Apparatus and method for concurrently monitoring active release and physical appearance of solid dosage form pharmaceuticals

An apparatus and method for monitoring the dissolution properties of a solid dosage form pharmaceutical or other material. The apparatus includes a hollow dissolution chamber for supporting the dosage form and subjecting it to a dissolution liquid so that the dosage form dissolves in the liquid. A dissolution liquid analyzing device (e.g., a spectrophotometer) analyzes the properties of the dissolution liquid as the dosage form dissolves. A video monitoring means (e.g., a stereo-microscope and video camera) provides a series of images of the dosage form as it dissolves. The series of images and data resulting from the analysis are recorded and correlated. The temperature, flow rate and chemical parameters of the dissolution liquid can be controlled (e.g., held constant or altered), if desired.

FIELD OF THE INVENTION

This invention relates generally to test apparatus and methods and more particularly to apparatus and methods for testing to determine the dissolution properties of solid dose form pharmaceuticals, agents and other materials.

BACKGROUND OF THE INVENTION

It is a well established practice in the pharmaceutical industry to test the dissolution properties of solid dosage form pharmaceuticals. The term solid dosage form as used herein means any dosage form, other than a liquid, and which can be delivered into the body of a being. Examples of such dosage forms are tablets, capsules, caplets, pills, suppositories, transdermal patches, etc. Moreover, the dosage forms may be immediate release or timed release.

As is known, dissolution is the process by which a solid substance dissolves in a solvent and is controlled by the affinity between it and the solvent. The sequence of events in a typical dissolution process entails several actions, e.g., the wetting of the dosage form, the subsequent penetration of the dissolution liquid into the dosage form, etc. Once this has occurred there are different modalities of release of the active ingredient(s) from the dosage form, such as erosion, diffusion, disintegration and combinations of those modalities.

Perhaps the primary reason for undertaking dissolution testing in the pharmaceutical industry is to measure the performance of a particular product. This is particularly important for oral solid dose forms of pharmaceuticals, but is not limited to oral dose forms, since release of the active ingredient(s) from the solid dose after oral administration is a prerequisite for absorption and bioavailability. Dissolution properties become even more significant if the solid dose form is of a sustained-release formulation, since dissolution is a key property of such a product.

Dissolution testing is also used as a key tool in research and development of new drugs since it can provide considerable information in the selection of an appropriate formulation for a proposed pharmaceutical. It also enables a manufacturer to accurately gauge the stability of a pharmaceutical to determine if it maintains its dissolution characteristics from the time of its manufacture to its expiry date.

In view of the above, and for other reasons as well, dissolution testing is now deemed of such importance that it is a mandatory United States pharmacopeial requirement. For example, the United States Pharmacopeial Convention presently identifies seven USP approved types of dissolution equipment for dissolution testing of solid dosage forms. Those types are referred to as USP I, USP II, USP III, USP IV, USP V, USP VI, and USP VII.

As is known USP I equipment is characterized by use of a rotating basket in which the solid dosage form of the pharmaceutical to be tested is held and immersed in a dissolution liquid in a flask or other concave bottom chamber. The flask or chamber typically has a volume of from 100 to 4000 ml. The basket is made up of a wire mesh of any mesh size, e.g., from USP mesh 10 to USP mesh 100. The basket is arranged to rotated about a vertical central axis at any suitable speed, e.g., from 50 to 125 rpm, within the dissolution liquid to enable the dissolution liquid to gain access to the solid dosage form to cause it to dissolve. With USP I equipment the dissolution liquid is sampled at a sampling point within the chamber, but outside the basket. The sample is provided to spectrophotometric, high performance liquid chromatographic or other suitable analyzer equipment for analysis.

While USP I apparatus may be generally suitable for their purposes, they nevertheless suffer from various significant disadvantages. One of the most significant disadvantages is the non-uniformity of the dissolution liquid in the chamber due to the production of poor eddy currents or inadequate stirring. Thus, within the chamber there are areas of the more concentrated dissolution liquid (so-called “hot spots”) and areas of less concentrated liquid (so-called “blind spots”). In addition, the baskets of USP I equipment are relative fragile and can be bent or otherwise deformed, whereupon their rotation in a bent or deformed state-may result in uneven stirring of the dissolution liquid. Another significant disadvantage of this USP I equipment is that the baskets may become clogged, thereby impeding the access of the dissolution liquid to the dosage form. Lastly, USP I apparatus is not particularly suitable for testing the dissolution of a solid dosage form under changing pH conditions, e.g., conditions where pH increases, such as occurs when the dosage form is taken orally by a patient.

USP II equipment is similar to USP I equipment, except that the solid dosage form is placed at the bottom of the chamber and a paddle is used to stir the dissolution liquid in the chamber. In some applications a stainless steel or glass helix or another holder (sometimes referred to as a “lobster pot”) may be used to encircle the solid dosage form and hold it slightly above the concave bottom surface of the chamber. The chamber typically has a volume of from 100 to 4000 ml. The paddle is disposed above the dosage form and is arranged to rotated about a vertical central axis at any suitable speeds, e.g., from 50 to 150 rpm to enable the dissolution liquid to have access to the dosage form to cause it to dissolve. The dissolution liquid is sampled within the chamber, but above the paddle and is provided to the same type of analysis equipment mentioned above for analysis.

