Abstract:
An automated MicroSampling dissolution testing system that is constructed of a base; a plurality of vessels mounted on an invertible, temperature controlled bath manifold; a cleaning manifold; a stirring and sampling assembly for each vessel; an integrated image capture device, a plurality of hydrodynamic, nonresident sampling probes; a non-resident dispensing manifold; a novel fluid handling system; a MicroSampler; a sample transfer mechanism; and a sample and filter storage apparatus.

Description:
PRIORITY CLAIM 
       [0001]    This application claims priority from provisional applications 60/884,238 filed Jan. 10, 2007, 60/884,242 filed Jan. 10, 60/884,252 filed Jan. 10, 60/884,253 filed Jan. 10, 60/961,636 filed Jul. 23, 2007, and 61/003,258 filed Nov. 15, 2007. 
     
    
     BACKGROUND OF THE INVENTION 
       [0002]    Dissolution testing is an analytical technique used to determine the rate at which a pharmaceutical dosage form, usually a tablet, capsule, or transdermal, dissolves into a given media over time. Generally, the release (or dissolution), of the Active Pharmaceutical Ingredient (API) from the dosage into the media is measured for a specified duration under controlled conditions. This measurement is made either by performing in situ measurements with fiber optic probes, or samples are taken at predetermined time points, filtered, and measured on an analytical instrument, most commonly, an HPLC or in-line UV analyzer. The release of API may be rapid, (within minutes), for immediate release dosage forms, or may be significantly longer, (occurring over hours or weeks) for controlled/modified release formulations. 
         [0003]    Conventionally constructed dissolution apparatus most commonly employ a solid base; a vessel manifold mounted on said base which is connected to a circulating, temperature programmable water bath; and a stirring element, which is rotated (or reciprocated) within the vessel. Automated dissolution testing systems generally contain additional dosage, media, and sample handling systems. Requirements for a dissolution testing apparatus are provided in United States Pharmacopeia (USP), Section 711, Dissolution (2000). The underlying process of dissolution testing and apparatus for performing such testing are known in the art. 
       SUMMARY OF THE INVENTION 
       [0004]    The MicroSampling dissolution testing system is comprised of a base; a plurality of vessels mounted on an invertible, temperature controlled bath; a cleaning mechanism; an agitation mechanism for each vessel; a plurality of hydrodynamic, nonresident sampling probes mounted on a sampling mechanism; a non-resident dispensing manifold; a novel fluid handling system; a MicroSampler; a sample transfer mechanism; and a sample and filter storage apparatus. 
         [0005]    In this invention, the base of the dissolution system is comprised of a wash bin, a collection grate, a vessel cleaning manifold, a bath mounting assembly, a locking mechanism, dispensing manifold tracks, and stirring and sampling assembly tracks. 
         [0006]    In accordance with the present invention, a temperature controlled bath is mounted to a mounting assembly. In the preferred configuration of the present invention, the bath mounting assembly is a rotary motor that enables the temperature controlled bath 360° of rotation along the horizontal axis. In addition, the base preferably incorporates a locking mechanism to secure the bath in a proper position (as defined by USP guidelines for dissolution) during testing. For example, a plurality of pneumatic locking pins may extend from the base of the system and insert said pins into a plurality of receiving cavities or bores thereof located linearly whereby said locking pins and cavities interlock the rotatable bath. 
         [0007]    In accordance with the present invention, the temperature controlled bath is comprised of three major components; a plurality of cavities for mounting a plurality of dissolution vessels; a plurality of watertight vessel mounting covers for centering and sealing said dissolution vessels within said bath; and a self-contained heating means for maintaining temperature uniformity within said dissolution vessels. The plurality of cavities contained within the bath enable mounting of a plurality of dissolution vessels wherein, adaptors may be preferably incorporated to accommodate a wide array of vessel sizes and manufacturer designs. In the preferred embodiment of the disclosed invention, each mounted vessel contains a vessel cover, which incorporates a watertight sealing means such as an o-ring. The sealing means should sufficiently seal the mounted vessels within the bath such that when the bath is inverted during a cleaning cycle, there is no possibility of material leaking from said bath. In the preferred configuration of the disclosed invention, the heating means is a submersible heating coil which intercalates the dissolution vessels and maintains the temperature of the surrounding media contained within the bath. In an alternative embodiment of the disclosed invention, the heating means may include strip heaters contained within the bath assembly, temperature controllable solid or semisolid heating blocks, a plurality of heating coils, or other heating means that are consistent with the spirit of the disclosed invention. 
