substrate 36 in
that no depressions are formed in the substrate of assembly 34. The
substrate of assembly 34 is also attached to a frame such as frame
38. The frames via their guide holes mate in guide pins (not shown)
at the input/output station 30a and the alignment station 44 which
aligns the frames 38 to the robot head of robot 46 at the
measurement station 48.
[0051] Alignment station 44 aligns the substrate assembly 34 to its
mating pick up robot 46 located at measurement station 48 for
providing accurate processing of the deposition powder/grains on
the substrate of assembly 34. Measurement station 48 includes a
dose measurement apparatus 50 having a measurement window (e.g.,
glass-not shown). The platform 26 includes a powder/grain
deposition station 52 and a lamination station 54 at which is
located a second robot 56. The robot 46 picks up and transports the
base 6 substrate assemblies 34 and the robot 56 picks up and
transports the cover 4 substrate assemblies 32 from the
corresponding input/output stations.
[0052] Charged powder/grains are delivered to the robotic platform
deposition station 52 from powder/grain feed apparatus 60, which
also is in an environmentally controlled enclosure. Environment
control 62 controls the environment of the platform 25 and
apparatus 60 by controlling temperature, pressure and humidity.
Computer and controller 62 operates the powder/grain feed
apparatus, the robots of the platform 26 and the measurements made
at station 48 by apparatus 50.
[0053] The deposition station 52 includes a deposition gasket 67
surrounding a deposition chamber 69 having an opening through which
charged powder/grains are forced to flow during deposition onto the
overlying substrate of assembly 34.
[0054] The robots of platform 26 can be based, for example, on a
Yaskawa RobotWorld linear Motor Robot. The robots are linked to
rails (not shown) for providing x-y movement via x-y linear stepper
motors (not shown). Each robot has telescoping components under
servo control (not shown) for moving a substrate receiver attached
its head (not shown) in the z axis normal to the x-y plane. Robot
46 has a receiver head 64, FIGS. 7, 8, 13 and 14 to which an
electrostatic chuck 68, FIGS. 7 and 8, is attached. Robot 56 has an
ultrasonic weld unit attached to its head for laminating the cover
4 and base 6 substrates at the lamination station 54.
[0055] Also, the robots 46 and 56 have control components to
provide servo control to rotate the respective robotic head and
receiver, such as receiver 64 in the x-y plane. Compressed air or
other gases at a flow rate of 8 SCFM at 80 psi operate the robotic
heads.
[0056] Receiver 64 is mounted with an electrostatic-vacuum chuck 68
as described, by way of example, in the aforementioned application
"Apparatus for Clamping a Planar Substrate, Ser. No. 09/095,321
filed Jun. 10, 1998 by Sun et al., APPARATUS FOR CLAMPING A PLANAR
SUBSTRATE. Vacuum lines, power lines and sensor monitoring
lines(not shown) are mounted to the receiver 64 to provide
operating resources for the chuck. Where substantial number of
lines are to be fixed to the receiver 64, the robots are selected
or modified to accommodate the additional weight.
[0057] The platform 26 is framed by supports 66 to which the walls
28 are secured. The atmosphere within the platform 26 may be air or
an inert gas.
[0058] The receiver 64 has circuitry which controls and operates
the chuck 68. FIG. 11 shows the upper surface of electrostatic
chuck 68 with through spaced holes ECH that are either slots or
linear arrays of small apertures that mimic a slot. The holes ECH
extend about the periphery of the chuck 68 in spaced arrays as
shown. Other configurations for the through holes ECH are
illustrated in the aforementioned application Ser. No. 09/095,321
filed Jun. 10, 1998 by Sun et al., APPARATUS FOR CLAMPING A PLANAR
SUBSTRATE. Powder/grain collection zones CZ formed by electrodes
are located on surface 70 otherwise composed of dielectric
material.
[0059] FIG. 12 illustrates a rear surface 72 of the chuck 68 which
has addressing electrodes 74 through which each row of the
electrodes forming the collection zones CZ can be connected by
driving electronics (not shown). Electrical contact pads 76 provide
contact points for connections to voltage sources for controlling
the amount of powder/grains deposited at each collection zone
CZ.
[0060] The pads 76 and collection zones CZ (FIG. 11) connected by
the electrodes 74 are arranged in eight columns 78 of 12 collection
zones each, for example, each collection zone corresponding to a
deposition location on the base substrate 6 (FIG. 1). Each contact
76 can receive a voltage independently of the voltage of the other
contacts to separately control the amount of powder/grains
deposited on the collection zones of a given column. The addressing
electrodes can be arranged in different patterns to allow different
control patterns. The voltage on each contact creates an
electrostatic field at the corresponding electrodes at the
collection zones CZ. This field attracts the powder/grains of
active ingredient to the associated base substrate 6 and also holds
the substrate 6 flat against the chuck.
[0061] FIGS. 15A-15C illustrate features of electrostatic chucks at
a collection zone CZ that can be employed in the present invention.
In FIG. 15A, a shield electrode A21 (also termed a "ground
electrode" based on a preferred bias) is layered with a dielectric
A22 which dielectric can comprise, for example, Kapton, a
registered trademark of DuPont de Nemours for a polyimide film.
Kapton material can be etched, punched and laser drilled and used
to form multilayer polyimide film laminates.
[0062] The powder/grain-attracting electrode A23 projects out at
the surface that attracts the planar substrate A40, for example
0.001 inches thick (0.0254 mm), and can project out at the opposing
side where electrical contacts are formed. The width d of the film
dielectric A22 forming the chuck can be 0.01 inches (.254 mm) for
example. This makes the chuck 68 relatively flexible. The planar
substrate A40 wraps over the outwardly projecting
powder/grain-attracting electrode A23 in relatively close fitting
relationship. This is most effective when a vacuum chuck is used in
conjunction with the electrostatic chuck. That is, a vacuum is
applied directly to the substrate via apertures (not shown) in the
chuck to hold the substrate flat against the chuck. As described,
the grain attracting electrodes play a role in adhering the planar
substrate to the chuck. Tight adherence of the planar substrate to
the electrostatic chuck increases the reliability of powder/grain
deposition at the collection zones.
[0063] FIG. 15B illustrates an embodiment where the through holes
ECH are formed at the powder/grain-attracting electrode A23. FIG.
15C illustrates an embodiment where an additional layer of
dielectric C22 separates the powder/grain-attracting electrode C23
from the planar substrate C40. The chuck of FIG. 15C can be termed
a "Pad Indent Chuck" which is useful, for example, for depositions
of less than about 100 mg per collection zone CZ (assuming a
collection zone of about 4 mm diameter). The electrostatic chuck
provided by the configuration of FIG. 15A can be termed a "Pad
Forward Chuck" which is useful, for example, for deposition so more
than about 20 mg per collection zone CZ, assuming a collection zone
of about 4 mm diameter, but which is more useful for higher dose
depositions than the Pad indent Chuck.