While USP II apparatus may also be generally suitable for their purposes they also suffer from various drawbacks. One drawback is the non-uniformity of the dissolution liquid in the chamber due to the creation of a conical “blind-spot” of less concentrated dissolution liquid directly under the paddle. Another drawback is that the dosage form is susceptible to floating, if not held in position by a helix or lobster pot, thereby interfering with its even dissolution. Moreover, since the dosage form is exposed, it can be struck by the paddle, possibly breaking the dosage form and thus interfering with its normal dissolution properties. Further still the dosage form may rest on or stick to the inner surface of the chamber, thereby reducing the surface area of the dosage form so that an accurate reading of its dissolution properties is compromised. The use of a helix, lobster pot or other device to surround the dosage form to lift it off the surface of the chamber may eliminate that problem, but is not conducive for use with dosage formulations that swell, e.g., hydrogels. Moreover, like USP I apparatus, USP II apparatus is not particularly suitable for testing the dissolution of a solid dosage form under changing pH conditions

USP III equipment is sometimes referred to as a “reciprocating cylinder” and is particularly suited for extended release products. USP III equipment basically comprises an array of plural rows of individual flat bottomed glass vessels or chambers for holding the dissolution liquid. The vessels are typically of a volume of 200 ml. A plurality of reciprocating cylinders having mesh tops and bottoms into which respective ones of solid dosage forms of the pharmaceutical are located are disposed over the array of vessels for reciprocation and immersion in selected rows of the array of vessels. For example, the reciprocating cylinders may be reciprocated into the first row of the array of vessels to immerse the dosage forms into the dissolution liquid in those vessels. Thereafter the row of cylinders can be reciprocated out of the first row of vessels and indexed to the next successive row of vessels to immerse the dosage forms into the dissolution liquid in the second row of vessels. This operation can continue until all of the rows of vessels have been used. The advantage of this type of equipment is that each row of vessels may include dissolution liquid of the same pH or of increasing pH. Moreover, the fact that this type of apparatus uses plural vessels into which each dosage form is immersed enables the apparatus to be used to test poorly soluble active ingredients, since there will be more dissolution liquid available to dissolve such formulations than exists in either USP I or USP II equipment. Notwithstanding these advantages, the USP III apparatus still suffer from various disadvantages. For example, poorly soluble formulations which disintegrate could experience a loss of sink conditions if disintegration occurs in one sample 250 ml tube. Moreover, the apparatus is difficult to use with a surfactant based dissolution liquid, as frothing of the liquid severely limits the sample holder reciprocation rate. Further still, clogging of the sample holder mesh is possible, thus obstructing the free flow of dissolution liquid past the sample formulation.

USP IV equipment is sometimes referred to as a “flow through cell” and is particularly suitable for testing poorly soluble drugs and for extended release products. Moreover, UPS IV apparatus is suitable for testing active substances, granulated substances and formulated dosages in the same equipment. To that end USP IV equipment basically comprises a reservoir and a pump for the dissolution liquid, a flow-through-cell and a water bath for maintaining the temperature of the dissolution liquid. The cell is a hollow cylinder having a conical bottom wall with a central opening forming the inlet to the cell. The dosage form to be tested is disposed in the center of the cell. The top end of the cell is in the form of a filter or sieve. The dissolution liquid is pumped into the bottom of the cell so that it flows past the dosage form to cause it to dissolve. The dissolution liquid exits through the filter at the top of the cell. Since this equipment exposes the dosage form to a flow of the dissolution liquid past it, the dosage form is always subjected to fresh dissolution liquid, making the equipment particularly suitable for low solubility drugs. Moreover, this equipment enables one to precisely change the pH of dissolution liquid and avoids the hot spots and blind spots that are inherent in USP I and USP II equipment. Notwithstanding these advantages, USP IV equipment still suffers from its own disadvantages, e.g., it requires large volumes of dissolution liquid, calibration tests are unavailable, and validation of the flow rate is difficult.

USP V equipment is sometimes referred to as a “paddle over disk apparatus.” It basically comprises the USP II equipment with the inclusion of a stainless steel disk located at the bottom of the chamber. The disk is arranged to hold a transdermal dosage form. While USP V equipment offers advantage over USP II equipment for transdermal dosage forms, it never the less suffers from the same disadvantages of that equipment insofar as the non-uniformity of the dissolution liquid in the chamber is concerned.

Other USP approved equipment is USP VI equipment (sometimes referred to as a “cylinder” apparatus), and USP VII equipment (sometimes referred to as a “reciprocating holder” or “reciprocating disk” apparatus). As is known USP VI apparatus basically comprises the USP I equipment, except that the mesh basket is replaced with a stainless steel cylinder stirring element. USP VII equipment is sometimes referred to as a “reciprocating holder” or “reciprocating disk” apparatus and basically comprises a set of volumetrically calibrated glass cylinders.

The patent to Martin et al. discloses an automated tablet dissolution apparatus that includes a camera under computer control for viewing the contents through the bottom of a dissolution vessel. A tablet to be tested is located with a basket disposed in the dissolution vessel and is exposed to a heated dissolution media the vessel. The camera is used to determine if the tablet was dropped into the dissolution vessel properly or has dissolved properly or to enable the contents of the vessel to be visually inspected. This testing of a sample of the dissolution media over a period of time is achieved in this patent by various techniques, e.g., spectrophotometry, high performance liquid chromatography, etc.

