Patent Document

STATEMENT OF RELATED APPLICATIONS 
     The present invention is related to International Application No. PCT/US99/12772 filed Jun. 8, 1999 entitled “Pharmaceutical Product and Methods and Apparatus for Making Same.” 
    
    
     FIELD OF THE INVENTION 
     The present invention relates to improvements in an apparatus for the manufacture of pharmaceutical products. 
     BACKGROUND OF THE INVENTION 
     In the pharmaceutical industry, pharmaceutical products are typically embodied as tablets, caplets, test strips, capsules and the like. Such products, which include diagnostic products, include one or more “unit dosage forms” or “unit diagnostic forms” (collectively “unit forms”). 
     Each of the unit forms typically contains at least one pharmaceutically- or biologically-active ingredient (collectively “active ingredient”) and, also, inert/inactive ingredients. Such active and inactive ingredients, typically available as powders, are suitably processed to create the unit forms. 
     In the above-referenced International Patent Application, which is incorporated herein by reference, applicant discloses an apparatus for manufacturing such unit forms. The apparatus utilizes an electrostatic deposition process whereby powder(s) containing active and/or inactive ingredients are deposited on a substrate at discrete locations thereby producing the unit forms. To provide context for the present invention, the deposition apparatus, its operation, and illustrative unit forms produced thereby are described below. 
     FIGS. 1-4 depict one embodiment of a unit form  6  produced by the electrostatic deposition apparatus. FIG. 1 depicts a plurality of such unit forms  6  arrayed on a strip  4 . In the illustrated embodiment, strip  4  comprises a substrate  8  and a cover layer  10 , each of which comprise a substantially planar, flexible film or sheet. In some embodiments, one of either substrate  8  or cover layer  10  include an array of semi-spherical bubbles, concavities or depressions (hereinafter “bubbles”)  12  that are advantageously uniformly arranged in columns and rows. 
     Unit form  6  comprises active ingredient  14 , a portion of cover layer  10  defining bubble  12 , and a region of substrate  8  within bonds  7 . FIG. 2 (showing cover layer  10  partially “peeled” back from substrate  8 ) and FIG. 3 (showing a cross section of a portion of strip  4 ) depict a deposit of dry active ingredient  14 , in the form of a powder, disposed between substrate  8  and cover layer  10  within bubble  12 . FIG.  3  and FIG. 4 (showing a top view of a unit form  6 ) depict substrate  8  and cover layer  10  attached to one another via bonds  7  that are near to and encircle bubble  12 . 
     Deposition Apparatus 
     FIG. 5 depicts, via a high-level block diagram, deposition apparatus  1  suitable for making unit form  6 . Apparatus  1  comprises platform  102  wherein unit forms  6  are produced. Platform  102  performs a variety of operations including the electrostatic deposition of dry powder on defined discrete regions of a substrate, materials handling, alignment operations, measurement operations and bonding operations. 
     Electrostatically-charged powder is delivered to platform  102  for deposition via powder feed apparatus  402 . In some embodiments, platform  102  and/or powder feed apparatus  402  are isolated from the ambient environment by an environmental enclosure. In such environments, environmental controller EC provides temperature, pressure and humidity control for platform  102  and powder feed apparatus  402 . Further description of platform  102  and powder feed apparatus  402  is provided later in this section. 
     Processor P and controller C control various electronic functions of apparatus  1 , such as, for example, the application of voltage for the electrostatic deposition operation, the operation of powder feed apparatus  402 , the operation of robots that are advantageously used in conjunction with platform  102 , and dose measurement operations. To facilitate such control functions, memory M is accessible to processor P and controller C. 
     FIGS. 6 and 7 depict a top view and a front elevational view, respectively, of illustrative platform  102 . In some embodiments, platform  102  comprises bench  214  that incorporates five processing stations that perform various operations used to produce the present product. Briefly, those processing stations include: storage station  220 , which advantageously comprises three substations  220 A,  220 B and  220 C for storing substrates and cover layers; alignment station  230  for assuring that the substrate and cover layer are properly adhered to a transport mechanism (e.g., robotic elements) that delivers them to other processing stations; deposition station  250  where powder is deposited on the substrate; dose measurement station  240  for measuring the amount of powder that is deposited on the substrate; and lamination station  260  where the cover layer is laminated to the substrate. 
     As depicted in FIG. 7, four supports  216  elevate bench  214  above a table or like surface. Additionally, supports  216  advantageously provide a frame or superstructure for optional side-mounted barriers  218 , depicted in FIG.  6 . The side-mounted barriers, in conjunction with a top barrier (not shown) and bench  214  define an environmental enclosure or chamber that isolates the region therein from the ambient environment under air or inert gas. 
     To facilitate the various processing operations, as well as materials handling between the processing stations, platform  102  advantageously includes a transport means. In the embodiment illustrated in FIG. 7, the transport means is a robotic system that includes first robotic transport element  270  and second robotic transport element  280  that are movable along first rail  290 . First rail  290  functions as a guide/support for movement in one direction (e.g., along the x-axis). An additional rail (not shown) movably mounted on first rail  290  functions as a guide/support for movement in a direction orthogonal to but in the same plane (e.g., the y-axis) as first rail  290 . Such rails collectively provide x-y motion. Drive means (not shown), such as x-y stepper motors, move robotic transport elements  270  and  280  along the rails. 
     Receiver  272  is attached to first robotic transport element  270  and “bonding” head  282  is attached to second robotic transport element  280 . Receiver  272  is operable to retrieve at least the substrate from the substation where it is stored (i.e.,  220 A or  220 B or  220 C) and to move it to at least some of the various operational stations  230 - 260  for processing. Bonding head  282  is operable to join/seal the substrate and cover layer to one another to create the unit forms  6 . 
     First and second robotic transport elements  270  and  280  have telescoping components under servo control (not shown) that provide movement along the z axis (i.e., normal to the x-y plane). Such z-axis movement allows receiver  272  and bonding head  282  to move “downwardly” toward a processing station to facilitate an operation, and “upwardly” away from a processing station after the operation is completed. 