[0064] In FIG. 7, the receiver 64 preferably comprises an
electronics housing 78, a vacuum manifold housing 80, and a gasket
82. The chuck 68 is preferably aligned with the receiver 64 with
locating pins and alignment holes. The vacuum manifold housing 80
has passageways 84 which convey reduced pressure to the through
holes ECH (FIG. 11) in chuck 68. Reduced pressure is applied to the
passageways 84 via inlet fitting 86, and via passageway outlet (not
shown). Because the chuck 68 is flexible, and therefore,
susceptible to deformation, and because it can be important to
deposit powder/grains on a flat surface, a mechanism is provided to
couple the powder/grain attracting electrodes to a voltage source
without applying significant distortion pressure to the chuck
68.
[0065] Coupled pins 88 provide this mechanism. Lower pin assemblies
88', FIG. 8a, of the coupled pins 88 are inserted thorough holes in
electronic housing 78, the vacuum manifold housing 80, and gasket
82, with a conductive adhesive, such as silver epoxy, on the lower
part of the lower pin assemblies 88', FIG. 8a. The lower pin
assemblies 88' have a notch 90, FIG. 8b, to allow excess adhesive
to relocate in the holes. The adhesive adheres the lower pin
assemblies 88' to the electrical contact pads 76, FIG. 12. The
upper parts of the coupled pins 88 are standard circuit board pins,
which couple with slots (not shown) on pin connector board 94, FIG.
8.
[0066] Gasket 82, FIG. 9, has slot holes 96 which allow reduced
pressure (e.g., vacuum) to be transmitted to the electrostatic
chuck 68 through holes ECH, FIG. 11. Another set of conduit holes
98 allow the coupled pins 88 to be inserted through the gasket 82.
The gasket 82 insulates preferably at least about 2000-2500 volts
and in one embodiment is coated on both sides with an adhesive. A
graphics art paper meeting these requirements, which is of 0.004
inches thickness (0.1 mm) and coated on both sides with an
aggressive rubber-based adhesive is available from Cello-Tak,
Island Park, N.Y.
[0067] The receiver 64 may be manufactured from a durable
non-conductive material such as a Noryl polymer (A registered
trademark of GE). Noryl engineered plastics are modified
polyphenylene oxide, or polyphenylene oxide and polyphenylene
ether, resins. The material is modified by blending with a second
polymer such as polystyrene or polystyrene/butadiene. A variety of
grades are produced by varying the blend ratio and other additives.
The material exhibits strong intermolecular attraction with extreme
stiffness and lack of mobility. The Noryl based support provides
firm support for maintaining a flat surface collection zone CZ
containing surface of the electrostatic chuck 68 while the low
weight reduces the burden on the robotic heads of robots 46 and 56
(FIG. 1a). The surface of the receiver 64 on which the
electrostatic chuck 68 is mounted is preferably flat to +/-0.001
inches for example.
[0068] The frame 38, FIG. 13, for the substrate is employed for
securing the substrate aligned to the various stations and robotic
heads of the system. The frame is also used to hold the substrate
to the chuck 68 via the chuck vacuum holes ECH, FIG. 11. The vacuum
releasably secures the frame 38 to the chuck by the applied vacuum
from the receiver 64. The frame 38 is preferably aluminum. The
frame may be about 200 mm by 300 mm with sides having 12.7 mm
width. Vacuum cup receiving fixtures on the frame 38, height
adjustable vacuum cups (not shown) and vacuum fittings (not shown)
on the receiver 64 may also be employed to hold the frame to the
chuck.
[0069] FIG. 13 shows the chuck 68 adhered to the underside 100 of
the receiver 64. Electrostatic chuck 68 has alignment mechanisms 40
which may comprise pins or holes for aligning the chuck to the
receiver 64 with mating pins or holes. In FIG. 14, receiver
underside 100 is shown without the chuck 68, showing passageways 84
and outlet 102 along with pin 88 conduits 104. Alignment mechanisms
106 are shown and can be pins or holes which mate with holes or
pins in the chuck 68.
[0070] Electronic control is integrated in the dry powder/grain
deposition apparatus 60. This control is coupled to a processor
board (not shown) in the receiver which functions as a
communication board. This board receives commands from the central
processor in controller 62 (FIG. 1a) and relays these commands to
an addressing circuit board (not shown) in the receiver 64. Also,
in some embodiments, an embedded processor circuit board (not
shown) in the receiver 64 receives data from sensors positioned on
or adjacent to the electrostatic chuck 68 and interprets locally
any adjustments to the voltages applied to the powder/grain
attracting electrodes A23-C23 (FIGS. 15A-15C) that are appropriate
in view of this data. These sensors are described below.
[0071] The addressing board, after receiving signals from an
on-board processor board (not shown-on the receiver 64) sends bias
control signals, DC or AC, e.g., about 2000 V at low current, for
controlling the voltage at the electrodes 76, FIG. 12. This thus
applies the voltage to the powder/grain-attracting electrodes
A23-C23, FIGS. 15A-15C, in individual columns 78 or rows of
electrodes or individual rows of electrodes according to a given
implementation. In FIG. 12, the addressing electrodes 74 allow
control individual columns of powder/grain-attracting electrodes at
the collection zones CZ, FIG. 11.
[0072] The bias signals from the addressing board can be used to
separate columns or rows of powder/grain attracting electrodes, or
to individual powder/grain attracting electrodes. Such adjustment
can be made, for example, where sensors as described below, or data
from the dose measurement station 50 based on a previous
deposition, indicate that an uneven distribution of deposition
amounts is occurring. As a result, the voltages at the collection
zones CZ may be advantageously increased or decreased
accordingly.
[0073] The chuck 68 of FIGS. 11 and 12 has addressing electrodes 76
that allow control of individual columns of powder/grain attracting
electrodes A23-C23 (FIGS. 15A-15C). Electrical signals manifesting
control patterns that control regions or individual collection
zones CZ can also be used.
[0074] The addressing board preferably has multiple channels of
synchronized output signals, e.g., square wave or DC. These signals
may be encoded with square wave pulses of varying magnitudes to
identify the powder/grain-attracting electrodes or group of
electrodes together with the appropriate voltage to be applied for
controlling the amount of powder/grains to be deposited. The bias
control signals are sent via a high voltage board (not shown) in
the receiver 64 which has multiple channels of high voltage
converters (transformers or HV DC-to-DC converters) for creating
the deposition control voltages, such as 200 V or 2,500 V or 3,000
V (of either polarity), for operating the powder/grain-attracting
electrodes. By forming the higher voltages within the receiver 64,
these high voltages can be isolated from other systems.