The patent, to Swon et al. (U.S. Pat. No. 4,855,821) discloses an apparatus for dissolution testing solid dosage forms, e.g., tablets, including one or more video cameras for the surveillance of a plurality of separate tablet containing vessels to record the dissolution of the tablets in a liquid dissolution media. Plural tablets are held on a wire mesh or screen.

The patent to Löfler (U.S. Pat. No. 6,163,149) discloses an apparatus for dissolution testing of medicaments in pressed form, such as tablets, pills, or capsules, and makes use of a basket-like frame supporting plural glass tubes, each of which is adapted to hold the medicament.

The patent to Martin (U.S. Pat. No. 6,170,780) is similar to U.S. Pat. No. 5,816,701 which was discussed above.

While all of the above identified apparatus and methods of use may be suitable for their intended purposes they still leave much to be desired from the standpoint that the information about the dissolution properties of the solid dosage forms that can be determined by their use is somewhat limited. In this regard prior art apparatus and techniques may enable one to determine the rate at which a particular solid dosage form dissolves (i.e., its so-called “dissolution profile”), but they do not provide accurate information about the mechanism of how the dosage form actually dissolved, e.g., by erosion, disintegration, diffusion and/or combinations of those actions. Moreover, while some prior art dissolution testing systems may have included utilizing a visualization device, e.g., a camera to record selected images of the dosage forms during their process of dissolving, such techniques have been very limited in the quality of the images provided, particularly where the dosage forms are susceptible to movement and displacement in the apparatus as they dissolve. For example, as is known the rotating paddles of USP II devices tend to cause the dosage forms to shift around and move in the dissolution vessel, thereby making sustained, accurate imaging difficult. Moreover, the stirring of the dissolution liquid causes surface turbulence, rendering image acquisition through the surface difficult. The rotating basket of USP I apparatus also presents an imaging problem since the basket in which the dosage form is located is moving and a relatively high speed, thereby tending to blur or otherwise obscure the dosage form during the dissolution process. Further still, where the dosage form is a sustained or timed release medication, e.g., a capsule with a large plurality of polymer coated active ingredient beads, with some of the beads having thicker coatings than others to enable the timed release of their active ingredient(s), the prior art systems have proved wanting to provide high quality images of the entire dissolution process from which accurate information about the manner and rate of release of the active ingredient(s) can be determined.

SUMMARY OF THE INVENTION

An apparatus and method for monitoring the dissolution properties of a solid dosage form pharmaceutical (e.g., capsule, tablet, pill, suppository, transdermal patch, etc.) or other agent or material having at least one active ingredient.

The method consists of disposing a solid dosage form in a chamber and introducing a dissolution liquid into the chamber to cause the dosage form to dissolve in the dissolution liquid. The dissolution liquid is analyzed as the dosage form dissolves in the dissolution liquid to determine the dissolution properties of the dosage form. A series of images of the dosage form is provided simultaneously with the analysis of the dissolution liquid.

In accordance with one exemplary aspect of the invention the temperature of the dissolution liquid is controlled.

The apparatus of this invention comprises a dissolution chamber, video monitoring means (e.g., a video camera and stereo-microscope, etc.), and dissolution liquid analyzing means (e.g., spectrophotometric, high performance liquid chromatography, etc. equipment). The dissolution chamber comprises a hollow vessel (e.g., a hollow body having a flat bottom wall, a circular sidewall, a baffle and an evaporation cover or lid). A dosage form support (e.g., a wire mesh) is located within the interior of the chamber. The chamber includes an inlet and outlet coupled to the interior of the chamber (e.g., the inlet and outlet are located in the side wall of the chamber, with the baffle located adjacent the inlet). The support is arranged to support the dosage form in the chamber within a predetermined visualization field in the chamber.

The inlet of the chamber is adapted to enable a dissolution liquid to enter the chamber and flow gently through the interior of the chamber for exposure to the dosage form. The support and the gentle flow of the dissolution liquid tend to prevent displacement of the dosage form from said visualization field. The flow of the dissolution liquid causes the dosage form to dissolve in the dissolution liquid. The outlet of the chamber is coupled to the analyzing means so that a sample of the dissolution liquid can be analyzed by the analyzing means to determine the properties of the dissolution liquid. The video monitoring means is adapted for aiming at the visualization field to provide a series of high quality images, e.g., a continuous video image, of the dosage form simultaneously with the analysis of the dissolution liquid by the analyzing means.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Referring now to the various figures of the drawing wherein like reference characters refer to like parts, there is shown inFIG. 1one exemplary embodiment of a system20for concurrently monitoring active release and physical appearance of solid dosage form pharmaceuticals constructed in accordance with this invention.