         [0008]    In accordance with this invention, a novel vessel cleaning system is employed to effectively dispose of spent test solution and insoluble dosage excipients, thereby eliminating carryover or cross-contamination. As previously mentioned, the disclosed invention includes a means to invert the dissolution vessels that are mounted on the bath such that the open side of said vessels are configured to face downward toward the cleaning manifold when inverted. The preferred configuration of the present invention is designed such that when the bath is rotated 180°; the spent test media, dissolved dosages, and testing devices are gravimetrically emptied from the dissolution vessels into a collection grate which is horizontally positioned above the wash bin and are both mounted on the base of the system. In this manner, the collection grate preferably contains a plurality of fissures to allow liquid media and dissolved material to flow through said grate to the wash bin which incorporates a waste port in said wash bin. In accordance with this invention, the collection grate is preferably constructed with a plurality of dedicated cavities in which the nozzles of the cleaning manifold extend through said collection grate and are positioned beneath the plurality of inverted dissolution vessels. In this manner, the collection grate is preferably formed to collect and accumulate dosage sinkers or baskets towards an accessible position of the system wherein an access door is mounted to the base. 
         [0009]    In accordance with the present invention, the disclosed apparatus of the present invention incorporates a vessel cleaning manifold. The cleaning manifold incorporates a plurality of spraying nozzles that extend through cavities within the collection grate wherein said nozzles are positioned to spray water, cleaning fluid or air into the interior of the inverted dissolution vessels. In the preferred configuration of the disclosed invention, the cleaning manifold may also include a series of programmable switches or valves that enable cleaning of the vessels with a variety of fluids and air. 
         [0010]    In accordance with the present invention, a dispensing manifold for dosage handling and fluid dispensing is horizontally mounted to the dispensing manifold tracks of the system base. The dispensing manifold in particular is a nonresident dispensing manifold wherein the manifold is positioned over the dissolution testing vessels during the media filling and dosage dispensing process. In this manner, a plurality of fluid dispense nozzles are mounted on the ventral side of the manifold wherein said nozzles are positioned above the plurality of dissolution vessels that are mounted to the bath. In accordance with this invention, a dosage carousel constructed of a fixed portion containing a single bore and a rotatable portion containing a plurality of cavities is rotatably mounted to said fixed portion thereof said carousel is mounted on the dorsal side of the manifold wherein an extended cylinder, herein referred to as a dosage dropper, is inserted into said bore within said carousel. In this manner, when the rotatable portion of the carousel rotates one position such that a cavity of the rotatable portion of the carousel aligns with the bore of the fixed portion of said carousel, a single dosage drops through the bore within the dosage carousel and dosage dropper into the vessel containing media. In the preferable configuration of the disclosed invention, the manifold is horizontally displaced along a manifold track such that it is moved away from the dissolution vessels during testing. The stirring and sampling assembly is subsequently lowered into the dissolution vessel and a plurality of paddles is rotated at a specified speed for a specified duration. 
         [0011]    In an alternate mode of operation, the dosage carousels may be replaced with a plurality of specialized basket carousels. In accordance with the present invention, the basket carousels contain a plurality of cavities wherein said cavities adopt a cylindrical shape to hold standard dissolution testing baskets and are rotatably mounted to the dispensing manifold. In this manner, a specialized o-ringed shaft that is contiguous with the stirring assembly is incorporated such that it may be lowered into an aligned basket until the o-ring of the shaft creates a seal and is temporarily attached with the rim of said basket, wherein said shaft and basket may then be raised from the carousel and the manifold may be horizontally displaced along a manifold track, and the basket may be subsequently lowered into the dissolution vessel and rotated at a specified speed for a specified duration. In accordance with this invention, a basket removal mechanism is incorporated, where said removal mechanism is preferably mounted to the obverse face of the dispensing manifold. In this manner, when aligned, the removal mechanism forms a clasp around the baskets that are attached to the specialized basket shafts and separates said baskets and shafts wherein said baskets are gravimetrically displaced into the dissolution vessels. 
         [0012]    In this invention, the stirring and sampling assembly is comprised of two main components, a stirring element and sampling mechanism. The stirring mechanism contains a plurality of fixed shafts in which said shafts are rotatably mounted to the stirring and sampling assembly and may be affixed with paddle or specialized basket shafts. In the preferred configuration of the disclosed invention, the fixed shafts are synchronously rotated at a predetermined speed for a specified duration by a programmable motor and driver means. In an alternative configuration of the disclosed invention, the system may incorporate a plurality of motors and drivers for individual shafts. In accordance with this invention, the sampling mechanism is mounted to the stirring and sampling assembly and preferably incorporates an additional motor and driver means wherein the sampling probes are lowered into the dissolution vessels, aspirate a sample, and raise said probes out of said vessels after sampling. 