[0075] The central processor unit controller 62, FIG. 1a, receives
performance input from multiple sources. This input provides data
on the rate of particle flux into and through the deposition engine
comprising feed apparatus 60 (FIG. 1a) and deposition station 52,
how evenly particles are being deposited at the chuck 68 and how
well previous depositions have met the required thickness values.
Various parameters of the system may be adjusted in view of this
data, including voltages at various locations on the chuck to
improve performance. The on-board electronics at the receiver 64
provides the means to make these adjustments on-the-fly to be
conveyed to the powder/grain attracting electrodes 74, FIG. 12.
[0076] A charge sensor 128, FIG. 14, is on the receiver 64 for
sensing the amount of charge on the powder/grains attracted to the
electrodes A23-C23. The sensor 128, which is schematically
represented by the dashed lines, monitors the amount of
powder/grains deposited, and is described in detail in the
copending application Ser. No. 09/095,425 now US Pat. No. 6,149,774
noted in the introductory portion. This application describes the
use of pulsed (AC) electrical potential waveforms for biasing an
electrostatic chuck to collect powder/grains such as on a
substrate. This biasing overcomes the problem of collecting the
powder/grains on a conductive substrate, where the
powder/grain-attracting field can decay rapidly after any given
application of a bias potential to the electrostatic chuck.
[0077] The use of AC bias waveforms for the powder/grain attracting
electrodes also solves another long-standing problem during
deposition sensing. During deposition sensing, one or more
collection zones are closely monitored for powder/grain
accumulation to allow regulation of the deposition process, to
produce, for example, precise pharmaceutical dosage or diagnostic
dosage unit amounts. This monitoring can be done optically or by
measuring accumulated charge using an "on-board" charge sensor at a
sensor associated collection zone, which can be correlated to
actual charged grain deposition by empirical data collection. In
dry powder/grain deposition, for example, dose monitoring is often
a difficult task, particularly for dosages below one milligram.
[0078] The difficulty is not that measuring devices are not
available--modern solid state devices, although costly, can make
measurements so precise that noise levels are on the order of the
voltage generated by the charge of a few hundred electrons. Rather,
the difficulty lies with various practical and environmental
factors that deteriorate charge sensing sensitivity by two or three
orders of magnitude. For quasi-static DC biased bead (deposited
powder/grains) transporter chucks, on board charge sensing is
particularly difficult. Data obtained by depositing on a
polypropylene film substrate with different potentials indicates
that the deposited dose is linearly related to the bias potential
if that potential is above a certain threshold potential. Data
indicates that threshold potential is about 100-200 volts DC, at
least for certain transporter chucks.
[0079] In FIG. 20, one possible equivalent circuit diagram for the
circuit provided by the electrostatic chuck and substrate is
illustrated. The chuck and substrate corresponding to this
equivalent circuit includes a planar bead electrode that is used to
provide a bead attracting field. Affixed to the bottom face of the
bead electrode is a planar first dielectric layer. The dielectric
layer is applied to or affixed to the bead electrode in parallel
using any known techniques such as laminating, powder deposition or
thin film deposition. Dielectrics may include Pyrex 7740 glass
(Corning Inc.) or polyimide resin of 10-20 mils thickness. A planar
shield electrode is affixed to the other face of the first
dielectric layer. The latter shield electrode comprises an aperture
to accommodate a floating pad electrode, coplanar with and
surrounded by the latter shield electrode.
[0080] The equivalent circuit provides AC biased charge and
deposition sensing for at least one of the collection zones, which
zone has a floating pad electrode. The floating pad electrode is an
isolated conductor which is capacitively coupled to a powder/grain
attracting electrode, such that the bias to the attracting
electrode indirectly creates a powder/grain attracting field
emanating from the floating pad electrode. One or more collection
zones are typically dedicated solely for sensing or are in general
use, but closely monitored. By measuring the lowering of the
attracting potential V.sub.CZ that occurs as charged powder/grains
collect on the collection zone, a measure of deposited charge can
be obtained. By knowing the average charge/mass ratio q/m of the
powder/grains, the accumulated deposition mass can be measured.
V.sub.CZ can be measured directly across a charge collector
electrode, but is often preferable to measure the potential across
a coupling capacitor, such as the floating pad electrode discussed
above.
[0081] The coupling capacitor as embodied by a floating pad
electrode described above will provide reasonably high fidelity
reproduction of the potential at the collection zone CZ on the
powder/grain contact surface, and in FIG. 21, the waveforms for
V.sub.CZ and V.sub.Pad show this. In either case, whether a charge
collector or charge coupling capacitor is electrically connected to
a separate sensing capacitor, the voltage generated across the
sensing capacitor can be a reliable indicator of the potential
V.sub.CZ.
[0082] The voltage across the sensing capacitor is measured with an
electrometer, such as a Keithly model no. 614, 6512, 617, 642,
6512, or 6517A electrometer as schematically shown in the figure.
Generally, the coupling capacitor is any electrode that is
capacitively coupled to a collection zone on the contact
surface.
[0083] A problem is that DC biasing can cause a steady drift in the
reading of the potential across the sensing capacitor. This drift
comes from many sources, mostly from natural leakage across the
dielectric material in the sensing capacitor, and because of charge
leakage in the substrate or grain composition accumulated on the
chuck. Drift can also be induced by noise factors such as shot
noise, Johnson (1/f) white noise, thermal noise, Galvanic noise,
triboeleectric noise, piezoelectric noise, amplifier noise, and
electromagnetically induced noise. See ref. The Art of Electronics,
by Paul Horowitz, Winfield Hill, 2nd Edition,, Cambridge University
Press, 1989, ISBN 0521370957.
[0084] If this drift is too large compared to the actual charge
collected at the collection zone, the accuracy of the charge sensor
as a dose or deposition measurement tool can be unacceptably low.
Using AC biased waveforms as disclosed herein will minimize the
creation of drift, in a manner similar to that used above for
avoiding the "drift" of charge dissipation on the collection zone,
allowing precise measurement of charge collected.
[0085] In FIG. 20, an AC bias source may be the same source as
discussed above, with the AC bias potential applied or administered
via the powder/grain attracting electrode. This in turn
electrically couples to the floating pad electrode or to the
collection zone, if it is connected directly to the sensing
capacitor as shown.
[0086] For example, if the sensing capacitor is chosen to be 0.1 iF
and the q/m of the powder/grains is 10 iC/g, a 100 Mv signal change
on the charge collector/coupling capacitor corresponds to 3 mg of
powder/grain in the actual deposition dose, then a 99 mg actual
dose will have a detectable potential change of 3.3 Mv. With a 5%
error tolerance, the corresponding background unpredictable noise
contribution cannot exceed 160 iV. This is achievable with careful
shielding and grounding. Preferably the charge collector is
integrated with the chuck to assure a consistent correlation.
[0087] In effect, the same benefits gained by using the AC bias
waveforms for V.sub.g to avoid charge dissipation in the substrate
can be used to greatly reduce drift in the charge sensing
circuit.