The system20includes a dissolution chamber22, whose details will be described later with reference toFIGS. 2 and 3, into which at least one, but preferably a plurality of solid dosage form pharmaceuticals10are disposed for exposure to a dissolution liquid12. The dosage forms10are located within a predetermined position within the chamber22in an area which defines a visualization field (to be described later). The dissolution liquid12is provided into the chamber22from a dissolution liquid reservoir24. The details of the reservoir24will also be described later. Suffice it for now to state that the reservoir24is a hollow member for holding a quantity, e.g., 1000 ml, of the desired dissolution media12, e.g., purified water, a phosphate buffer with a pH of 6.8, 0.01 normal hydrochloride solution, or any other liquid known for use in dissolution testing and which is preferably transparent (for reasons to be appreciated later). The dissolution chamber22is arranged to receive the dissolution liquid from the reservoir24and to return it to the reservoir. In particular, the dissolution chamber includes an inlet26connected via a line or conduit28. The conduit28is connected to the output of a peristaltic pump30. In accordance with one exemplary embodiment of this system20, the pump is available from Icalis Data Systems of the U.K. under the model designation PCP490. The input to the pump30is provided via a line or conduit32extending into the interior of the reservoir24. The pump is operated at any desirable speed, e.g., 1 to 200 rpm. The dissolution chamber also includes an outlet34. That outlet is connected via a gravity return line or conduit36back to the reservoir24. The pump30is operated under control of a computer38via electrical lines39. When the pump30is operated the dissolution liquid12within the reservoir24is pumped via lines32and28and inlet26so that it flows into the interior of the dissolution chamber22. Accordingly, the plural solid dosage forms10to be tested that are located within the chamber are exposed to the dissolution liquid, so that they can begin to dissolve, thereby releasing their active ingredient(s) into that liquid. As will be described in detail later, the dissolution chamber is constructed in such a manner that the flow of dissolution liquid through it is sufficiently gentle so that the flow does not disturb the solid dosage forms10from their position in the visualization field, while still providing sufficient mixing of the liquid in the chamber ensure substantial uniformity of concentration . The dissolution liquid with the dissolved active ingredient(s) is returned to the reservoir24via the dissolution chamber's outlet34and the associated return line36. This operation is effected on a continuous basis under the control of the computer38, as will be described in detail later.

In accordance with one preferred aspect of the invention, the temperature of the dissolution liquid12is controlled, e.g., maintained at a predetermined temperature, such as body temperature 37° C. To that end, in the exemplary embodiment shown inFIG. 1, the system20includes two temperature control devices, e.g., water jackets40and42, whose details will be described later. Suffice it for now to state that the jacket40is disposed contiguous with, e.g., below, the dissolution chamber22, while the jacket42is disposed contiguous with, e.g., surrounding the liquid reservoir24. The water jacket40is a hollow member which includes an inlet44to which a line or conduit46is connected. The line46is connected to a source of heated water, e.g., a heating unit48. In accordance with one exemplary embodiment of this system20, the heating unit48is available from Neslab Instruments, Ltd. of the U.S.A. under the model designation R-134A. The heating unit48includes its own pump (not shown) and is arranged to heat a supply of water to bring the water to a desired temperature, e.g., 38° C., and to maintain it at that temperature under the control of the computer38. To that end the heating unit48is arranged to heat the water to any desired temperature within the range of 25° C.–50° C. and at a rate of up to 5 liters per minute. The heating unit is connected to the computer via electrical lines50. The water jacket40includes an outlet52which is connected to a line or conduit54. The line54is connected to the heating unit48to return the water from the jacket40back to the heating unit for reheating. It should be pointed out at this juncture that heat dissipation properties of the conduit46carrying the water to the jacket40and the heat dissipating properties of the jacket40are such that water heated to 38° C. in the heater unit is kept at a temperature of 37° C. in the jacket40of the dissolution chamber to hold the dissolution liquid12in the chamber22at that temperature.

The liquid reservoir's water jacket42includes an inlet line or conduit56, which is a branch of the inlet line46, for carrying the heated water from the heating unit48to the interior of the jacket42. The jacket42also includes an outlet line or conduit58, which is a branch of line54, returning the water to the heating unit48. Accordingly, heated water from the heating unit48is pumped through lines46and56into the water jackets40and42, respectively, to heat the dissolution chamber22and the reservoir24, respectively, under control of the computer38. The liquid reservoir includes a cover59to prevent evaporation of the liquid therein. This cover includes various opening through which the various lines or conduits carrying the dissolution liquid to and from the dissolution chamber and carrying the dissolution liquid sample to and from the system's analyzer (to be described later) extend. Thus, evaporation of the dissolution liquid from the reservoir (which serves as the source for the liquid sample to be analyzed), and which could result in concentrating the dissolution liquid to give false dissolution data, is deterred by the presence of the lid59.

Evaporation of the dissolution liquid from the dissolution chamber22is similarly deterred by the presence of an evaporation lid or cover60disposed over the dissolution chamber. The details of the cover or lid60will be described later. Suffice it for now to say that the lid60is preferably a heated member, e.g., a transparent glass member which includes transparent electrically operated heating elements (not shown). In accordance with one exemplary embodiment of this system20, the heated cover is available from Pilkington in the U.S.A. under the model designation TECGLASS™. The electrically heated cover60is connected to an electrical controller62via electrical lines64. The controller62is, in turn, electrically connected to the computer48, via electrical lines66, and is controlled thereby.