         [0013]    In this invention, the sampling probe geometry is constructed in accordance with a hydrodynamic shape that minimizes disturbance to the laminar flow within the dissolution vessels when sampling whereby velocity differentials between the leading and lagging edge of the probe are effectively reduced. In this manner, the probe may be constructed to adopt an oval, elliptical, or tear-drop shape. In the preferable configuration of the present invention, the sampling probe is constructed to incorporate additional temperature and pH probes or sensors. In the present embodiment of the disclosed invention, the probe may be formed as one contiguous structure; or in alternate embodiments of the disclosed invention, the probe may be three separate pieces that are fused and shaped. In addition, the sampling probe may optionally include a shaped pre-filter to preclude solid material from clogging the sampling probe, sampling lines, or pump. 
         [0014]    In accordance with the present invention, an image capturing device for monitoring the dissolution test is preferably incorporated. In the preferred configuration of the present invention, the image capturing device is mounted to the bath such that it is able to visually capture and record the dissolution tests. In alternate configurations, the image capturing device may be mounted to the base or auxiliary components of the system. The image capturing device includes at least one means for capturing real-time video or still images that are preferably streamed to a recording device. In addition, the video or image is preferably time stamped and indexed to match the testing data. The means for capturing the video or still images may be a single image capturing device or a plurality of devices. For example, a camera may be provided at each of the testing vessels to record the process therein. 
         [0015]    In accordance with the present invention, a novel sample collection and filtration apparatus which will be referred to herein as a MicroSampler is incorporated. The MicroSampler is comprised of a sampling means, a sample dispensing mechanism, a filter holding mechanism, a sample pre-flush assembly, a sample collector holding mechanism, and a mechanism for forcing a plurality of aspirated samples through said filter to said holding mechanism. 
         [0016]    In the preferred embodiment of the disclosed invention, the sampling means is a peristaltic pump containing a plurality of channels, wherein each channel is dedicated to a single dissolution test vessel. In this manner, sample tubing is installed in each channel and connected to a sampling probe that is mounted on the stirring and sampling assembly and an indexable dispensing mechanism that is mounted to the MicroSampler. In accordance with this invention, the indexable dispensing mechanism is attached to the MicroSampler wherein said dispensing mechanism may align itself with dedicated, preprogrammed positions of the filtration and collection mechanisms throughout the dissolution test. 
         [0017]    In the present invention, the MicroSampler incorporates a filter holding mechanism that is capable of positioning the filter assembly disclosed herein. In accordance with this invention, the MicroSampler preferably incorporates a filter pre-flush assembly that is preferably mounted to said MicroSampler on a sliding means wherein said pre-flush assembly may be horizontally displaced from said filter. In accordance with this invention, the pre-flush assembly is preferably configured with a plurality of bores capable of collecting and dispensing to waste samples or portions of sample that are passed through the filters. In addition, the pre-flush assembly may incorporate a vacuum or pressure means for more efficiently collecting samples that are flushed through the filter assembly. 
         [0018]    In accordance with the present invention, the MicroSampler incorporates a collection assembly. The collection assembly preferably incorporates a sample assembly holder that ensures proper alignment of the filter assembly and sample assembly. In the preferred configuration of the present invention, the collection assembly is movably mounted to the MicroSampler wherein the sample and filter assemblies are engaged and disengaged as described below. 
         [0019]    In the present invention, the Microsampler incorporates a novel filter plate assembly is provided for receiving, filtering and retaining a plurality of samples taken during dissolution testing. Generally, the filter plate assembly of the present invention is configured in two parts. The upper filter plate receives and filters a plurality of samples and is then engaged with the lower sample well to deposit the samples therein. The upper filter apparatus, which may be a plate, cartridge, or individual filter, receives and filters the samples and is then engaged with the lower sample collection apparatus to deposit the samples therein. The sample collection apparatus preferably further includes a seal arrangement disposed on top of a sample collection well or vial. The dispensing end of the upper filter plate pierce through the resilient seals to allow deposit of the samples into the sample collection wells. However, when the upper filter plate is withdrawn the seals close. The filter and collection apparatus configuration also allows for a compact, orderly and addressable format for the collected samples which is advantageous for interfacing with an analytical instrument and for storage of the samples. 