[0088] In FIG. 22, a further possible equivalent circuit provides
AC biased charge and deposition sensing. This circuit reduces noise
by separating the AC bias source from the electrometer, the sensing
capacitor or the charge collector/coupling capacitor. All of these
components have a sensitivity to noise that is critical. The AC
bias source is connected to the primary of a transformer T. In this
manner, only the periodic magnetic field generated by V.sub.g (not
V.sub.g itself) is introduced into the sensitive components on the
right side of the figure. The secondary winding of transformer T is
connected across a stabilizing bleed resistor R, with one pole,
biasing pole BP connected to the charge collector/coupling
capacitor, and the other pole, at the sensing capacitor, is
connected to ground. The electrometer can then measure the voltage
change on the sensing capacitor with respect to ground, as
shown.
[0089] These two grounding points can be combined to reduce
electromagnetic noise further. The transformer can be a step-up
transformer as discussed so that complex AC bias waveforms supplied
here and to the grain attracting electrode can be generated at low
cost. For example, the step-up ratio can be 50. This greatly
reduces drift and makes accumulated charge sensing more accurate,
where previously the coupling current of 100 pico-Amperes or less
made drift and noise a problem.
[0090] If desired, transformer T can be an isolation transformer,
where the primary and secondary windings are separated by a Faraday
cage. This can prevent coupling between the primary and secondary
windings, where the primary winding acts as one capacitor plate,
and the secondary as the other capacitor plate.
[0091] With this improved signal to drift ratio, the amount of
charge sensed can decrease substantially. Measurements can be made
using a 1000 picoF capacitor as the sensing capacitor instead of
the 0.1 .mu.F value used previously. Also, the AC bias source,
FIGS. 20 and 22, can be separate from the AC waveform bias V.sub.g
on the chuck, by delivering a separate AC bias to the charge
collector/coupling capacitor directly, via a dedicated wire,
electrode, bus, etc. This separate AC bias can be frequency matched
or detuned with respect to V.sub.g to insure consistent correlation
of the behavior of the charge collector/coupling capacitor to
actual depositions.
[0092] Overall, too, these techniques allow V.sub.g biasing with
voltage peaks much higher than previously possible. Using 8000
molecular weight polyethylene glycol as a substrate, bias peaks of
2 kV have been used. It is important also to keep in mind that any
kind of powder/grain (bead) transporter chuck can be used,
including those that operate with bias electrodes directly exposed
to the powder/grain (bead) contact surface.
[0093] The substrate of assembly 34 must be kept flat during
deposition. To do this electrostatic forces may be applied to the
dielectric layer A22, for example, FIG. 15A, of the chuck to hold
the substrate layer against a reference surface on the chuck. In
the alternative, vacuum ports, not shown, may be used to hold the
substrate dielectric layer flat. See the aforementioned application
Ser. No. 09/095,321 filed Jun. 10, 1998 by Sun et al., APPARATUS
FOR CLAMPING A PLANAR SUBSTRATE, for example. This flatness of the
layer A22 is important in order to control the thickness, and thus
the volume, of the deposited powder/grains to the desired
range.
[0094] It is important, for example, that the deposited
powder/grains at collection zones CZ, FIG. 11, do not vary from a
predetermined amount by more than about 5%. While this value may
vary somewhat depending upon the drug or diagnostic agent being
deposited, generally the value of about 5% variation from a
predetermined amount of deposited powder/grains is sufficient for
most applications. While such variation might be exceeded in the
actual deposition of the powder/grains, the measurement station
provides non-destructive actual measurements of the amount (i.e.,
the thickness over an area) of the powder/grain layers deposited at
each of the collection zones CZ.
[0095] These values are stored in memory and displayed (by display
not shown) so that any unit dosage or diagnostic forms that exceed
or are less than the desired range can be selectively discarded. In
the present embodiment, a particular column of deposited
powder/grains would be identified and discarded at a later
processing step if any of the zones of that column are out of the
desired range.
[0096] The deposition engine may be any known process for
depositing the powder/grains. The engine disclosed in the
aforementioned application Ser. No. 09/095,246 now U.S. Pat. No.
6,063,194 is preferred. However, the deposition processes of the
aforementioned U.S. patents and applications may also be used. The
deposition in the former feeds powder/grains through an induction
tube to which a bias is applied. This bias provides a charge of the
desired polarity on the powder/grains. The tube is of a length
sufficient to charge all of the expected powder/grain particles
flowing therethrough to the deposition station 52. The particles
flow into the chamber 69 via a nozzle (not shown).
[0097] The particles pass through an electrified metal control grid
(not shown) that has a polarity of the charge on the powder/grains
to repel the powder/grains. The grid is about 0.5 to 1.0 inches
below the target, and biased about 500 volts per 1/2 inch at the
polarity of the powder/grains. This action collimates the
powder/grains as they are propelled upwardly toward the overlying
chuck by the electrostatic forces on the chuck and toward the
attached substrate 6 then receiving the powder/grains.
[0098] The grid also attracts the powder/grains with the wrong
polarity. The grid may be parallel wires formed of a zig-zagging
switchback of one wire or a grid of wires (not shown). The rate of
powder/grain cloud of powder/grain flux can be monitored by
measuring light attenuation between a light emitter (not shown),
e.g., a laser, and a light detector (not shown). This value is
transmitted to the controller 62, FIG. 1a.
[0099] A rotating baffle (not shown) is coupled to the nozzle (not
shown) outlet in the deposition station 69 to disperse the
powder/grains prior to the grid to more uniformly apply the
powder/grains to the substrate 6. The baffle may comprise three
equally spaced radially extending rotating planar baffle supports
(not shown) on which rests a horizontal baffle disk (not shown)
through which are a plurality of powder/grain aperture outlets. The
powder/grains are fed to the nozzle with a gas at about 20 psi and
about 2.5 liters per minute. The gas is preferably substantially
free of water, oil and other impurities, and is preferably
chemically inert such as nitrogen or helium.
[0100] The baffle should be preferably about 1/4 inch to about 1/2
inch above the outlet of the powder/grain charging feed tube nozzle
such as 1/2 inch cross section where a 1/4 inch powder/grain charge
feed tube nozzle is used. Rotating the baffle at about 5 to 25
revolutions per minute increases the uniformity of the powder/grain
cloud reaching the target.
[0101] The powder/grains may be fed by an auger (not shown)
rotating, e.g., 10 to about 80 RPM, to feed the powder/grains to a
Venturi feed valve (not shown). The auger is supplemented by the
powder/grain Venturi feed tube which pulls the powder/grain from
the auger and at the same time pushes the powder/grains through the
feed tube to the nozzle at the chamber 69. A modified Venturi
feeder valve with a Venturi well that delivers grains in a
substantially straight line from the vertical auger feed to the
powder/grain charging feed tube avoids compaction of the
powder/grains falling to the bottom of the Venturi well. A simple
gas source may be used in place of the Venturi to propel the
powder/grains. A gas jet directs gas pressure toward the outlet of
the mechanical device that feeds the powder/grains, the gas jet
being adjusted to deagglomerate the powder/grains at the
outlet.