     Moreover, robotic transport elements  270  and  280  advantageously include θ control components under servo control (not shown) that allow receiver  272  and bonding head  282  to be rotated in the x-y plane as may facilitate operations at a processing station. Compressed dry air or other gas is suitably provided to operate the robotic transport elements. Robotic transport elements  270  and  280  can be based, for example, on a Yaskawa Robot World Linear Motor Robot available from Yaskawa Electric Company of Japan. 
     As previously indicated, powder comprising an active ingredient is electrostatically deposited at discrete locations on substrate  8  at deposition station  250 . In the illustrated embodiments, accomplishing such deposition requires that, among other things, substrate  8  is transported to deposition station  250  from some other location, and that an electrostatic charge is developed that causes the powder to electrostatically deposit on substrate  80 . Such transport and charging operations are facilitated, at least in part, via receiver  272  and electrostatic chuck  302 . 
     FIG. 8 depicts a view of first surface  304  of electrostatic chuck  302 . Electrostatic chuck  302  comprises a layer  303  of dielectric material. The electrostatic chuck has a thickness of about 0.01 inches (0.25 mm), and, as such, is relatively flexible. Illustrative electrostatic chuck  302  has “through holes” ECH implemented as slots that are disposed at its periphery. First surface  304  further includes a plurality of powder collection zones CZ. In illustrative electrostatic chuck  302 , collection zones CZ are advantageously organized in eight columns  306   C1-C8  of twelve collection zones each for a total of ninety-six collection zones CZ. As will be described in further detail later in this specification, each collection zone CZ corresponds to a powder deposition location on the substrate (see substrate  8  in FIG.  1 ). Collection zones CZ are formed within electrostatic chuck  302  by an arrangement of dielectric and conductive regions, several embodiments of which are described later in this section in conjunction with FIGS. 10 a - 10   c.    
     FIG. 9 depicts a view of second surface  308  of electrostatic chuck  302 . As depicted in more detail in FIGS. 10 a - 10   c , collection zones CZ are formed via electrical contact pads  310 . Such electrical contact pads  310  provide contact points for connection to a controlled voltage source. 
     Electrical contact pads  310  are electrically connected to selected other electrical contact pads via address electrodes  312 . By virtue of such groups of selected electrical connections (e.g., the pads  310  within a given column  306   C1-C8  of illustrative chuck  302  of FIG. 9 defines an illustrative grouping), a first voltage can be applied to contact pads  310  in column  306   C1 , while a second voltage different from the first voltage can be applied to contact pads  310  in second column  306   C2 , and so forth varying the voltage applied to contact pads  310  on a column-by-column basis as desired. It will be understood that the application of such different voltages to such different columns results in depositing a different amount of powder at collection zones CZ in each of such columns. In other embodiments, address electrodes are arranged differently thereby creating electrical interconnects between differently-arranged groupings of contact pads  310 . For the layout of contact pads  310  and address electrodes  312  depicted in FIG. 9, voltage need only be applied to a single contact pad  310  within a given column  306  to develop substantially the same electrostatic charge at each contact pad  310  within that column. 
     FIGS. 10 a - 10   c  depict several illustrative embodiments of structural arrangements suitable for forming collection zones CZ within an electrostatic chuck, such as electrostatic chuck  302 . For clarity of illustration, the structure associated with only a single collection zone CZ of an electrostatic chuck is depicted in FIGS. 10 a - 10   c.    
     In a first embodiment depicted in FIG. 10 a , a conductive material  314  is disposed through layer  303  of dielectric at each region designated to be a collection zone CZ. The conductive material overlays a portion of first surface  304  and second surface  308  of the electrostatic chuck. The portion of conductive material  314  overlying first surface  304  comprises a powder-attracting electrode  316 A, while the portion of conductive material  314  overlying the second surface  308  comprises electrical contact pad  310 A (which is one embodiment of electrical contact pad  310  previously mentioned). A shield electrode  318  (also termed a “ground electrode” based on a preferred bias) is disposed within layer  303 . 
     Applying a voltage to electrical contact pad  310 A generates an electrostatic field at powder-attracting electrode  316 A at collection zone CZ. As described later in this section, the electrostatic field attracts charged powder to the substrate  8  that engages first surface  304  of the electrostatic chuck. Additionally, the electrostatic field aids in holding substrate  8  flat against first surface  304 . Tight adherence of the substrate  8  to the electrostatic chuck increases the reliability, consistency, etc., of powder deposition at the collection zones. A reduced pressure that is developed in receiver  272  to which the substrate  8  is exposed also assists in adhering the substrate to the electrostatic chuck. 
     FIG. 10 b  depicts a second illustrative embodiment where via hole V is formed at electrical contact pad  310 B and powder-attracting electrode  316 B. FIG. 10 c  depicts a third illustrative embodiment wherein an additional layer  305  of dielectric material separates powder-attracting electrode  316 C from substrate  8 . Electrical contact-pad  310 C overlays second surface  308 . 
     The electrostatic chuck provided by the configuration depicted in FIG. 10 c  can be termed a “Pad Indent Chuck” which is useful, for example for powder depositions of less than about 2 mg, preferably less than about 100 μg, per collection zone CZ (assuming, for example, a collection zone having a diameter within the range of 3-6 mm diameter). The electrostatic chuck provided by the configuration depicted in FIG. 10 a  can be termed a “Pad Forward Chuck” which is useful, for example, for powder depositions of more than about 20 μg per collection zone CZ (again assuming a collection zone of about 3-6 mm diameter). The Pad Forward Chuck is more useful than the Pad Indent Chuck for higher dose depositions. 