         [0020]    In accordance with the present invention, a sample and filter transfer means is preferably used in conjunction with the MicroSampler and interfaces with an analytical instrument and hotel. The sample transfer means may include a robot, a conveyer, or other apparatus that is capable of removing used filter and sample collection apparatuses and replacing said apparatuses. In this manner, the samples may be subsequently transferred from the MicroSampler and placed in an analytical testing instrument for analysis or a hotel for storage, whereas the spent filter apparatus may be subsequently placed in the hotel or a designated waste means, while a new collection and filter apparatus may be acquired from the hotel and placed in the MicroSampler for the next dissolution test. 
         [0021]    In accordance with this invention, a novel fluid handling system is preferably incorporated. In the disclosed configuration of this invention, liquid media is pumped from bulk containers, the liquid volume is gravimetrically confirmed, and is then pumped into a plurality of holding vessels. The preferred configuration of the present invention has one dedicated holding vessel for each dissolution vessel. The holding vessel stores pumped media and maintains a preset temperature until it is time to dispense it into its respective dissolution vessel. When media is dispensed from the holding vessels, it is dispensed in parallel through dispense valves and tubing that are dedicated to each dissolution vessel. In addition, a temperature controller is preferably incorporated for each holding vessel in order to maintain media temperature uniformity at the predetermined testing temperature. The holding vessel temperature controllers ensure that media is pre-equilibrated prior to dispensing it in the test vessels. As a result, media equilibration time is minimized and temperature fluctuation is virtually eliminated. This mitigates the potential adverse impact with temperature sensitive formulations and APIs, and minimizes the downtime between media changes. 
     
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT 
       [0022]    Turning to  FIG. 1 , a flow chart has been drawn according to the described invention disclosed in the preferred embodiment. In the diagram pumps are denoted by P, valves by V, holding vessels by H, and dissolution vessels by D for parsimony. All arrows illustrate the preferable flow path and mode best known of the described invention. 
         [0023]    Four-way valve (V 1 )  6  controls the flow of liquid from bulk vessel  1 , weighing vessel  45 , and wash fluid  15  that are pumped through fluid lines by way of fluid handling pumps  5 ,  46 , or  47  respectively; to the holding vessels  17 - 24  or purged to waste  47 . Two-way valves  7 - 13  act independently and control the flow of liquid to  17 - 23 , respectively. Three-way valve  14  controls the flow of liquid between holding vessel  24  and the purge line  47 . Holding vessels  17 - 24  are insulated by a temperature controller  25  at a preset testing temperature and the flow of liquid media is controlled by two-way valves  26 - 33 . Valves  10 - 17  act in parallel such that when media is dispensed from holding vessels  17 - 24  into dissolution vessels  34 - 41 , it is done synchronously. Waste pump  48  controls the flow of liquid media for aspirating fluid from dissolution vessels  34 - 41  to waste. 
         [0024]    In normal operating mode, a bulk container  1  holds liquid media that is dispensed into weighing vessel  4  by pump  2  and the volume is confirmed by a scale  3 . After the volume dispensed into weighing vessel  4  has been confirmed, it is pumped by pump  5  through valve  6  to a predetermined holding vessel  17 - 24  that are controlled by a series of valves  7 - 14 , respectively. For example, if one wanted to add liquid media from bulk container  1  to holding vessel  8 , the media would follow the aforementioned path and valve  14  would switch to the fill position, thereby dispensing liquid media from bulk container  1  to holding vessel  24 . This action would be repeated for all holding vessels that were designated to be filled with liquid media from bulk container  1 . The holding vessels that will be filled with liquid media from bulk container  1  are predetermined and input in a software program before starting an experiment. The liquid media that was dispensed into the designated holding vessel(s) is then incubated by temperature controller  25 . 
         [0025]    After all the holding vessels that were designated to contain liquid media from bulk container  1  were filled, the common lines are cleaned. The wash pump  16  pumps wash fluid from wash fluid vessel  15  through the common lines to purge waste  47 . Three-way valves valve  6  and valve  14  are in the purge position when fluid lines are flushed with wash fluid. 
         [0026]    An additional fluid line flush with the subsequent liquid media may also be performed by switching valve  6  from the wash position to a designated bulk container position and valve  14  would remain in the purge position. For example, if one wanted to flush the common lines with liquid media from bulk container  42  prior to filling holding vessels with liquid media; then a predetermined volume of liquid media would be pumped from the bulk container  42  to weighing container  45 . The liquid media would then be pumped by pump  46  through valve  6  to the purge waste  47  until it was confirmed by scale  44  that weighing vessel  45  was completely empty. After the common lines were completely flushed, valve  14  would switch to a closed position. 