[0102] Nitrogen may be used to feed the powder/grain particles via
the venturi. The auger and feed tube connected to the auger through
a venturi valve are vertically aligned. A vibrator (not shown)
coupled to the feeding apparatus is preferable to keep the
particles flowing. Other grain feed arrangements may also be used
such as a gear wheel apparatus (not shown) or a jet mill (not
shown) for dosages of about 2 ig to about 50 ig-100 ig applied to
an area of about 3 to 4 mm diameter.
[0103] Induction induced charge may be applied to the jet mill by
applying a potential to the mill such as with a 1,800 V potential.
A suitable mill may be a TROST Air impact Pulverizer jet mill
marketed by Plastomer Products Division of Coltec Industrial
Products, Inc. This mill utilizes directly opposing streams of
compressed gas and operates at a flow rate of about 2.0 to 2.2
liters/minute.
[0104] The powder/grains may by charged by triboelectric charging,
the charge to the powder/grains colliding with the sides of its
feed tube as the powder/grains transit the tube. Teflon,
perfluorinated polymer may be used to impart a positive charge to
the powder/grains and Nylon, amide based polymer, is used to impart
negative charges. To minimize charge build up on the tube, the tube
may be wrapped in metal foil or coated with conductive material
such as graphite.
[0105] In the induction charging, a portion of the feed tube is
stainless steel biased by one pole of a power supply with the
opposite pole grounded. With an appropriate bias, an electric field
is created in the stainless steel tube such that powder/grains
passing through it pick up a charge. The length of the
induction-charging tube is set to a sufficient length to assure the
amount of charging desired. In one embodiment, induction charging
is used in conjunction with tribocharging.
[0106] The charge relieved by the grounding procedures outlined
above can be monitored to provide a measure of powder/grain flux
the charging feed tube (not shown). This data can be sent to the
controller 62 (FIG. 1a) to modify various parameters of the
deposition apparatus. For example, a capacitor (not shown) can be
put in series with the powder/grain charging feed tube to lower the
potential generated by the charges collected in the charging feed
tube. A 1 iF capacitor will build up 1 V for a 1 iC charge. The
other pole of the capacitor is connected to ground potential. An
electrometer (not shown) connected to the capacitor provides an
accurate measure of collected charge.
[0107] Powder/grains not utilized at the deposition station are
returned via a pressure differential through a powder/grain
evacuation tubes (not shown) to a powder/grain trap (not shown).
The trap utilizes biased baffles biased at for example either +2000
V or -2000 V. Grains not charged are charged by impact with a
baffle of one polarity and collected by an oppositely charged
baffle.
[0108] Shutdown of the deposition process for example as a result
of the feedback data such as from the charge sensor or pursuant to
a timing schedule involves reducing the voltage (or the amplitude
in the case of a pulsed voltage profile) directed to the
powder/grain attracting electrodes, preferably to about 400 V from
2000 V, and shutting down the powder/grain feed apparatus. The
amount of voltage reduction appropriate will vary depending upon
such factors as the substrate, the powder/grains and the level of
the powder/grains applied. The voltage is generally selected to
maintain substrate adherence to the chuck and grain adherence to
the substrate without attracting further grain accumulations.
[0109] The dose measurement station 48 includes apparatus 50 for
measuring the thickness, i.e., the amount of powder/grains
deposited on the substrate 109. Two optical measurement methods may
be employed: diffuse reflection and optical profilometry. Diffuse
reflection has been used to characterize powder/grains using light
sources that emit in a range that is absorbed by the powders. A
theory has been developed for using non-absorbing radiation which
derived a term for the thickness of a powder/grain layer. It is
believed that no commercial development has been made from this
latter theory. Applicants have discovered that this measurement
gives a strong correlation with the deposited amount, at least up
to a certain amount, which varies with the character of the
powder/grain/grains and are believed to correspond to amounts past
which light penetration into lower layers is prevented.
[0110] Diffuse reflection is based on the reflection or scattering
of a laser beam or a probe light beam off of the powder/grain
surface into directions that are not parallel to the specular
reflection direction. This scattered light is generally uniformly
distributed in all directions. Dose depositions which exhibit this
property are said to be "Lambert radiators," an important property
for dose weight measurements.
[0111] In addition, the relation between the Lambertian scattering
and the optical properties of powder/grains is defined by the
scattering model of Kubelka and Munk. Non-absorbing radiation is
used to create diffuse reflection. Typical radiation is the visible
red lines provided by common gas and diode lasers such as 732.8,
635 and 670 mm. When non-absorbing radiation is used and when the
dose deposition is of a finite thickness, d, the Kubelka-Munk model
provides a known relation as disclosed in the aforementioned
application Ser. No. 09/095,246. Pat. No. 6,063,194.
[0112] In FIG. 16a, a diffuse reflection measurement apparatus 108
includes a laser 110. When a low energy beam from laser 110
impinges on deposited particles 111, the particles scatter LHT in
all directions. To have a coherent laser, it is desirable that the
laser be focused through beam splitting mirror 115. a reference
beam detector 114 assists in determining the quality and intensity
of the focused beam. The scattered light LHT is captured by an
array of two or more detector zones 113. There can be for example 2
to 6 or more such zones. Amplifiers (not shown) may be used with
the detectors. The detector zone outputs is connected to a
commercial A/D converter (not shown). The resulting signal is
scanned by using a computer controlled scanning mechanism 116,
which is in communication with the central electronic processor of
controller 62, to generate powder/grain thickness profile and thus
the dose weight measurements of the depositions.
[0113] It is preferred the powder/grains be deposited on a
substrate that has a specular surface and the substrate be
absorptive so that the measurement will not be sensitive to diffuse
reflections off of its back surface or off of the surface of the
receiver 64.
[0114] Diffuse reflection in non-absorbing regions provides a good
accuracy in measuring dose deposition amounts ranging from 50-400
ig or as high as 750 ig to 1 mg. for a 3 or 4 mm diameter
powder/grain deposited dot depending upon powder/grain
characteristics. The powder/grain dots may have a diameter of about
4-7 mm in this embodiment. This method can detect substantially
less than a monolayer of powder/grain.
[0115] If the deposit is more than a monolayer, accurate
measurement requires that the probe light beam partially penetrate
the upper layers so that it can be affected by the reflection off
of the lower layers. However, to exhibit Lambertian
characteristics, there tends to be a practical limit to suitable
thickness, depending on the powder/grain. The diffuse reflection is
also a measure of the physical uniformity of the dose deposits at
the above ranging.