     As described further below, electrostatic chuck  302  is engaged to receiver  272  during at least some deposition-apparatus operations (e.g., during electrostatic deposition of powder on the substrate  8 ). FIG. 11 depicts underside  274  of receiver  272  with electrostatic chuck  302  adhered thereto. Electrostatic chuck  302  has alignment features  320 , such as pins or holes, by which it is aligned to complementary holes or pins (not shown) in the receiver. Also depicted are alignment pins  276  that are received by complementary holes in bench  214  for aligning receiver  272  to various processing stations (e.g., deposition station  250 ). Height-adjustable vacuum cups  278  are advantageously used to attach an alignment frame (not shown), which can be used in conjunction with the substrate, to the receiver. 
     The powder deposition process proceeds via electronic control of electrostatic chuck  302 . As previously described, the deposition apparatus  1  advantageously includes central processor P and controller C for performing calculations, control functions, etc. (see FIG.  5 ). Processor P receives performance input from multiple sources, including, for example, on-board sensors and historical data from dose measurement station  240 , and uses such information to determine if operating parameters should be adjusted to keep powder deposition within specification. Such input includes, for example, data pertaining to the rate of powder flux into and through the deposition engine (made up of powder feed apparatus  402  and deposition station  250 ) and the degree to which powder is being evenly deposited at electrostatic chuck  302 . The “on-receiver” electronics described below, either alone or in conjunction with processor  401  and controller  403 , provide a means for adjusting apparatus  1  during operation. 
     In embodiments in which processor P has primary responsibility for processing functions, a secondary processor (not shown) located in receiver  272  functions as a communications board that receives commands from processor P and relays such commands to an addressing board (not shown), also located in receiver  272 . The addressing board then sends bias control signals (DC or AC signals) for controlling the voltage applied to electrical-contact pads  310 . Depending upon the addressing scheme (e.g., the arrangement, if any, by which individual electrical-contact pads  310  are electrically interconnected via address electrodes  312 ), voltage is either regionally (e.g., by columns, rows, etc.) or individually applied. 
     The addressing board preferably has multiple channels of synchronized output (e.g., square wave or DC). The signals sent to the addressing board can be encoded, for example, with a pattern of square wave voltage pulses of varying magnitudes to identify a particular electrical-contact pad/powder-attracting electrode, or a group of such electrodes, together with the appropriate voltage to be applied thereto. 
     The bias control signals are sent via a high voltage board (not shown), which advantageously has multiple channels of high-voltage converters (transformers or HV DC-to-DC converters) for generating the voltages, such as 200 V or 2,500 V or 3,000 V (of either polarity), that energizes powder-attracting electrodes  310 . The high voltage board is advantageously located in receiver  272  so that other systems are isolated therefrom. 
     In some embodiments, the “secondary” on-receiver processor receives data directly from “charge” sensors (not shown) that are positioned on or adjacent to electrostatic chuck  302 . Such sensors monitor the amount of powder being deposited. The on-receiver processor locally interprets and responds to data from such sensors by suitably adjusting the voltage applied to the electrical contact pads/powder-attracting electrodes. 
     Operation of the Deposition Apparatus 
     In operation, first robotic transport element  270  moves receiver  272  and electrostatic chuck  302  adhered thereto (see FIG. 11) to storage station  220 . At station  220   a , electrostatic chuck  302  engages a “virgin” substrate and, in some embodiments, also engages an alignment frame (not shown) that is joined to the substrate. 
     In one embodiment, after engagement, robotic transport element  270  moves receiver  272 , electrostatic chuck  302 , the substrate and frame to alignment station  230 . At the alignment station, the substrate is brought into contact with a pad (e.g., urethane foam, etc.). Such contact advantageously smoothes the substrate against electrostatic chuck  302 . After the substrate is smoothed against the substrate, a suction force is applied that holds the substrate against electrostatic chuck  302 . Flattening and smoothing the deposition surface (ie., the substrate) in such manner improves the consistency of the powder deposits thereon. 
     Robotic transport element  270  then moves engaged receiver  272 , electrostatic chuck  302 , the substrate and frame to dose measurement station  240 . After aligning with a measurement apparatus  242  at station  240 , the substrate is scanned via a measurement device and distances from a reference point to the substrate at each collection zone CZ (see FIGS. 8,  10   a - 10   c  and  11 ) are calculated and recorded to provide baseline data. 
     Robotic transport element  270  then moves engaged receiver  272 , electrostatic chuck  302 , the frame and virgin substrate to deposition station  250 . At deposition station  250 , the substrate abuts gasket  259  that frames deposition opening  258  (see FIG.  6 ). The powder deposition engine (see FIG. 13) is turned on and powder is electro-deposited through deposition opening  258  on the substrate at regions overlying the electrostatic chuck&#39;s collection zones CZ. 
     At the completion of the powder-deposition operation, robotic transport element  270  returns the substrate, with its complement of discreetly deposited powder, to dose measurement station  240 . At that station, the measurement device again scans the substrate to, determine the distance between the reference point to the surface of each “deposit” of powder. From such distances, and the previously obtained baseline data, the amount (e.g., volume) of powder in each deposition is calculated. If the calculated amount is outside a desired range of a predetermined target amount, such information is displayed. An operator can then suitably adjust operating parameters to bring the process back into specification. In another embodiment, automatic feed back is provided to automatically adjust the process, as required. The “out-of-spec” unit forms may be discarded. 
     Regarding dose measurement, either one or both of two optical measurement methods may be used: diffuse reflection and optical profilometry, both of which methods are known in the art. 
     The diffuse reflection method is based on reflecting or scattering a probe light beam, such as a laser beam, off of the powder surface in directions that are not parallel to the specular reflection direction. Applicants have discovered that measurements obtained based on diffuse reflection using non-absorbing radiation provide a strong correlation with the deposited amount of powder in a unit form, at least up to a certain amount. The limiting amount varies with the character of the powder and is believed to correspond to an amount of powder that prevents light penetration into lower layers. 