         [0027]    To fill designated holding vessels with liquid media from bulk container  42 , the normal mode of operations is identical to that as described for bulk container  1  where bulk container  1  is replaced by bulk container  42 ; pump  2  is replaced by pump  43 ; scale  3  is replaced by scale  44 ; weighing vessel  4  is replaced by weighing vessel  45 ; and pump  5  is replaced by pump  46 . In addition, valve  6  is switched to open the fluid path from bulk container  42 . 
         [0028]    In an alternative embodiment of the disclosed invention, a plurality of bulk containers, scales, weighing vessels, and pumps are incorporated to increase flexibility of experimentation. Valve  6  is replaced with a valve that enables additional flow paths or a series of valves may be incorporated to accommodate alternative configurations and instrumentation. 
         [0029]    In the preferred embodiment of the invention, holding vessels may be filled at any time before, after, or during a dissolution test, enabling preheated (-cooled) liquid media to be dispensed on demand. For example, during an experiment, when a predetermined amount of time has passed, two-way valves  26 - 33  synchronously open, dispensing media from holding vessels  17 - 24  to dissolution vessels  34 - 41 , respectively, in parallel. Because the media was preheated (-cooled) to the dissolution test temperature, the experiment is able to resume without a temperature incubation period. 
         [0030]    After a dissolution test is complete, media can be removed from the dissolution vessels using specialized non-resident sampling probes and waste pump  48 . The used media is pumped to a common or designated waste container/drain and the vessels are automatically cleaned. Before or during the cleaning procedure, holding vessels are filled with media as previously described. After the cleaning procedure is complete, preheated liquid media is dispensed from holding vessels  17 - 24  to dissolution vessels  34 - 41  and a subsequent dissolution test may begin. 
         [0031]    In an alternate embodiment of the disclosed invention, specialized sampling probes and pumps  48  may be used to remove media from the dissolution vessels  34 - 41  when necessary. 
         [0032]    Turning to  FIG. 2  and  FIG. 3 , the apparatus of the present invention generally includes a temperature controllable bath manifold  50  that is configured to receive and retain an array of testing vessels  51  therein. The testing vessels  51  contain the doses and solution being tested. The bath manifold  50  is positioned above a collection grate  54 , wash bin  52 , and plurality of spray heads extending from the cleaning manifold  53  configured wherein said spray heads are aligned to direct jets of water, cleaning fluid, and air upwardly to clean the inverted testing vessels  51  in a manner that will be more fully described below. Finally, the wash bin  52  incorporates a collection grate  54  positioned therein to catch and retain any objects such as baskets, sinkers or other objects that may be contained within the testing vessels  4  and dumped into the wash bin  52  upon their inversion. 
         [0033]      FIG. 3  illustrates an enlarged view of the bath manifold of the present invention. It can be seen that upon completion of the testing cycle, the apparatus either withdraws the stirring paddles and sampling probes from the testing vessels  51  or lowers the bath manifold  50  so that the vessels  51  are positioned clear of the stirring and sampling assembly. The bath manifold  50  then rotates 180° around a horizontal axis into the position depicted in  FIG. 4 . The rotation of the bath manifold  50  causes the testing vessels  51  to be positioned in an inverted fashion over the wash bin  52  causing any test fluid and non-dissolved doses contained therein, and any objects such as baskets, sinkers, or other objects that may have been contained within the testing vessels to be emptied into the wash bin  52 . The spray nozzles of the cleaning manifold  53  then direct jets of water, cleaning fluid, or air into the testing vessels  51  to rinse out any residual testing solution or non-dissolved doses and thoroughly clean the said vessels  51 . The testing fluid and wash fluid drains from the testing vessels  51  through the collection grate  54 , to the wash bin  52 , which is molded to gravimetrically direct fluid to a common waste port. Upon completion of the washing cycle, the bath manifold  50  again rotates 180° thereby returning the testing vessels  51  to an upright position, as depicted in  FIG. 2 , thereby resetting the test vessels to begin a new cycle of dissolution testing. 