[0116] Optical profilometry is useful for the implementation of
high dose measurements beyond the ranges that can be measured by
the diffusion reflection method. In FIG. 16b, a laser beam is
focused on a high dose deposition 117 on substrate 109a. The light
is deflected with an angle of deflection indicative of the height
of the deposition layer, which can be calculated by triangulation.
The coherence of deflected light, which may be somewhat scattered,
can be assisted by a lens 118 before the scattered light is
captured by one or more position sensitive detectors 119. The
output data from the detector is scanned by using a scanning
mechanism 116 to generate a profile of the powder/grain
surface.
[0117] The profilometer can be, for example, a confocal
profilometer, meaning light is directed to the substrate through a
lens system, and returned light passes at least in part through the
same focusing system, though typically the returned light is
reflected to a detection site. In one suitable confocal
profilometer, a Model LT8105, Keyence Corp., Japan, or Keyence
Corporation of America, Woodcliff Lake, N.J. focuses source light
through a pinhole, and a similar focusing through a pinhole of the
return light helps establish focus. A source of back and forth
dithering movement applied to one of the lenses helps establish
oscillations in the focus which help identify the optimal focus
point.
[0118] In one embodiment, a slit can be used in place of a pinhole
and a spatially resolvable light detector, such as a charge-coupled
device (CCD), is used to simultaneously retrieve data for multiple
points along a linear area of the substrate. In some embodiments,
there can be an issue of the powder/grain attracting electrode or
some other feature of the receiver creating strong reflections that
could overwhelm efforts to establish the baseline surface of the
substrate. However, since the substrate is preferably uniform,
these issues can be normalized away. Once material is deposited on
the substrate, or where the substrate is sufficiently opaque, clean
reflections can be obtained.
[0119] To obtain accuracy by optical profilometry, a pre-dose
measurement of the substrate 109a is preferred. The beam is scanned
across the surface and the height of the surface from a reference
location is established by triangulation. The difference in height
from the reference before and after the deposition is calculated.
This difference is attributable to the dose weight.
[0120] This difference is calculated for each column of collection
zones CZ, FIG. 11, and for each collection zone CZ. The controller
62 stores these values in memory and displays the difference as a
measure of the dosage amount for each dosage unit. When any of the
individual unit dosage amounts is beyond the predetermined amount
by the preferred 5% value, those units can be later identified and
selectively discarded for each substrate that is produced and
measured providing 100% inspection with non-destructive testing of
the actual amounts of each unit.
[0121] Since dry powders/grains are generally good diffuse
reflectors, it is convenient to use an optical triangulation system
that is optimized for diffuse reflection. To determine the pre-dose
surface profile, and to establish the height of the substrate at
issue during the post-dose measurement, it is preferred that the
substrate surface 109b be also diffuse. The surface should also be
absorptive so that the triangulation system not be confused by
reflections from the back surface of the substrate or from the
receiving system.
[0122] For purposes of illustration, only a single laser 110 is
shown. However, more than one laser can be used to impinge on the
powder/grain particles in different areas of a deposition site. The
scattered light is captured by different detection zones which
ultimately are scanned for the desired characterization.
[0123] In some embodiments, the deposition sites are excited in
succession and the powder/grain profile is characterized after each
light source excitation through the scanning mechanism 116 by
moving the scanner, for example, from a first site to a second site
and so on until all of the deposition sites are characterized.
[0124] In other embodiments, more than one deposition site is laser
excited at a time and data is obtained by scanning the sites
simultaneously. In such situations, it is desirable to optimize
conditions for reducing the interference from nearby sites that are
being characterized simultaneously. This can be accomplished by,
for example, optimizing the spacing between deposition sites or by
alternating the excitations of different sites.
[0125] It is desirable that the laser be movable in different
directions. An industrial process grade (x,y) stage can assist the
laser to move in the x,y directions. A solid state laser suitable
for industrial applications such as, for example, LAS -200-635-5
from LaserMax Inc. can be used as a laser source. the detectors can
be any suitable device, preferably, silicon, detector such as those
sold by UDT Sensors, Inc. (Hawthorne, Calif.). alternatively, large
area solar cells can also be used.
[0126] It is often desirable to combine both of the dose
measurement systems into a single system so that both the low dose
and high dose measurements can be made and the range of the dose
measurement is not limited by any single method used. In FIG. 17,
substrate 109 is striated and is useful for both the profile and
diffuse reflection systems. Striated substrate 109 has surface
striations running in only one direction. The surface profile
measurements are made by positioning the triangulation system with
incident and reflected beams in a plane perpendicular to the
striation direction. The striations thus act like a diffuse surface
for this measurement. The diffuse reflection measurements are made
in a plane that contains the striations.
[0127] Ideally, striations do not scatter light in a direction
parallel to themselves, so that any scattered light is attributable
to the powder/grain on the surface. For both measurements, the
substrate can also be dyed so that reflections from the substrate's
back surface or from the receiving system's surface do not
interfere with the measurement of either the profile or of the
diffuse reflection. The system of FIG. 17 combines two modes of
measurement with the use of just one light source, while the system
of FIG. 19, discussed below, shows a system where measurement modes
each have a separate light source.
[0128] In embodiments that do not use frames or another mechanism
for alignment of the substrate at the deposition station and the
measurement station are the same, the dose measurement system is
arranged to identify the positions of the depositions. Such a
mechanism could be a video camera that collects data, for example,
in a charge-coupled device (CCD) and electronics to analyze the
contents of the CCD to determine the boundaries of the
depositions.
[0129] It should be understood that the unit pharmaceutical or
diagnostic dosage powder/grains deposited at a collection zone CZ
are measured both in area and thickness to provide a volume measure
manifesting the amount of powder/grains deposited in a deposited
collected powder/grain dot at each zone. The above diffuse and
profilometer measurements while described in terms of thickness are
also measured in conjunction with areas that are determined by the
scanning beams.
[0130] Adjacent scan beams are closely spaced, for example 1 mm
apart, so that the transverse region occupied by a collection zone
CZ is also measured and considered in the calculations of the
amount of powder/grains present at each deposited location. The
beams are about 6 i(microns) in diameter in this embodiment. For a
deposition zone of about 4-7 mm, each deposited powder/grain dot
will be scanned with four to seven scans, respectively. These scans
are then used to calculate the amount of dosage at each collection
zone CZ. The system remembers the calculations for each zone for
future selective screening of out of specification of
pharmaceutical or diagnostic unit dosage forms.
[0131] Polyethylene glycol (PEG) powder, by way of example, in a
about 3 mm diameter dot has been deposited onto a Mylar substrate.
The diffuse reflectance data was obtained using a laser (670 mm)
based Keyence instrument (Keyence Corp. of America) operating in
the intensity mode. Data was obtained using different, usually
larger, fractions of the diffusely scattered light. The analytical
properties of the measurement did not appear to be very sensitive
to the fraction of collected light, i.e., the measurement is, in
this context, unusually robust and ideal for use as an industrial
measurement process.