In order to monitor the temperature within the interior of the dissolution chamber22the system20includes a temperature probe68, e.g., a thermocouple. The probe68extends through the dissolution chamber cover60into the interior of the dissolution chamber for immersion in the dissolution liquid12. The probe68is electrically connected to an electrical controller70via electrical lines72. In accordance with one exemplary embodiment of this system20, the thermocouple and associated controller is available from Hanna Instruments, Ltd. of the U.K. under the model designation Hi-93531. The controller70is in turn electrically connected to the computer38, via electrical lines74, and is controlled thereby.

In order to monitor the parameters of the dissolution liquid during the dissolution test procedure, the system includes a dissolution liquid analyzer76. In the exemplary embodiment the analyzer76is a UV spectrophotometer. In accordance with one exemplary embodiment of this system20, the spectrophotometer is available from Unicam, Ltd. of the U.K. under the model designation UV3-200. Other conventional spectrophotometric or other analyzers, such as a high performance liquid chromatograph, can be used as well. In the system20shown inFIG. 1the analyzer76is arranged to continuously receive a sample of the dissolution liquid12from the dissolution chamber22, whereupon the sample flows through the analyzer76. The analyzer provides data representative of the percentage of the active ingredients dissolved in the dissolution liquid as the sample flows past its sensors (not shown), as is conventional. The computer38controls the operation of the analyzer76via electrical lines78and receives the data output from the analyzer via those electrical lines.

The dissolution liquid sample is provided into the analyzer76via a conduit or line80extending into the reservoir24. This sample outlet line80is connected to the input of a pump82. In accordance with one exemplary embodiment of this system20, the pump82is available from Icalis Data Systems of the U.K. under the model designation PCP490. The outlet of the pump is connected via a conduit84to the input of the analyzer76. The operation of the pump82is controlled by the computer38via electrical lines86. The liquid sample is returned from the analyzer back to the reservoir24via a line or conduit88.

Since the analyzer76receives the dissolution liquid12sample from the interior of the liquid reservoir24, it is of considerable importance that the liquid within the reservoir be of a uniform concentration. To that end, the system20includes a stirring paddle or propeller90mounted on a rotating shaft92extending into the interior of the reservoir24. The shaft92is connected to an electrical motor or rotary driver94, which is connected to the computer38via electrical lines96. In accordance with one exemplary embodiment of this system20, the electric motor94is available from Stuart Scientific, Ltd. of the U.K. under the model designation SS3. The speed of rotation of the paddle/propeller90, e.g., 1 to 2500 rpm, is controlled by the operation of the computer to stir the liquid within the reservoir so that it is uniform throughout.

As mentioned earlier in order to provide additional valuable information regarding the dissolution properties of the solid dose forms10, the system20makes use of imaging means which is arranged to operate concurrently with the analyzer so that a series of images taken by the imaging means can be coordinated with the data resulting from the operation of the analyzer76. In the embodiment shown the imaging means basically comprises a video camera98and an associated stereo-microscope100. In accordance with one exemplary embodiment of this system20, the video camera98is available from JVC (Victor Company of Japan, Ltd.) under the model designation TK-C1381EG and the stereo-microscope is available from Helmut Hudd, GmBH of Germany under the model designation SM33. The stereo-microscope100is located adjacent the dissolution chamber22so that the plural solid dosage forms10within the dissolution chamber22are in the microscope's field of view or visualization field. The stereo-microscope provides an enlarged stereo image (e.g., from 5× to 45×) of the dosage forms in the visualization field at its eyepiece. The video camera98is mounted adjacent the microscope's eyepiece so that it can record the enlarged stereo image of the dosage forms as they dissolve during the dissolution test. The camera98is connected to the computer38via electrical lines102, so that the computer can control its operation. A photo-printer104is connected to the video camera98, via electrical lines106, to provide a hard copy print of the any one of the series of images taken by the camera. The output of the camera98can be fed directly into the computer38for storing the images therein, e.g., on a hard disk drive associated with the computer.

In any case, the images of the dosage forms showing their condition at any point in their dissolution cycle can be correlated by an operator of the system with the data received from the analyzer to provide valuable information regarding the dissolution properties of the dosage forms. This operation will be described later. In fact, the computer38may include software for automatically analyzing the images provided by the video camera to produce data representing those images for comparison, correlation and analysis with the data provided by the analyzer76, thereby resulting in an automatic dissolution testing system.

It should also be pointed out that the series of images captured by the video camera can be provided back to the computer through some other means than that shown, e.g., if the video camera utilizes videotape or some other media, e.g., a solid state memory device, a CD or some other recordable medium, the medium bearing the images can be input into the computer through any conventional technique. Moreover, the series of images need not be coordinated by the computer at all. Thus, the system of this invention contemplates manual viewing the series of images and the data to draw conclusions therefrom.

In order to ensure that the video camera98has sufficient light to provide a good quality image of the dosage forms as they dissolve, the system20may include a lamp or other light source108disposed adjacent to the lid60of the dissolution chamber22so that the light produced thereby can illuminate the dosage forms10within the chamber. The lamp108is connected via electrical lines110to an electrical power supply112, which is in turn connected via electrical lines114to the computer38. Accordingly, the light output from the lamp108can be controlled by the computer and directed through the evaporation lid to evenly and brightly illuminate the visualization field. If a stereo-microscope is utilized in the system20and it includes its own light source, as does the exemplary stereo-microscope of Helmut Hudd, GmBH disclosed above, a separate lamp108and its associated power supply need not be used.

