WO2008157584A2

WO2008157584A2 - Apparatus and methods for automatic insertion, debubbling, cleaning and calibration of a spectral probe during dissolution testing

Info

Publication number: WO2008157584A2
Application number: PCT/US2008/067302
Authority: WO
Inventors: Laurence Dwayne Chin; Archibald Williams; Martin Schwalm; Brett Andrew Feeney
Original assignee: Varian, Inc.
Priority date: 2007-06-20
Filing date: 2008-06-18
Publication date: 2008-12-24
Also published as: EP2162725A2; MX2009013778A; JP2010530542A; CN101688825A; DE08771330T1; BRPI0813135A2; WO2008157584A3; KR20100023963A; EP2162725A4

Abstract

A dissolution test apparatus includes an optical probe, an automated actuator. The probe takes an optics-based measurement in dissolution media contained in a test vessel and transmits the measurement to an analytical instrument situated remotely from the vessel. The optical probe is movable by the actuator into and out from the vessel. The dissolution test apparatus may include a bubble removal apparatus that communicates with the optical probe and is configured for transmitting a variable vibrating force to the probe, wherein bubbles are removed from a light path gap of the probe. In another dissolution test apparatus, the bubble removal apparatus rotates the probe to remove bubbles. Another dissolution test apparatus includes a movable cleaning mechanism, a movable calibration mechanism, or both mechanisms.

Description

APPARATUS AND METHODS FOR AUTOMATIC INSERTION, DEBUBBLING, CLEANING AND CALIBRATION OF A SPECTRAL PROBE DURING

DISSOLUTION TESTING

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Patent Application Serial No. 60/936,257, filed on June 20, 2007.

FIELD OF THE INVENTION [0001] The present invention relates generally to methods and apparatus to perform spectral analysis in pharmaceutical and medical device product testing. More specifically, the present invention relates to an automated apparatus and method for inserting and removing spectral probes into and out of media when performing a dissolution test, for detecting and removing bubbles from the viewing windows or light path gaps of the probes when immersed in the dissolution media, and for cleaning and calibrating probes before, after, and/or between spectral measurements.

BACKGROUND OF THE INVENTION

[0002] In general terms, dissolution testing is used to determine the rate at which a pharmaceutical solid dosage form, usually a tablet, capsule, or transdermal dosage form, dissolves into a given media over time. The media is generally used as a surrogate for the fluid in gastrointestinal tract of a human or animal. The concentration of the Active Pharmaceutical Ingredient (API) released into the media from the dosage form is measured over time. This release may be rapid (e.g., within 10 -15 minutes) for immediate release dosage forms, or may be significantly longer (e.g., hours, weeks or months) for controlled/modified release formulations. Testing is often performed by physically removing a sample from the dissolution media, filtering the sample, and then using an analytical instrument such as an HPLC (high- performance liquid chromatography) to analyze the sample. Alternatively, in situ measurements can be performed by using a fiber-optic probe which is immersed in the dissolution media for the entire dissolution test. Requirements for such 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. For example, U.S. Pat. Nos. 4,279,860; 4,335,438 and 6,948,389, and R. Hanson and V. Gray, Handbook of Dissolution Testing, 3rd Edition, Dissolution Technologies, Inc. (2004), all provide general descriptions of the art of dissolution testing.

[0003] Conventionally constructed apparatus for dissolution testing of pharmaceutical products include a dissolution unit having several dissolution vessels, into each of which a media and a dosage to be tested is placed. After the dosage to be tested is placed in the media within the dissolution vessel, a stirring element is rotated (or reciprocated) within the test solution at a specified rate, for a specified duration. An example of such a conventionally constructed dissolution apparatus is shown in U.S. Pat. No. 5,589,649. An analytical measurement is performed in each vessel at specified time points throughout the dissolution test. Each sample is individually measured with a spectral analyzer, which is attached to a fiber optic probe that is placed in residence within the vessel at the beginning of the dissolution test. The test solutions are individually measured/analyzed using the spectral instrument that measures concentration of API (active pharmaceutical ingredient), which represents the degree of dissolution at a given point in time. Such dissolution systems incorporate both reflective and transmittance fiber-optic probes to make this spectral determination within the test solution as a function of time. Many pharmaceutical APIs contain aromatic functional groups, while excipients generally lack functional groups that have spectral properties in this region. UV measurements are convenient as they provide nearly instantaneous measurements. [0004] As appreciated by persons skilled in the art, a typical fiber-optic probe includes an elongated shaft or body containing a light transmitter and light receiver (light pipes or optical fibers) optically communicating with a spectral analyzer, one or more focusing lenses, and sometimes one or more mirrors or prisms depending on design or operating principle. The light transmitter provides a light transmitting path from a light source (often provided by the analytical instrument) to a liquid sampling region formed in the body of the probe that receives dissolution media from the test vessel into which the probe has been inserted. The light receiver provides a light transmitting path from the liquid sampling region to the detector of the analytical instrument. The liquid sampling region represents a light path gap or viewing window of the probe. [0005] While the existing methodology and apparatuses employed for spectral dissolution testing are well known, there are several shortcomings in the art that have yet to be addressed. The particular problems addressed in the present invention are 1) minimizing disturbance of laminar fluid flow in the test vessels due to the continually resident probes, 2) effective removal of air or gas bubbles from the spectral probe light path gap or viewing area, 3) automatic standardizing and normalization of the probes 4) the effective cleaning of the spectral probes between testing points.