     Diffuse reflection in a non-absorbing region provides good accuracy in measuring dose deposition amounts ranging from 50-400 μg, or even as high as 750 μg to  1  mg, for a 3 or 7 mm deposition “dot,” depending on the characteristics of the powder. The diffuse reflection method can detect substantially less than a mono-layer of powder. If the deposit is more than a mono-layer, the probe light beam must partially penetrate the upper layers so that it can be affected by the reflection off of the lower layers to provide an accurate measurement. There tends, however, to be a practical limit (dependent upon the powder) to deposition thickness for it to exhibit “Lambertian” characteristics required for measurement via diffuse reflection. Diffuse reflection is also a measure of the physical uniformity of the dose deposits at the above-listed ranges. 
     Optical profilometry is useful for obtaining dose measurements that are above the ranges that can be accurately measured by the diffuse reflection method. In optical profilometry, light is directed to the deposit and scattered therefrom at an angle that is indicative of the height of the deposit. That height is readily calculated by triangulation. The profilometer can be, for example, a confocal profilometer. A confocal profilometer suitable for use in conjunction with the present invention is available from Keyence (Keyence Corp., Japan, or Keyence Corporation of America, Woodcliff Lake, N.J.) as Model LT8105. 
     Continuing, second robotic transport element  280  picks up a cover layer and, advantageously, an alignment frame from storage station  220  and delivers them to lamination support block  502  (see FIG. 12) at lamination station  260 . After measurements are completed at dose measurement station  240 , first robotic transport element  270  delivers the substrate with the deposited powder to lamination station  260 . First robotic transport element  270  places substrate  8  on cover layer  10  such that the deposits of powder  14  are properly aligned within the perimeter of the bubbles  12  in the cover layer  10  (see FIG.  12 ). 
     After first robotic transport element  270  moves away, second robotic transport element  280  returns and, by the operation of bonding head  282 , attaches the substrate and cover layer together, forming a plurality of unit forms on a strip (see FIG.  1 ). In an automated system, the unit forms may be automatically transferred to a packaging station wherein out-of-specification unit forms are screened out and in-spec unit forms are appropriately packaged. 
     Apparatus  1  for electrostatic deposition provides a product containing a plurality of pharmaceutical or diagnostic unit forms, each comprising at least one pharmaceutically or diagnostic active ingredient that advantageously does not vary from a predetermined target amount by more than about 5%. 
     The deposition “engine,” which comprises deposition station  250  on platform  102  and powder feed apparatus  402 , can be a source of a variety of operational problems. Such problems include, for example, powder compaction, non-uniform powder flux, powder loading difficulties, operating instabilities and powder size limitations, among others. While the powder feed apparatus that is disclosed in International Application No. PCT/US99/12772 (and described briefly below) has been designed to avoid many of such problems, room for improvement in that apparatus exists. Such improvement is a goal of the present invention. Before addressing such improvements, which are described later in this Specification in the “Summary” and “Detailed Description” sections, an embodiment of the existing powder feed apparatus is described. 
     The Deposition Engine 
     Illustrative powder feed apparatus  402  includes powder-delivery system  403 , which charges the powder via a powder-charging system  416  and delivers it to powder distributor  418 . The powder distributor delivers the charged powder to deposition station  250  for deposition on the substrate  8  (electrostatic chuck and receiver not shown for clarity of illustration) that abuts gasket  259  framing deposition opening  258 . Powder that is not deposited on the substrate is drawn back by a pressure differential through powder-evacuation tubes  426  to powder trap  428 . Gas exiting powder trap  428  is delivered to HEPA filter  430 . 
     In the illustrated embodiment, powder-delivery system  403  comprises auger rotation motor  404 , hopper  406 , vibrator  408 , auger  410 , clean gas source  414  feeding modified venturi feeder valve  412 , and powder-charging system  416 , interrelated as shown. In some embodiments, feeder valve  412  feeds powder-charging system  416 . With the exception of powder-charging system  416 , illustrative powder delivery system  403  is disposed substantially within enclosure  432 , which is depicted in phantom for clarity of illustration. 
     In the illustrated embodiment, the powder-charging system is realized as a tube, referred to hereinafter as powder-charging feed tube  416 . It will be understood, however, that in other embodiments, arrangements for powder charging other than the illustrated tube may suitably be used. 
     In place of venturi  412 , a gas source can be provided to propel powder through powder charging feed tube  416 . In one embodiment, gas source  414  directs gas pressure towards the outlet of a mechanical device that feeds powder. The gas jet can be directed and adjusted to act to de-agglomerate powder at that outlet. 
     In an alternate embodiment (not depicted), the hopper and auger arrangement depicted in FIG. 13 can be replaced with a rotating drum that temporarily stores powder and delivers it to a movable belt. The movable belt then transports the powder to a means for removing the powder from the belt. An example of such a means is a thin, high velocity jet of gas that blows the powder into powder charging feed tube  416  or a conduit in communication therewith. 
     For electrostatic deposition, the powder must be charged. This function is accomplished, as described above, by the powder-charging system (e.g., powder-charging feed tube  416 ). Some further details concerning powder charging is now provided. 
     In one embodiment, powder charging feed tube  416  is made of a material that imparts, by triboelectric charging, the appropriate charge to the powder as it transits the tube making periodic collisions with the sides thereof. As is known in the art, TEFLON®, a perfluorinated polymer, can be used to impart a positive charge to the powder (where appropriate for the powder material) and Nylon (amide-based polymer) can be used to impart a negative charge. 
     In so charging the powder, the tube builds up charge which can, if not accommodated, discharge by arcing. Accordingly, a conductive wrap or coating is applied to the exterior of powder charging feed tube  416  and grounded. Tube  416  can be wrapped, for example, with aluminum or copper foil, or coated with a colloidal graphite product such as Aquadag®, available from Acheson Colloids Co. of Port Huron, Mich. Alternatively, powder charging feed tube  416  can be coated with a composition comprising graphite or another conductive particle such as copper or aluminum, an adhesive polymer, and a carrier solvent, mixed in amounts that suitably preserves the “tackiness” of the adhesive polymer. An example of such a composition is 246 g trichloroethylene, 30 g polyisobutylene and 22.5 g of graphite powder. 