         [0034]    It should be appreciated by one skilled in the art is the provision of a system and method that is capable of resetting the testing vessels automatically thereby allowing recycling of the dissolution testing apparatus without the need for operator intervention. In this manner, part of the novelty of the present invention resides in the ability to empty and clean the testing vessels. Accordingly, other structures and arrangements that provide for at least partial inversion (i.e. less that a total 180° inversion) to dump the remaining test solution from the vessels should be considered to fall within the scope of the present invention. Further, systems that utilize any fluid to clean the vessels including solvents, water, compressed air and combinations thereof also are presumed to fall within the scope and intent of the present disclosure. 
         [0035]    Turing to  FIG. 5 , it can be seen that in the present invention, in contrast with those of the prior art, additional features are required to enable the novel fluid handling, cleaning, sampling and dispensing mechanisms. In order to reset the vessels  51  through inversion, the stirring and sampling assembly  55  and dispensing manifold  56  need to be moved away from the bath manifold  50 . In the prior art, this was not an issue because as a result of the temperature controlled water bath manifold being stationary, all of these ancillary assemblies could be installed onto a header that rested on top of the vessels. To overcome the need for creating movable assemblies to accommodate inversion of the testing vessels  51 , the present invention utilizes moving headers that allow the stirring and sampling assembly  55  to be displaced vertically relative to the bath manifold  50 . Further, an automatic dispensing manifold  56  is provided that is configured to add indexed doses into the testing vessels  51  by moving laterally to an indexed position over the testing vessels  51 , dropping a dose and then returning to its starting position, thereby reliably loading a dose into the testing vessel  51  and moving out of the way so that the stirring and sampling assembly  55  can be reengaged with the testing vessel  51 . The automatic dispensing manifold  56  of the present invention is laterally displaceable along tracks  57  thereby allowing the dispensing manifold  56  to move into an indexed position over the vessels  51  and then return to a storage position displaced from the vessels  51 . 
         [0036]    Turing to  FIG. 6 , a plurality of dosage carousels  58  are disposed and arranged on the dispensing manifold  56  in a manner that corresponds to and matches the arrangement of testing vessels  51  in the bath manifold. Each of the automatic dosage carousels  58  includes a plurality of movable cavities  59  therein such that each cavity  59  within the carousel  58  receives and contains one dose. A stepping motor controls the movement of the automatic dosage carousels to selectively move the carousel  58  to align one of the cavities with the dosage dropper  60  in the dispensing manifold. When the cavity  59  containing a dose is positioned over the dosage dropper  60 , the dose is allowed to drop therethrough and into the dissolution vessel  51  below to commence a subsequent testing operation. 
         [0037]    In operation, the dispensing manifold  56  first slides into position over the dissolution vessels  51 , the stepping motor operates to move the carousels  58  one position thereby exposing a cavity  59 , containing a dose to the dosage dropper  60  in the dispensing manifold  56  positioned over the vessel  51 , the dose drops into the testing vessel  51  and the dispensing manifold  56  slides back to its home position. The carousels  58  may be rotatable devices as are depicted in the figures. Further the carousels  58  may be linearly displaceable. It is also possible that the carousels  58  are arranged horizontally or vertically as these are merely design choices related to the size or type of dose being tested. 
         [0038]    It can also be seen in referring to  FIG. 7  and  FIG. 8  in particular, that the cavities of the carousels  58  and basket carousels  62  include a fixed portion that is mounted to the dispensing manifold  56 , a rotatable portion  64  mounted to said fixed portion, and a shoulder  59  along the sidewalls thereof. The shoulder  59  is provided in order to receive and retain dosages, dosages with sinkers, and baskets  63  such as are also commonly utilized in the art. In this regard, the shoulders  59  prevent the baskets  63  from shifting in the basket carousel  62  and dosages from moving within the carousels  58  to assure proper alignment when acquiring a basket or dropping a dosage respectively. Additional inserts may be incorporated with dosage carousels wherein said dosages are formed in non-conventional shapes and have a propensity to shift within said carousels. In addition, covers or lids may be further incorporated for both types of dosage carousels described herein. 
         [0039]      FIG. 9  is a sectional view of a conventionally constructed dissolution testing apparatus. The apparatus is shown running a dissolution test with a paddle type apparatus  67  and the sampling probe  65  is shown inserted into the dissolution vessel  51 . In the preferred embodiment of the present invention, the sampling probe  65  is coupled to a sampling bar  66  that is operatively attached to the stirring and sampling assembly  55  wherein said sampling probes  65  may be lowered and raised from the dissolution bath during testing. 