The system20includes a second, data printer116connected to the computer38via electrical lines118. The printer116is arranged to be controlled by the computer for providing hard copies of the data produced by the analyzer, and if desired for providing hard copies of the images captured by the video camera (e.g., to accomplish the same function as provided by the photo printer104). In accordance with one exemplary embodiment of this system20, the second printer116is available from Mitsubishi Electric Corporation of Japan under the model designation CP700E(B).

In order to start any particular dissolution test, the system20can include a start switch120, connected to the computer38via electrical lines. Alternatively, the computer may provide the start signal for initiating any test procedure by depression of a suitable keyboard key or by mouse activation.

Referring now toFIGS. 2 and 3the details of the dissolution chamber22and its associated water jacket40will now be described. The dissolution chamber22basically comprises a petri dish-like hollow member having a generally planar bottom wall124of a circular periphery and from which a circular sidewall126projects upward. The top surface of the sidewall126lies in a common plane parallel to the bottom wall124. The heretofore identified inlet26to the chamber22is in the form of horizontally disposed nozzle128extending into the interior130of the chamber22and terminating at an open end132. The nozzle includes a central passageway (not shown) in fluid communication with the conduit or line28carrying the dissolution liquid from the reservoir24. Disposed in front of the nozzle's outlet132is an upstanding arcuate wall forming a baffle134against which the flow of dissolution liquid12entering the chamber's interior130is directed. The outlet34of the chamber is located in the sidewall128diametrically opposed to the inlet26. In accordance with one exemplary embodiment of this system20, the diameter of the bottom wall124is 90 mm, the height of the sidewall126is approximately 20 mm, with the inlet and outlet each being located halfway up from the bottom wall, i.e., 10 mm from the bottom wall.

As best seen inFIGS. 3 and 4the plural dosage forms10are arranged to be supported in the interior130of the chamber22by a support means in the form of a wire mesh136. The mesh is a generally flat member of approximately square shape, although other shapes can be used as well, formed of intersecting stainless steel wires and having slight upstanding peripheral wall138. The various solid dosage forms to be tested are placed on the mesh, with each dosage form being disposed in its own respective interstitial space created between the crossing wires forming the mesh (seeFIG. 4). The mesh is itself supported slightly off of the inner surface of the bottom wall124via a plurality of spherical legs140fixedly secured to the bottom wall of the chamber. This arrangement ensures that the dissolution liquid flowing into the chamber call flow all about the dosage forms, from under, over and around their sides. The support mesh136can be of any mesh size within the range of USP mesh 10 to USP mesh 100.

As best seen inFIG. 2the support legs140are arranged in a square array located immediately adjacent the sidewall126between the inlet26and outlet34and spaced from the center of the chamber22. Accordingly, the mesh support136with the dosage forms10thereon is out of the way of direct impingement from the dissolution liquid12exiting the nozzle128. In particular, the liquid exiting the nozzle's open end132impinges the inner surface of the baffle134from whence it spreads out, slowing in velocity, and flows gently around the baffle on one side to engage and flow past the dosage forms on the mesh136, while another portion flows about the other side of the baffle. The flows merge, mix and then exit the chamber through the outlet34.

In accordance with a preferred operation of the system20the rate of flow of dissolution liquid12into the chamber is controlled by the pump30via signals from the computer38to ensure that the liquid fills the chamber only up to the height of the outlet34and into the outlet, but not completely submerging the outlet as shown by the liquid level line14inFIG. 3. The surface tension of the dissolution liquid12ensures that it flows through the outlet into the return line36, while enabling air to escape from that line above the liquid level. Accordingly, the dissolution liquid flows back to the reservoir uniformly under the influence of gravity. In this exemplary arrangement the volume of dissolution liquid within the dissolution chamber is approximately 28 ml.

As should be appreciated by those skilled in the art, the spreading of the dissolution liquid throughout the interior of the chamber as just described effectively mixes the liquid within that chamber. Accordingly, the incoming and less concentrated dissolution liquid12is sufficiently mixed with the liquid in the chamber to ensure consistent dissolution of the dosage forms, all without disturbing the position of the dosage forms from within the camera's visualization field. Moreover, the gentle flow of the liquid through the chamber ensures that the surface of the liquid12in the chamber22is relatively smooth and non-turbulent so that it does not interfere with the imaging of the dosage forms by the camera through it and the liquid in which the dosage forms are submerged.

It should be pointed out at this juncture that the support mesh136with the solid dosage forms thereon can be located in the interior of the chamber at a diametrically located position than that shown inFIG. 2, i.e., immediately adjacent the sidewall between the inlet and outlet on the opposite portion of the sidewall, if desired. Location of the mesh at either the center of the chamber or adjacent its outlet is not particularly desirable.