     The charge relieved by the grounding procedures outlined above can be monitored to provide a measure of powder flux through powder charging feed tube  416 . This data is advantageously sent to processor P for analysis. As a result of such analysis, deposition operating parameters can be modified, as appropriate, to maintain an on-specification operation. 
     Another way to impart charge to the powder is by “induction” charging. One way to implement induction charging is to incorporate an induction-charging region in powder charging feed tube  416 . More particularly, at least a portion of powder charging feed tube  416  comprises a material such as a stainless steel, which is biased by one pole from a power supply, with the opposite pole grounded. With an appropriate bias, an electric field is created in the induction-charging region such that powder passing through it picks up a charge. The length of the induction-charging region can be adjusted as required to impart the desired amount of charge to the powder. In one embodiment, induction charging is used in conjunction with the tribocharging features described above. 
     In yet another embodiment, powder is charged by “corona charging,” familiar to those skilled in the art. See, for example, J. A. Cross, “Electrostatics: Principles, Problems and Applications,” IOP Publishing Limited (1987), pp. 46-49. 
     As previously indicated, powder charging feed tube  416  feeds charged powder via powder distributor  418  into deposition station  250 , which is enclosed by enclosure  252 . In the illustrated embodiment, powder distributor  418  comprises rotating baffle  424  that depends from nozzle  422 . Nozzle motor  420  drives the rotating baffle. 
     Powder moving towards substrate  8  passes through control grid  254 . Control grid  254  is advantageously disposed a distance of about one-half to about 1.0 inch below collection zones CZ of the electrostatic chuck (not shown in FIG.  12 ), and is biased at about 500 V per one-half inch of such distance at the polarity intended for the powder. Control grid  254  thus “collimates” the powder cloud thereby attracting powder having an opposite charge (to the charge on the control grid). 
     Control grid  254  can be, for example, a series of parallel electrical wires, such as can be formed from “switchbacks” of one wire, or, alternatively, a grid of wires. Spacing between parallel sections of wire is advantageously within the range of about 5 to about 15 mm. The rate of powder cloud flux can be monitored by measuring light attenuation between light emitter  256  (e.g., a laser emitter) and light detector  257 . This value can be transmitted to processor P. 
     It has been found that fluctuations occur in the gas/powder flow through the deposition engine described above. Such fluctuations negatively impact deposition performance. The fluctuations are due, at least in part, to: 
     (1) the non-axisymmetric geometry of some embodiments of rotating baffle  424  and deposition station  250 ; 
     (2) the pulsing manner in which powder is delivered by some embodiments of powder delivery system  403 ; and 
     (3) flow instabilities due to boundary layer separation and vortex shedding. 
     It will be appreciated that it is desirable to reduce such gas/powder flow fluctuations to improve the performance of the deposition apparatus. 
     SUMMARY OF THE INVENTION 
     In accordance with the illustrative embodiment of the present invention, flow fluctuations observed in the existing deposition apparatus are reduced using a flow diffuser. The flow diffuser, which replaces the powder distributor of the existing deposition apparatus, comprises a conduit having a cross-sectional area that increases in the direction of powder flow. The increase in cross section controllably slows the gas flow to a velocity wherein electrostatic forces dominate the motion of the powder transported via the gas. 
     In some embodiments, the diffuser includes one or more flow control features. A first flow-control feature comprises one or more appropriately-shaped annular slits through which gas is injected into a “boundary layer” near the wall of the diffuser. The injected gas has a greater momentum than the gas in the boundary layer. Such injected gas serves several purposes, as itemized below. 
     1. Reducing the tendency for boundary-layer separation. 
     2. Directing/shaping the “powder cloud” (ie., the powder-transporting gas) towards a central axis of the diffuser. Such shaping counteracts an existing tendency for charged particles to repel one another, which tendency would otherwise cause the powder to migrate away from the central axis of the diffuser. 
     3. Providing a “gas-curtain” effect that reduces the tendency for powder contained in the powder cloud to get stuck against the diffuser wall. 
     A second flow control feature comprises one or more annular slits, or a multiplicity of slots/holes that are disposed at appropriate locations around the circumference of the diffuser. Such openings are in fluid communication with a pressure-differential generating means. The pressure-differential generating means generates a pressure differential across the openings in the diffuser such that pressure on the exterior of the diffuser is less than the pressure in the interior of the diffuser. As such, a portion of the powder-transporting gas in the slow-moving boundary layer is removed. Removing such slower-moving gas contributes to a flattening of the velocity profile of the powder-laden gas in the diffuser. And, such velocity-profile flattening tends to stabilize the powder-laden gas flow by preventing flow separation or at least delaying its onset. 
     Thus, the diffuser, the flow control features, and other elements related to powder delivery to the deposition station advantageously reduce spatial and temporal variations in the velocity of the powder-laden gas. The resulting increase in the uniformity of the flow-field improves control over the deposition operation. Such improved control results in an improvement in the uniformity and precision (i.e., the variation in the amount of active ingredient from a target amount) of depositions. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     FIG. 1 depicts an isometric view of a strip containing a plurality of unit forms. 
     FIG. 2 depicts a cover layer of a strip package partially separated from a substrate. 
     FIG. 3 depicts a side view of an illustrative unit form. 
     FIG. 4 depicts a top view of the illustrative unit form of FIG.  3 . 
     FIG. 5 depicts a high-level block diagram of an apparatus suitable for producing the unit forms of FIGS. 1-4. 
     FIG. 6 depicts a top view of a platform wherein processing operations occur. 
     FIG. 7 depicts a side elevation of the platform of FIG.  7 . 
     FIG. 8 depicts a plan view of a first surface of an illustrative electrostatic chuck. 
     FIG. 9 depicts a plan view of a second surface of an illustrative electrostatic chuck. 
     FIGS. 10 a - 10   c  depict side cross-sectional views of embodiments of the electrostatic chuck of FIGS. 8 and 9 near a collection zone. 
     FIG. 11 depicts the underside of the illustrative receiver with the electrostatic chuck adhered thereto. 