         [0040]    Turning to  FIG. 10 , the sampling probe  67  is preferably comprised of at least two distinct ends, a shaped sampling end  68  and a connector end  69  that creates a water tight seal with sample tubing  70 . During a dissolution test, the sampling end  68  of the sampling probe  67  is inserted into the dissolution test vessel. A sample is aspirated from the sampling end  68 , through the probe  67 , and through the tubing that is generally coupled to a sample collection apparatus or sample analyzer. 
         [0041]      FIG. 11  depicts a plan view of different probe shapes that may be adopted for the sampling probe. The shapes shown are a tear-drop  71 , oval  72 , and ellipse  73 . The leading edge of the probes, which is described by the edge that faces the direction of fluid flow, are preferably rounded in shape to ensure that laminar flow is not disturbed during sampling. 
         [0042]    Turning to  FIG. 12 , the probe may also include a pre-filter  74  that is attached to the sampling end of the probe  68 . The pre-filter  74  preferably adopts that same hydrodynamic shape of the sampling probes. 
         [0043]      FIG. 13  is a 2-dimensional plot of vorticity maps for a conventionally constructed sampling probe used with automated dissolution testers and the sampling probe disclosed in the present invention. The plot for the conventionally constructed sampling probe demonstrates the influence of the sampling probe on the laminar flow when it is inserted during dissolution testing. Alternatively, the plot for the disclosed invention demonstrates that the hydrodynamically shaped sampling probe does not affect the laminar flow when sampling during dissolution testing. 
         [0044]    The filter plate assembly of the present invention is illustrated and generally indicated as  75 . As will hereinafter be more fully described, the filter plate assembly  75  has a unique configuration that allows secure and reliable transfer of the samples taken while also facilitating the use of reduced sample sizes including samples having a sample size as small as 1 μl. 
         [0045]    Turning to  FIG. 14  and  FIG. 15 , the filter plate assembly  75  can be seen to include an upper filter plate  76  and a lower sample well array  78 . A seal  79  component as will be discussed in further detail below can be seen installed on top of the lower sample well array  78 . The upper filter plate  76  can be seen to include an array of bores  77  having openings at the top ends thereof. The bores  77  extend downwardly and terminate in a hollow dispense tip  80 . The dispense tip  80  is preferably sharp enough to be effective at piercing the seal  79  located on top of the lower sample well array  78  as will be discussed in detail below. The upper filter plate  76  is preferably formed from a polymer material and is more preferably injection molded. Further, the dispense tip  80  may also be polymer or may be formed from metal. 
         [0046]    Turning now to  FIGS. 17 and 18 , it can be seen that the lower ends of the cavities  77  include a shoulder formation  82  where the cavity  77  transitions to the top end of the dispense tip  80 . The shoulder formation  82  is configured to receive and support and secure a filter material insert to screen out impurities and any small, non-dissolved excipients or API from the doses that may have been contained in the sample that was taken from the dissolution vessel. 
         [0047]    The lower sample well portion  78  of the filter plate  75  includes an array of sample wells  81  arranged in a manner that corresponds to the array of dispense tips  80  in the upper filter plate  76 . Further, as discussed above a seal member  79  of resilient material is provided on top of the lower sample well array  78 . The seal member  79  is preferably an elastomeric material and may be a thermoplastic elastomer or a thermosetting elastomer. In one embodiment of the present invention, the seal component  79  is snapped onto the top of the lower sample well array  78 . In an alternative embodiment, the seal component  79  may be molded directly onto the top of the sample well array  78  using a method such as a dual shot molding process. 
         [0048]    In operation, the samples are each deposited into a dedicated opening in a single cavity  77  at the top of the upper filter plate array  76 . After the samples have been deposited, the upper filter plate  76  as is shown in  FIG. 17 , is lowered onto the lower sample well array  78  as is depicted in  FIG. 18 . As the upper filter plate  76  is lowered, the tips of the dispense tips  80  each pierce the seal  79  over the respective sample wells  81  with which the dispense tips  80  are aligned. Once the upper filter plate  76  is engaged with the lower sample well array  78 , compressed air or gas is introduced to the top of each of the cavities  77 . The compressed air or gas serves to discharge the sample downwardly through the filter material and through the hollow dispense tip  80  causing each of the samples to be deposited in their respective sample wells  81 . After the samples have been deposited, the upper filter plate  76  is raised to withdraw the dispense tip  80  from the sample well  81  thereby allowing the resilient seal material  79  disposed on the top thereof to return to a closed position effectively sealing the sample well  81  containing the sample. 