As best seen inFIGS. 1 and 3, the evaporation lid60is a dome-shaped member of the same outside diameter as the chamber22and is arranged to be disposed on the top edge of the chamber's sidewall126. The dome shape of the lid ensures that any dissolution liquid that should condense on its inner surface (notwithstanding the fact that the lid is heated) will run down the arcuate inner surface of the lid and down the inner surface of the chamber's sidewall, thereby preventing dropping into the center of the chamber, since such action could result in agitation of the surface of the liquid at the visualization field, thereby impeding the acquisition of good images of the dosage forms as they dissolve. The evaporation lid is formed of a transparent material, e.g., glass, to enable the camera to visualize the solid dosage forms through it and the liquid12in which those forms are immersed.

The water jacket40basically comprises a petri dish-like hollow member having a generally planar bottom wall142having a circular periphery from which a circular sidewall144projects upward. The top surface of the sidewall144lies in a common plane and is secured to the undersurface of the dissolution chamber's bottom wall124, thereby forming an enclosed hollow interior146. The heretofore identified inlet44to the water jacket extends through the sidewall144immediately under the location of the support mesh136in the chamber22located above the jacket. The outlet52of the water jacket42is located in the sidewall144diametrically opposite the inlet44as best seen inFIG. 2. Accordingly, hot water introduced into the inlet flows through the chamber, whereupon its heat is picked up through the dissolution chamber's bottom wall124to ensure that the temperature of the dissolution liquid in the dissolution chamber is maintained at the desired temperature, e.g., 37° C.

It should be pointed out at this juncture that the control of the dissolution liquid temperature need not entail heating of the same, but, may entail cooling for some applications. In such a case water jackets or other temperature control devices utilizing some cooling medium can be utilized. In fact, any other means for either raising or lowering the temperature of the dissolution liquid in the dissolution chamber and/or in the liquid reservoir can be utilized in accordance with the teachings of this invention. Moreover, the temperature control, if any, need not be accomplished on a continuous or even repetitive basis, but may be used as needed. Also the composition of the dissolution liquid may be changed during the dissolution testing operation, e.g., a dissolution liquid of one pH can be used for a portion of the cycle of testing and then a dissolution liquid of a higher or lower pH can be used at a later part of the cycle.

InFIG. 4there is shown a photograph of a mesh supporting a plurality of solid dosage forms of a solid dosage form pharmaceutical taken from the series of images produced by the system20of this invention and which photograph can be compared to the data provided by the analyzer76at the time of that photograph. With that information the person studying the photograph and data can determine the mechanism of dissolution and if there are any anomalies present.

The following constitutes one exemplary operation of the system20. The user first switches on the water heater unit48to heat the reservoir24and the dissolution media located therein. For example, if the dissolution liquid is water, the user takes a vial of water and degasses it with helium to remove any dissolved air which could pose dissolution problems. When the water is degassed sufficiently it is poured into the reservoir22and the stirrer90is turned on to stir that liquid around gently. Then the inlet and outlet conduits80and88, respectively, for the analyzer76are extended through respective openings in the reservoir's cover59. So too, the inlet and outlet26and34, respectively, of the dissolution chamber22are extended through respective openings in the reservoir cover59. Once this is done the pump30for the dissolution chamber22is turned on to carry the water12into the chamber22to fill it to the height14at the outlet34, whereupon the water exits through the outlet and the return line36to the reservoir24. Once this has been accomplished, the pump82coupled to the input of the analyzer76is turned on to circulate the water to the analyzer. The temperature of the dissolution water12within the dissolution chamber22is then measured by the temperature probe68. This enables the system to reach equilibrium or “equilibrate.” The analyzer is then set to zero.

A standard sample of the pharmaceutical making up the dosage form to be tested is then prepared for calibrating the analyzer76. To that end, a sample solution of the product(s) that will be tested is run through the analyzer, e.g., the spectrophotometer76, to get a absorbence measurement to be used as the standard. In particular, the standard solution is pumped for a period of time, e.g., five minutes, through the inlet line84to the spectrophotometer76, where readings are taken, and from the spectrophotometer to the outlet line88. The outlet line88is at this time directed into a waste container (not shown) to collect the sample solution for disposal. The running of the sample solution through the analyzer enables one to get a true and accurate measure of the amount of the active ingredient(s) in the standard solution. The lines80and88to and from the spectrophotometer are then washed out to ensure that none of the standard solution remains in them or in the spectrophotometer76. Once that has been accomplished the lines80and88are reconnected to the reservoir24and the pump82is restarted to carry the dissolution liquid, e.g., water, back through the spectrophotometer76to equilibrate it again.

The system is now ready for the dissolution test of the dosage form(s). To that end, the user weighs out a known weight, e.g., 100 mg, of plural of the dosage forms to be tested. These dosage forms are then transferred onto the support mesh136. Preferably the amount of dosage forms that are weighed out will be such as to only form a single layer on the mesh (such as shown inFIG. 3) so that all the dosage forms can be imaged by the camera. In fact, it is desirable that the plural dosage forms being tested are isolated from each other physically on the support mesh, so they do not touch one another's sides. The best images of the dosage forms can be obtained when each dosage form is not immediately adjacent to another dosage form to impede the visibility of its surface. This is made more difficult by filling the support mesh completely with dosage forms. Accordingly, it is preferred that the entire surface of the support mesh136not be covered with dosage forms, e.g., only half of the mesh is filled. If the amount of dosage forms to be tested would be too many for a single support mesh to viably accommodate and a minimum amount of the drug is required in order for the dissolution analysis to be accurate, a second mesh support can be used to split up the plural dosage forms onto two groups within the dissolution chamber. In such a case the dissolution chamber includes a second mesh support located diametrically opposite to the first support mesh and supported on plural spherical legs in the same manner as the first support mesh. The plural dosage forms can then divided up between the first support mesh (the one in the visualization field) and the second support mesh. Since there will be sufficient dosage forms on the first support mesh for visualization by the imaging means, there is no requirement to visually record the dosage forms on the second mesh.