     FIG. 12 depicts a lamination support block for laminating the substrate and cover layer together. 
     FIG. 13 depicts a deposition engine for electrostatically depositing powder on a substrate. 
     FIG. 14 depicts a portion of an improved deposition apparatus in accordance with the present teachings, the depicted portion including a diffuser. 
     FIG. 15 depicts an illustrative boundary-layer gas injector. 
     FIG. 16 depicts a top cross-sectional view of a first illustrative embodiment of an annular channel in a boundary-layer gas injector and four injection nozzles. 
     FIG. 17 depicts a top cross-sectional view of a second illustrative embodiment of an annular channel in a boundary-layer gas injector and four injection nozzles. 
     FIG. 18 depicts an illustrative embodiment of a manual control system for adjusting boundary-layer gas injection responsive to the powder deposition data. 
     FIG. 19 depicts an illustrative embodiment of an automatic control system for adjusting boundary-layer gas injection responsive to the powder deposition data. 
     FIG. 20 depicts a characteristic angle used to describe the diffuser configuration. 
     FIG. 21 depicts a further embodiment of a diffuser in accordance with the present teachings. 
     FIG. 22 depicts an illustrative flow straightener for use in conjunction with the present diffuser. 
     FIG. 23 depicts a cross-sectional end-view depicts tubes within a flow straightener. 
     FIG. 24 depicts a side view of a focusing electrode for use in conjunction with electrostatic deposition. 
     FIG. 25 depicts the focusing electrode as viewed from the bottom of the electrostatic chuck. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     In this Detailed Description, reference is made to well-understood fluid dynamics concepts, including, for example, “boundary layer” and “flow separation” theory. Since such concepts are well-known to those skilled in the art, they will not be defined or discussed herein. 
     FIG. 14 depicts a portion of deposition apparatus  1 A in accordance with the present teachings. The portion of apparatus  1 A depicted in FIG. 14 includes a region of powder-charging feed tube  416 , flow straightener  517 , diff-user  518 , and deposition station  550 . FIG. 14 also shows substrate  8 , electrostatic chuck  302  and receiver  272  all engaged to deposition station  550 . 
     Powder-laden gas leaves powder-charging feed tube  416  and enters flow straightener  517 , wherein turbulence in the powder-laden gas is reduced. As described in further detail later in this Specification, the flow straightener can be used to tailor the flow profile within the diffuser. From the flow straightener  517 , the powder-laden gas enters diffuser  518 . The cross-sectional area of diffuser  518  increases in the direction of flow. As such, average fluid velocity decreases as the powder-laden gas  540  moves through diffuser  518 . As the powder-laden gas flows through the diffuser, it eventually encounters a region wherein the gas velocity slows to the extent that electrostatic forces generated by the spacecharge of the powder, electrostatic chuck  302  and optional focusing electrode (see FIGS. 16 and 17) dominate the motion of the powder. This region is referred to herein as “particle drift zone  534 .” The specific location of particle drift zone  534  is dictated by flow parameters and electrostatic-field strength. By way of illustration, in some embodiments, the particle drift zone may occupy as much or more than the latter one-half of the diffuser. 
     Diffuser  518  is formed from a material that is compatible with the deposition process being used. For example, in the illustrated embodiments, the diffuser is used in conjunction with an electrostatic deposition process. As such, the interior surface of wall  521  of diffuser  518  must be capable of accepting an electrical charge and maintaining it. Moreover, the material must be compatible with the charging characteristic of the powder and the charging method (e.g., if the powder is positively charged, the material comprising wall  521  must not change the positive charge to a negative charge). Furthermore, to the extent that the diffuser is used in conjunction with a process that is producing pharmaceuticals, the material must satisfy pertinent FDA regulations. 
     As will be apparent to those skilled in the art, when the present diffuser is used in conjunction with an electrostatic deposition process, the diff-user should be formed from a dielectric material, such as any one of a variety of plastics, including, without limitation, acrylic and polycarbonate plastics. To the extent that the present diffuser is used in conjunction with other types of powder deposition processes, or more generally, in other types of powder-delivery systems, other materials requirements may be controlling. 
     Charged powder  544  is moved through the diffuser under the control of aerodynamic forces of the flowing fluid until it enters particle drift zone  534 . In the particle drift zone, electrostatic forces control powder movement, since, in this region of the diffuser, such forces dominate aerodynamic forces. In other words, in particle drift zone  534 , the powder does not follow the flow streamlines of the gas. 
     Gas  542 , substantially sans powder, is withdrawn from diffuser  518  at annular slit  530 . The gas is ultimately withdrawn via several circumferentially-located outlets  526 . The annular slit  530  is advantageously well rounded, as depicted at region  532 , to avoid introducing turbulence into the uniform flow profile established by diffuser  518 . Powder  544  is deposited on substrate  8  at regions overlying the collection zones (not shown) of electrostatic chuck  302 . 
     In some embodiments, one or more flow-control features are advantageously used in conjunction with diffuser  518 . A first flow control feature is the injection of gas  548  into the “boundary layer” flow within the diffuser. The injected gas, which can be, for example, nitrogen, should have a greater momentum than the powder-laden gas flowing in the boundary layer (such momentum calculations are readily performed by those skilled in the art). The injected gas is introduced through a boundary-layer gas injector, which comprises one or more annular slits in diffuser  518 . In the embodiment depicted in FIG. 14, gas is injected into the boundary-layer at two locations: a first injection slit  520  disposed near the inlet of diffuser  518  and a second injection slit  522  disposed near the mid-point of the diffuser. 
     The boundary-layer injection gas is injected into the diffuser in the form of a thin stream, and is “directed” to flow along wall  521 . In one embodiment, the gas is directed toward wall  521  by having the injection slits (e.g.,  520  and  522 ) inject the gas towards wall  521 . In a second embodiment, the injection slit is substantially perpendicular to wall  521  of the diffuser (ie., nominally directing injected gas away from nearby wall  521  and towards the central flow region). In the second embodiment, the “upstream” wall of the slit (i.e., the slit wall nearest the diffuser inlet) is provided with a sharp edge, and the “downstream” wall of the slit is provided with a well-rounded edge. As a result of this arrangement, the injected gas turns the rounded edge to remain near wall  521 . This effect, known as the Coanda effect, is known to those skilled in the art. 