[0132] The data set forth in Table I below which was obtained using
diffuse reflection method was the basis for the graph of FIG. 18,
for the four points of the data set. The first three points were
highly correlated and the least squares fit gave an R value, a
measure of correlation, of 0.999. Perfect correlation gave a
maximum value of R which is 1 and, with less correlation, the value
is correspondingly less than 1. The fourth point show variation and
the least squares fit for the data set as a whole gave an R value
of 0.98. Both R values were well within accepted norms for
analytical procedures to determine dry powder/grain dose
weights.
1TABLE I Experimental diffuse reflectance and dose weight data PEG
Dose Weight, Micrograms, by Assay Calculated R/(1-R) 108.6 0.35
86.6 0.312 50.6 0.254 36.6 0.201
[0133] Subsequent measurements had shown that a high degree of
correlation existed for the diffuse reflection and dose weight for
various types of dose samples. Based on these data, the degree of
correlation is thought to be closely related to the structure of
the dose, specifically whether the structure exhibits Lambertian
characteristics.
[0134] In FIG. 19, a detection array 130 is mounted on a support
(not shown) in the measurement station. The support is positioned
on a detection platform (not shown) at the measurement station. The
detection array 130 includes a diffuse reflectance system
comprising a diffuse reflectance light source 110A and detection
zones 132-137, inclusive.
[0135] A profilometry system comprises profilometry light source
lens 138. Lens 138 is part of a confocal system so that returned
light passes through the same lens. The diffuse reflectance light
source 110A is, for example, offset from the center point (where
lens 138 is located) so that specular reflections, as opposed to
diffuse reflections will be centered in an area 140 and away from
the detector zones 132-137. These zones 132-137 include detectors
that are preferably angled and arranged to accept only light from
an appropriate direction.
[0136] After the dose (or diagnostic) unit measurement step, the
robot 46 moves the electrostatic chuck 68 and the attached
substrate 6 and frame assembly with the deposited powder/grains to
the lamination station 54, FIG. 1a. During this period the reduced
400 V. holding signal is applied to the chuck electrodes at the
collection zones CZ to hold the powder/grains to the chuck and the
substrate flat against the chuck. The frame is continuously held to
the chuck by the vacuum through the holes ECH, FIG. 11.
[0137] During deposition, a relatively high voltage, e.g., 2000 V
as mentioned above, is used to create a deposition charge at each
collection zone. This charge also holds the substrate flat against
the electrostatic chuck during deposition. The charge also holds
the dots of deposited powder/grains to the substrate which is in
inverted orientation with the powder/grains beneath the substrate.
After the desired deposition value has been sensed by the charge
sensor circuit, the deposition voltage value is reduced
sufficiently to stop the deposition of powder/grains. However, a
charge is maintained at the reduced voltage sufficient to hold the
base substrate 6 flat against the electrostatic chuck 68 and to
hold the deposited powder/grains to the chuck as the chuck 68 is
displaced to the measurement and lamination stations.
[0138] Just prior to this time, the substrate cover 4 is
transported to the lamination station 54 by robot 56 from an
input/output station 32. The cover 4 is placed on fixture 122. The
depressions 8 of the cover 4 are placed in aligned mating
depressions in the fixture 122. Alignment devices, e.g., pins and
holes, on the frames of the substrate assemblies 32 and 34 and at
the lamination station fixture 122 assure that the locations with
the deposited powder/grains on the base substrate 4 are matched
with the depressions 8 in the cover 4 substrate, FIG. 10.
[0139] The robot 46 then transports the base substrate 6 and frame
assembly 34 from the measurement station 48 measuring apparatus 50
over the fixture 122 and places the substrate 6 with the deposited
dosages on the cover substrate 4, FIG. 10. At this time the
deposited dosages are no longer held in place by charges.
[0140] The robot 56 at the lamination station has vacuum cups (not
shown) and an ultrasonic welding head 124. After the head of robot
46 moves away from the station 54, the robot 56 returns to perform
the welding operation. The robot 56 head has a pad 126, FIG. 10,
that holds the two substrates in intimate tight contact prior to
the start of the welds. Once the other robot 46 releases the
substrate 6, the electrostatic charge on the chuck 68 holding the
deposited dosages in place is removed. The powder/grains are thus
free to move about at this time. The pad 126 compresses the base
substrate 6 against the cover substrate 4 to lock the powder/grains
in place in the depressions 8 during the weld operation.
[0141] The weld head 124 then commences welding the substrates to
form each unit form whether of dosage or diagnostic active
ingredients. The welds may by made one form at a time or preferably
by one or more weld heads simultaneously for all of the dosage
forms on the substrates on the fixture 122. When the welds are
complete, the robot 56 displaces to its idle position and the final
package of dosage forms is removed for final processing into the
package 2 (FIG. 1) or capsules 12 (FIG. 3a).
[0142] It will be appreciated that other sealing methods may be
employed such as thermal or adhesive lamination. The illustrated
bonding method is useful when one desires to keep the deposited
powder/grains free of admixture with other components such as film
polymers, though it will be recognized that this can be achieved in
other ways.
[0143] In operation, covering frames and substrate assemblies 32
are stored at stations 30b and 30c, FIG. 1a. The frames are located
by holes in the frames mating with pins in the stations. The base
frames and substrate assemblies 34 are stored at station 30a and
are also located by mating pins and holes. The robot 46, moves the
receiver 64 to the station 30a. Alignment mechanisms in the
receiver comprising alignment holes 65 and pins 67, FIGS. 13 and
14, mate with pins and holes at the input/output and alignment
stations for aligning the robot receiver, and chuck 68 to the
stored frame and substrate assemblies. Similar alignment mechanisms
are located on the cover and welding robot 56.
[0144] In the profilometer process, robot 46 picks up the assembly
34 and carries it to the alignment station 44. Here the substrate
assembly 34 is aligned to the electrostatic chuck via the alignment
mechanisms 40, FIG. 13, on the chuck to assist in the alignment of
the chuck to the substrate.
[0145] The assembly 34 is then transported from the alignment
station 44 to the measurement station and aligned with the
measurement apparatus 50. The apparatus 50 then scans the substrate
6 and records its distances at each of the collection zones CZ,
FIG. 12, to the reference location as discussed above.
[0146] The robot 46 then transports the measured empty substrate 6
and frame assembly 34 to the deposition station 52. The frame is
during this time secured to the chuck via the vacuum ports slot
holes ECH. At the deposition station, the frame is placed on gasket
67 in a sealing relation therewith. Then the powder/grain
deposition engine is turned on and the powder/grains deposited as
described.