After the dosage forms are placed on the mesh, the evaporation cover60of the dissolution chamber22is then removed to provide access to the interior of the chamber and the mesh136with the dosage forms10thereon is then carefully introduced into position in the chamber. To that end, some means, e.g., a spatula, may be used to hold the dosage forms on the mesh as the mesh is gently lowered into the dissolution liquid. This prevents displacement of any of the dosage forms if they would have a tendency to float during immersion.

The system is started, e.g., the start button120is depressed at the moment that the dosage forms on the mesh become submerged in the dissolution liquid. The evaporation lid60is then replaced on the dissolution chamber22. The stereo-microscope100and camera98are then checked to make sure that the dosage10forms within the visualization field are sharply in focus through the transparent dissolution liquid, e.g., the water. Once this has been accomplished an input can be entered into the computer38to cause the video camera98to commence operation and to cause the photo-printer104to produce a hard copy photograph of the condition of the dosage forms at the start of the test. The inherent delay, e.g., approximately 15 seconds, between the start of the system and the start of the video recording should not present any problem from the standpoint of accuracy of the testing. This delay can be reduced to almost zero if the system20is fully automated.

Once the system starts, the video camera98provides a series of sequential images of the dosage forms10as they dissolve at the same time that the analyzer76is providing its data the computer38until the test is deemed over. In particular, in the exemplary embodiment shown the spectrophotometer76electronically measures the amount of light absorbed by the dissolution liquid sample12, e.g., water, flowing past the spectrophotometer's sensor and provides an output signal indicative of that light absorbency to the computer38via lines78. The computer takes that data and compares it against the data previously input into it from the spectrophotometer reading the standard solution preceding the test run. Based on a comparison of the weights and the absorbancies of the sample solution to the standard solution, the computer38calculates the percentage release of the active ingredient(s) from the sample. This data is stored in the computer for subsequent analysis by the user of the system to correlate the dissolution data with the images at any time during the test that the user desires to consider. Hard copies of the results of the analysis can be provided by the printer116. In particular, the system can provided hard copy images or photographs showing the state of dissolution of the dosage forms at any time during the dissolution test, with indicia printed thereon indicating the elapsed time from the start of the test and the percentage of the active ingredient(s) dissolved, e.g., “elapsed time: 10 minutes and 30 seconds; 12% dissolution.”

One of the significant advantages of this invention is that the imaging means can provide a high quality image of either the whole visualization field or only small portion of it. This feature enables a person (or an automated image morphology analysis system) to examine the details of the surface of selected, e.g., one or more, dosage forms within the entire visualization field. Examining such surface details can be of considerable importance in testing dosage forms making use of a shell containing the active ingredient(s), where the outer shell is a polymer coating designed to remain intact for the total of the dissolution run, while the active ingredient(s) is(are) supposed to diffuse through that coating into the dissolution liquid. For example, if in an hour's time there is 40% release of active ingredient(s) and the image shows the coating is intact, without any blisters or ruptures, this indicates that the formulation appears to be working as designed. If at the end of the test, e.g., after eight hours time, you have 100% released and the image at that time still shows no blisters or ruptures, i.e., the formulation coating is still perfect, one can conclude that the formulation has, in fact, worked as designed. If, for example, on the other hand after 15 minutes one gets an image showing the coating is perfect, but there is very little drug release, e.g., 1% drug release, yet the image of the dosage forms taken at forty-five minutes shows that the shell or coating of the formulation has ruptured and the active ingredient dissolved in the dissolution liquid has abruptly reached 60%, the user of the system can accurately draw the inference that the mechanism of drug release in that formulation is by rupture and not by diffusion. Thus, the system of this invention can be a valuable diagnostic tool to ensure that the formulation acts in its designed manner.

It should be pointed out at this juncture that the subject invention is not limited to use for time release or coated formulations. The system can be used with un-coated products which are designed for immediate release. Moreover, the system can be used to take photographs and analyze multi-drug release at selected intervals, e.g., every 60 seconds. From the data and photographs one can accurately determine how the pharmaceutical product behaves. For example, in some formulations one might have some gas bubbles produced because of a chemical interaction which wouldn't be seen in any other apparatus that's currently available and that may be of concern to organic chemists who feel that there should be no gas bubble generation from the drug. So too, the system can be used for determining the action of transdermal patch formulations. In this regard most transdermals have a gel membrane over the gel formulation in the center of the patch. Thus, images showing membrane changes, e.g., small tears or ruptures, pieces breaking off, etc., that are provided by this system can prove invaluable to determine the viability of the formulation.

Without further elaboration the foregoing will so fully illustrate my invention that others may, by applying current or future knowledge, adopt the same for use under various conditions of service.