     The boundary-layer gas injection improves flow uniformity. In particular, such injection reduces or prevents flow separation at the interior surface of wall  521  of diffuser  518 . Moreover, gas injection effects a “shaping” or “steering” of powder-laden gas  540  toward central axis  519  (see FIG. 15) of diffuser  518 . Such steering counteracts the tendency of the charged particles to move away from the central axis due to the mutual repulsion of such similarly-charged particles. Additionally, such gas injection provides a “gas curtain” effect, wherein powder contained in the gas  540  is kept away from the interior surface of diffuser wall  521 , thereby reducing the tendency for powder to accumulate thereon. 
     Further embodiments of illustrative boundary-layer gas injectors are described in conjunction with FIGS. 15-19. FIG. 15 depicts an “enlargement” of the region near injection slit  520  of diffuser  518  depicted in FIG.  14 . In the embodiment depicted in FIG. 15, the boundary-layer gas injector further comprises two nozzles  660 A and  660 B, annular channel  662 , and fasteners (received by bores  664 A and). The gas that is to be injected into the boundary layer is delivered to annular channel  662  from nozzles  660 A and  660 B. Fasteners, such as screws or the like (not shown),that are received by bores  664 A and  664 B control the size of slit  520 . In particular, tightening one of the fasteners (e.g., the fastener in bore  664 A) more than the other fastener (e.g., the fastener in bore  664 B) causes the slit to be slightly larger at one region (e.g., near bore  664 B) than at another region (e.g., near bore  664 A). 
     When the flow rate of injection gas into nozzles  660 A and  660 B is equal, the flow of injection gas through injection slit  520  will be relatively greater at a region at which the injection slit is relatively larger. It has been found that such a variation in the boundary layer gas injection will affect flow distribution near the outlet of diffuser  518  and can ultimately affect the powder distribution on substrate  8 . 
     In a further embodiment of a diffuser in accordance with the present teachings, boundary layer gas injection is regionally varied by introducing additional injection nozzles, as is depicted in FIG.  16 . FIG. 16 depicts a top-cross sectional view of the annular channel  662 . As shown in FIG. 16, four nozzles  660 A- 660 D deliver injection gas to annular channel  662 . By individually varying the flow of injection gas through nozzles  660 A- 660 D, the flow distribution near the outlet of diffuser  518  can be affected (e.g., a greater amount of powder can be directed to a particular region of the substrate). While four nozzles are depicted in FIG. 16, a greater number of nozzles can be used, thereby providing an even greater measure of control over the downstream powder distribution. 
     FIG. 17 depicts yet a further embodiment wherein annular channel  762  is segmented into regions via dividers  766 . The flow of injection gas within a particular region of the channel is thus dictated via the nozzle feeding that region. Such an arrangement is expected to provide a greater measure of control over downstream powder distribution than continuous annular channel  662  depicted in FIG.  16 . 
     As described earlier in this Specification, “charge” sensors (which actually measure current) disposed on or near electrostatic chuck  302  can be used to determine the amount of powder being deposited on a regional basis on the substrate. In some embodiments, sensors are provided at each collection zone CZ such that the powder distribution is known at each point across substrate  8 . Such information can be used as the basis for a closed-loop control system (feedback or feedforward) wherein the boundary-layer gas injection flow is adjusted to correct any deviations in the powder distribution. 
     FIG. 18 depicts a manual control scheme wherein the output from the charge sensors CS is delivered to processing electronics PE, and an indication of the powder distribution is provided to an operator (e.g., displayed on a display device DD). The operator can then manually adjust the boundary-layer gas injection via flow-control means, such as mass-flow controllers MFC, that individually control the flow of injection gas through each nozzle  660 . 
     FIG. 19 depicts an automatic control loop wherein the output of the charge sensors CS is delivered to appropriate processing electronics PE including a suitably-programmed processor PP that determines how the boundary layer flow should be adjusted to correct deficiencies in the powder distribution. One or more signals RS are generated that reset the set-point of a controller FC that controls the operation of a flow-control valve CV feeding each nozzle  660 . Controllers FC generate a control signal CS that causes the controlled valve to incrementally open or close thereby increasing or decreasing flow therethrough. 
     A second flow control feature that is used in conjunction with some embodiments of the present diffuser comprises a “boundary layer” gas suction, wherein gas is withdrawn from the slowly-moving boundary layer (not depicted) adjacent interior surface of wall  521  through a boundary-layer gas aspirator. The boundary-layer gas aspirator comprises one or more openings in wall  521  for withdrawing gas  546 , and a pressure-differential-generating means that creates a pressure differential across such openings to draw gas  546  therethrough. In the embodiment depicted in FIG. 14, the boundary-layer gas aspirator comprises multiple rows of slots  524  disposed in wall  521 . As depicted in FIG. 14, slots  524  are advantageously offset, on a row-by-row basis, from slots  524  in an adjacent row. In other embodiments, an annular slit configured in the manner of injection slits  520  and  522  can be used for the boundary layer gas suction. 
     In the illustrated embodiment, the pressure-differential-generating means includes a pressure-tight shell/enclosure  528  and a suction flow generating means (not shown) that is in fluid communication with shell  528 . The suction flow generating means creates a flow  550  out of said enclosure  528 . Flow  550  establishes the pressure differential across holes  524  that withdraws gas  546  from the boundary layer. Flow  550  can be generated in a variety of well-known ways, such as, for example, by using a piston or diaphragm-type vacuum pump or a jet ejector. 
     In some embodiments of the present invention, “vanes” (not shown) are disposed within the diffuser. In one of such embodiments, the vanes are arranged radially about central longitudinal axis  519 . In another of such embodiments, the vanes are configured as a multiplicity of concentric rings that are centered about longitudinal axis  519 . The vanes flatten the velocity profile of powder-laden gas  540 , forestalling flow separation. Such vanes may, however, have a tendency to collect powder from powder-laden gas  540 . 