[0147] At the end of the deposition, the deposition voltage is
reduced to stop the deposition, but maintained at the reduced value
to hold the deposited powder/grains and substrate to the chuck. The
robot 46 returns the substrate 6 and deposited powder/grains to the
measuring station 48 to measure the distance to the deposited
layers of powder/grains of active pharmaceutical ingredients or
diagnostic ingredients at each zone CZ. The distances are measured
and the volume amounts of deposited powder/grains calculated for
each dosage or diagnostic collection zone. After measurement, if
the calculated amount is outside the desired range from a
predetermined amount, the information is displayed. The operator
can then make adjustments to the voltages on the receiver to
correct the deposition values.
[0148] In the alternative, automatic feed back can be provided to
automatically adjust the voltages for a given set of collection
zones. The system remembers which zones are defective and the
operator or automated system can then remove and discard the out of
specification unit dosage or diagnostic forms.
[0149] In an automated system, the laminated unit forms may be
automatically transferred to a packaging station for screening out
of specification unit forms and for packing the unit forms in the
desired packaging.
[0150] It should be appreciated that there has been shown an
apparatus and method for making a product containing a plurality of
pharmaceutical or diagnostic unit dosage forms, each dosage form
comprising at least one pharmaceutically or diagnostic active
ingredient that does not vary from a predetermined amount by more
than 5%.
[0151] It will occur to one of ordinary skill that various
modifications may be made to the disclosed embodiments. Such
modifications may include testing each unit dosage form by
techniques other than laser scanning, for example.
[0152] Further, feedback may be provided based on the measured
thickness of active ingredient for automatically adjustment such
that the thickness of the deposited pharmaceutically or diagnostic
active ingredient is reset during the measuring of the active
ingredients of the next preceding formed plurality of unit dosage
forms.
[0153] Further, while an induction device is preferred for inducing
charges on the active ingredient particles, other known techniques
may be used to charge these particles.
[0154] While a certain particle feed arrangement is disclosed for
feeding the active ingredient particles, it will occur to one of
ordinary skill that other feed arrangements may be provided as
disclosed in the aforementioned patents in the introductory
portion.
[0155] The present invention is also applicable to a package which
includes separate units of diagnostic ingredients such as reagents
for use in tests, antibodies, antigens and so on. The reagents may
be part of a diagnostic kit unit which includes several different
reagents.
[0156] With respect to a specific diagnostic reagent in a test, the
test may include a plurality of separate units of the diagnostic
reagent comprising the diagnostic reagent deposited on a substrate
wherein the amount of diagnostic reagent in each unit does not vary
from a predetermined amount by more than about 5%. Each unit of the
diagnostic reagent may be In a separate package or vial in a kit or
may be separate independent units in a single package or vial in a
kit.
[0157] Cover Layer
[0158] As previously described, the cover layer is used in the
electrostatic deposition process to cover the substrate thereby
trapping the deposited active ingredient therebetween. Materials
suitable for use as a cover layer advantageously possess the
following properties: immediately soluble in all conditions of pH,
temperature and the like; deformable to accept a range of doses;
and easily dyed for color coding.
[0159] Candidate materials for a cover layer possessing the
above-listed desirable properties include, without limitation,
commerical hydroxypropylmethyl cellulose, methyl cellulose,
hydroxypropyl cellulose, poly(vinyl pyrrolidinone), poly(vinyl
alcohol), poly(ethylene oxide).
[0160] Sample Reservoir Layer
[0161] Where integrated diagnostic structural unit forms are
desired instead of pharmaceutical dosage unit forms, a "spreading
layer" or "sample reservoir layer" may be added in lieu of the
above-described cover layer. The spreading layer is a porous layer,
composed of particles of controlled particle size, which serves to
retain and spread a sample of liquid which is to be assayed. For
example, the spreading layer functions to trap cells or to retard
the mobility of macromolecules such as proteins.
[0162] In general, the particles in the spreading layer should be
inert and wettable. Additional properties of the spreading layer
may include, for example, the ability to define a known volume of
liquid in a known area, which is a function of particle size. In
certain embodiments, the spreading layer provides a white or
reflective surface for optical spectroscopy.
[0163] Preferred particulate materials for the spreading layer
include commercially available latex beads with a diameter of from
below 1 micron to several hundred microns, most preferably from
about 40 to about 200 microns. Cellulose acetate or inorganic
particulate materials such as barium sulfate also can be used. The
distance between particles in the spreading layer should result in
average pore sizes of from about 1.5 microns to about 50 microns,
most preferably from about 10 to about 30 microns. The void volume
in the spreading layer should range between from about 60% to about
90%.
[0164] Latex and cellulose acetate are preferred materials for the
spreading layer because manufacturers can control the
polymerization reaction for these materials and, thus, can control
particle size. Control of particle size is important to control the
volume of liquid retained, as previously discussed. Moreover, with
respect to electrostatic deposition of the spreading layer,
particle size influences the degree of charging, deposition and,
ultimately, the accuracy and uniformity of coverage. These
relationships are well-known to those of skill in the art.
[0165] It is preferred that the particles of the spreading layer be
deposited in a uniform layer with a thickness of at least a
monolayer. The thickness of this layer will be dictated by particle
size and by the desired volume capacity. Various geometries of the
spreading layer, for example, a concave geometry to form a "cup"
for the liquid sample, are also within the scope of the present
invention.
[0166] Additional materials may be deposited onto, or codeposited
with, the spreading layer. Such additional materials may include
surfactants, carriers or binders (for example, polysaccharides),
buffering agents, solvents or reagents for detection. Examples of
reagents for detection that can be deposited electrostatically
include, for example, those utilized in enzyme-coupled reactions,
such as alkaline phosphatase.
[0167] Adhesives
[0168] Adhesives are used, in some embodiments, for bonding the
substrate and cover layer together, and for bonding various
overcoat/overwrap layers to other layers. For buccal, gingival and
nasal locations, the adhesive advantageously provides good adhesion
and is non-toxic. Suitable adhesives include, without limitation,
synthetic rubber, acrylic pressure-sensitive adhesives, dental
temporary, and maltodextrin. For dermal applications, the adhesive
advantageously provides good adhesion and is non-allergenic. A
suitable adhesive is the type used for adhesive bandages. For
vaginal and rectal applications, the adhesive advantageously
exhibits poor adhesion and is non-allergenic. A suitable adhesive
is a "swell-in-place" material such as polysaccharide.
[0169] All patents and patent applications cited in this
specification are incorporated herein by reference in their
entirety. Any patent application to which this application claims
priority is also incorporated herein by reference in its
entirety.
[0170] It will be understood by those skilled in the art that
variations in the illustrated devices and methods may suitably be
used in conjunction with the present invention and that the
invention may be practiced otherwise than as specifically
described. Accordingly, this invention includes all modifications
encompassed within the spirit and scope of the invention as defined
by the claims that follow.
* * * * *