         [0049]    Turning now to  FIG. 19 , the MicroSampler  86  is mounted to a mounting assembly such as a plate, wherein positions of the analytical device  83  (shown as an HPLC with a plate transfer apparatus), filter plate and microplate storage means  84 , and sample transfer means  85  (depicted as a plate handling robot), are defined and programmed thereto which sampling, transfer, analysis, and resetting are operatively configured. Turning to  FIG. 20 , the MicroSampler assembly configuration depicted includes a peristaltic pump  91 , a compression or vacuum means  93 , a plurality of sensors  92 , a dispensing assembly  90 , a sample flush assembly  89 , a filter pre-flush assembly  88 , a plurality of mounting brackets  87 , a microplate  78  and filter plate  76 . The compression or vacuum means  93  is depicted as valves to which compressed air is connected to an indexable assembly wherein after a sample is dispensed in the filter plate assembly, said indexable assembly aligns and compresses said filter plate assembly creating and airtight seal and further delivers pressurized air or gas thereby forcing the dispensed sample into the sample wells of the microplate  78 . In the preferred embodiment of the present invention, a plurality of sensors are incorporated to ensure samples are dispensed, pushed through filter plates, and collected in microplates. In addition, a sample flush assembly  89  and filter pre-flush assembly  88  are preferably incorporated. The sample flush assembly  89  is depicted as a trough wherein said trough collects and disposes of fluid that is flushed through sample lines during cleaning cycles or prior to collecting samples in the filter assembly  76 . In addition, many APIs and excipients bind filter materials such that it may be required to saturate said filter material with API and excipient prior to collecting a sample for analysis; as such a filter pre-flush assembly  88  is preferably mounted to the MicroSampler on a sliding means wherein said pre-flush assembly may be horizontally displaced from said filter. In addition, the pre-flush assembly is preferably configured with a plurality of bores capable of collecting and dispensing to waste samples or portions of sample that are passed through the filters. In addition, the pre-flush assembly may further incorporate a vacuum means for more efficiently collecting samples that are flushed through the filter assembly. 
         [0050]    The present invention is believed to represent a significant advancement in the art, which has substantial commercial merit. While there is shown and described herein certain specific structure embodying the invention, it will be manifest to those skilled in the art that various modifications and rearrangements of the parts may be made without departing from the spirit and scope of the underlying inventive concept and that the same is not limited to the particular forms herein shown and described except insofar as indicated by the scope of the appended claims. 
       DRAWINGS 
       [0051]      FIG. 1  Depicts a process flow chart detailing the components of the described invention disclosed in the patent. 
         [0052]      FIG. 2  is a sectional view of the testing assembly of the present invention. 
         [0053]      FIG. 3  is an enlarged sectional view of the testing assembly of the present invention. 
         [0054]      FIG. 4  is an enlarged view of the inverted bath manifold and cleaning manifold mounted on the dissolution system. 
         [0055]      FIG. 5  is a sectional view of the dissolution system detailing components of the dispensing manifold. 
         [0056]      FIG. 6  is an enlarged sectional view of the dissolution system detailing components of the dispensing manifold. 
         [0057]      FIG. 7  is an enlarged, lateral sectional view of the dispensing manifold containing a plurality of dosage carousels. 
         [0058]      FIG. 8  is an enlarged view of basket carousels that are mounted to the dispensing manifold. 
         [0059]      FIG. 9  is a sectional view of a conventional dissolution apparatus. 
         [0060]      FIG. 10  is a lateral view of the sampling probe. 
         [0061]      FIG. 11  is a plan view of probe shapes 
         [0062]      FIG. 12  is a lateral view of the sampling probe and hydrodynamic probe pre-filter. 
         [0063]      FIG. 13  Data for two dimensional vorticity maps of a conventional sampling probe compared with the disclosed invention 
         [0064]      FIG. 14  is a perspective view of the filter plate of the present invention; 
         [0065]      FIG. 15  is an enlarged perspective view of the filter plate of  FIG. 1 ; 
         [0066]      FIG. 16  is an end view of the filter plate of  FIG. 1 ; 
         [0067]      FIG. 17  is a cross-sectional view of the filter plate of  FIG. 1  with the upper filter plate and the lower collection wells separated; and 
         [0068]      FIG. 18  is a cross-sectional view of the filter plate of  FIG. 1  with the upper filter plate and the lower collection wells engaged. 
         [0069]      FIG. 19  is an overall view of the main components within the sampling assembly of the disclosed invention. 
         [0070]      FIG. 20  is an enlarged view of the MicroSampler assembly of the present invention.