     It should be understood that the aforementioned flow-control features (i.e., boundary-layer gas injection, boundary-layer gas suction and vanes) are used individually in some embodiments, and in various combinations in other embodiments. 
     The “cone angle” of the diffuser, which is expressed as  2 θ (see FIG.  20 ), affects diffuser performance. While well-known equations express relationships between cone angle and performance parameters, suitable cone angles for the diffuser are best determined by fabricating sample diffusers and then evaluating their performance. 
     The flow-control features described herein facilitate use of greater cone angles, which results in relatively “shorter” diffusers. A cone angle of about 15° has been found to be suitable for a diffuser that does not rely on the additional flow-control features described above. More generally, it is expected that a cone angle within the range of about 10° to about 17° is suitable for such an application. Use of such flow- control features, and ensuring smooth, well rounded surfaces in transition regions (e.g., axial slits, boundary between flow straightener and diffuser, etc.) allows for a significantly greater cone angle. Specifically, in such circumstances, it is expected that satisfactory performance can be obtained with a diffuser cone angle as great as about 25° to about 30°. 
     Illustrative diffuser  518  has a constant cone angle (e.g. 15 degrees). In a further embodiment depicted in FIG. 21, first portion  870  of diffuser  818  has a constant cone angle and second portion  876  of the diffuser  818  has an increasing cone angle. Compare cone half-angle θ 1  at location  882  on the surface of the diffuser nearer beginning  878  of second portion  876  with cone half-angle θ 2  at location  884  on the surface of the diffuser nearer outlet  880  of second portion  876 . 
     In first portion  870 , a relatively moderate cone angle (e.g., 10°-17°) aids in establishing the desired flow profile in diffuser  818 . Once established, the cone angle can be progressively increased while maintaining the desired flow profile. Increasing the cone angle reduces the length of the diffuser (given a target diameter near the outlet of the diffuser). Since abrupt transitions at the wall of the diffuser will disrupt the flow profile, the cone angle at beginning  878  of second portion  876  is advantageously equal to the cone angle at end  874  of first portion  870 . 
     Selecting cone angles for the first and second portion of the diffuser is an application specific task. More particularly, the cone angle is dependent on the gas feed rate, the powder feed rate and the electric charge. By way of illustration, not limitation, the cone angle for first portion  870  is typically in the range of about 10° to about 17°. The cone angle at beginning  878  of second portion  876  is typically in the range of about 10° to about 17° and the cone angle near end  880  of second portion  876  is typically in the range of about 25° to about 35°. 
     It was previously stated that in some embodiments of the present invention, a flow straightener is used in conjunction with the diffuser to “tailor” or adjust the flow profile within the diffuser. FIGS. 22 and 23 depict embodiments of a flow straightener suitable for tailoring the flow profile of powder-laden gas  540  in the diffuser. 
     FIG. 22 depicts flow straightener  917  engaged to diffuser  518 . Transitional region  920  between the flow straightener and the diffuser reduces the likelihood of flow instabilities (e.g., powder settling out of powder-laden gas  540 , etc.). Flow straightener  917  comprises a plurality of tubes  922 . Tubes  922  have a length-to-diameter ratio (L/D) in the range of about 10/1 to 60/1. Passing powder-laden gas  540  through such tubes results in a relatively flat flow profile as the powder-laden gas  540  enters diffuser  518 . 
     It has been discovered that the flow profile of the powder-laden gas near the outlet of the diffuser is dependent, to some extent, on the flow profile of the powder-laden gas before such gas enters the diffuser. Therefore, in some embodiments, flow straightener  917  is advantageously used to tailor the flow profile of the powder-laden gas  540 , as desired. 
     In one embodiment, the flow profile of powder-laden gas  540  is tailored by providing a variation in the diameter of tubes  922  within flow straightener  917 . FIG. 23, which shows a cross-sectional end view of a flow straightener  1017 , depicts an embodiment wherein the diameter of tubes  922  increase with increasing radial distance from the central axis of the flow straightener. Thus, tube  922 D, aligned with the central axis, has the smallest diameter, six tubes  922 C have a somewhat larger diameter than tube  922 D, six tubes  922 B have a larger diameter than tubes  922 C, and six tubes  922 A near wall  924  of the flow straightener have the largest diameter. 
     The arrangement depicted in FIG. 23 generally increases the velocity of the gas near wall  521  as compared to a flow straightener having tubes of equal diameter. Thus, such an approach can be used to flatten the flow profile across the diffuser if a particular diffuser design exhibits an unacceptable radial velocity gradient. In other embodiments, other arrangements of tubes of unequal diameter are used to cause other changes in the flow profile in the diffuser as desired. 
     It was previously indicated that a “focusing electrode” is advantageously used in conjunction with the electrostatic chuck to deposit powder on substrate  8 . An embodiment of such a focusing electrode  1152  is depicted in FIG. 24 (side view) and FIG. 25 (bottom view of electrostatic chuck). 
     In the embodiment depicted in FIG. 24, focusing electrode  1152  is located near substrate  8 . The focusing electrode is configured for easy removal, such as for cleaning, etc. 
     In the embodiment shown in FIG. 25, focusing electrode  1152  comprises a dielectric material coated with a conductor, such as copper. Electrode  1152  includes a plurality of openings  1154  aligned with the collection zones (not shown) of electrostatic chuck  302 . Electrode  1152  is in contact with a controlled voltage source (not shown) operable to place a charge on the conductor that has the same polarity as the charge on the powder. Powder is thus “steered” away from the conductor and through holes  1154  to substrate  8 . 
     It is to be understood that the above-described embodiments are merely illustrative of the invention and that many variations may be devised by those skilled in the art without departing from the scope of the invention. It is therefore intended that such variations be included within the scope of the following claims and their equivalents.

Technology Category: 4