[0006] Accordingly, there continues to be a need for improved fiber-optic probes and related apparatus and methods that produce accurate analytical signals from liquid samples.

SUMMARY OF THE INVENTION

[0007] To address the foregoing problems, in whole or in part, and/or other problems that may have been observed by persons skilled in the art, the present disclosure provides methods, processes, systems, apparatus, instruments, and/or devices, as described by way of example in implementations set forth below.

[0008] According to one implementation, a dissolution test apparatus is provided. The dissolution test apparatus includes an optical probe and an automated actuator. The optical probe is configured for taking an optics-based measurement in dissolution media contained in a test vessel and transmitting the optics-based measurement to an analytical instrument situated remotely from the test vessel. The optical probe includes a body and a light path gap formed in the body for receiving dissolution media. The automated actuator is coupled to the optical probe and is movable along at least one dimension, wherein the optical probe is alternately movable by the automated actuator into and out from the test vessel. [0009] The optical probe may include a light transmitter and a light receiver disposed in the body, with the light path gap positioned in optical communication with the light transmitter and the light receiver. When the optical probe is moved by the automated actuator into the test vessel, the light path gap is submerged in the dissolution media. When the optical probe is moved by the automated actuator out from the test vessel, the light path gap is removed from the dissolution media. The optical probe may be kept out of the dissolution media between the taking of optics-based measurements.

[0010] According to another implementation, the dissolution test apparatus further includes a bubble removal apparatus contacting the optical probe and configured for transmitting a variable oscillating force to the probe, wherein bubbles are removed from the light path gap. [0011] According to another implementation, the dissolution test apparatus further includes an elastomeric coupling attached to the probe and configured to return the probe to a set/registered position after the bubble removal apparatus is deactivated. [0012] According to another implementation, the bubble removal apparatus is configured for transmitting an oscillating force to the probe with a variable frequency, a variable amplitude, or both a variable frequency and a varying amplitude.

[0013] According to another implementation, the bubble removal apparatus is further configured for rotating the probe at an angle to a nominal axis of the probe.

[0014] According to another implementation, the bubble removal apparatus is configured for varying the angle at which the probe is rotated, varying the speed at which the probe is rotated relative to the nominal axis, or varying both the angle and the speed. [0015] According to another implementation, the dissolution test apparatus further includes an automated cleaning mechanism including a bath for containing a cleaning solution. The automated cleaning mechanism is movable to and from a position below the optical probe, wherein the optical probe is movable by the automated actuator into and out from the bath. [0016] According to another implementation, the dissolution test apparatus further includes an automated calibration mechanism including a calibration bath for containing a calibration medium. The automated calibration mechanism is movable to and from a position below the optical probe, wherein the optical probe is movable by the automated actuator into and out from the bath.

[0017] According to another implementation, a dissolution test apparatus is provided. The dissolution test apparatus includes an optical probe, an automated actuator, and an automated cleaning mechanism. The optical probe is configured for taking an optics-based measurement in dissolution media contained in a test vessel and transmitting the optics-based measurement to an analytical instrument situated remotely from the test vessel. The optical probe includes a body and a light path gap formed in the body for receiving dissolution media. The automated actuator is coupled to the optical probe and is movable along at least one dimension, wherein the optical probe is movable by the automated actuator into and out from the test vessel. The automated cleaning mechanism includes a cleaning bath for containing a cleaning solution. The automated cleaning mechanism is movable to and from a position below the optical probe, wherein the optical probe is movable by the automated actuator into and out from the cleaning bath. [0018] According to another implementation, a dissolution test apparatus is provided. The dissolution test apparatus includes an optical probe, an automated actuator, and an automated calibration mechanism. The optical probe is configured for taking an optics-based measurement in dissolution media contained in a test vessel and transmitting the optics-based measurement to an analytical instrument situated remotely from the test vessel. The optical probe includes a body and a light path gap formed in the body for receiving dissolution media. The automated actuator is coupled to the optical probe and is movable along at least one dimension, wherein the optical probe is movable by the automated actuator into and out from the test vessel. The automated calibration mechanism includes a calibration bath for containing a calibration medium. The automated calibration mechanism is movable to and from a position below the optical probe, wherein the optical probe is movable by the automated actuator into and out from the calibration bath.

[0019] According to another implementation, a dissolution test apparatus is provided that includes both an automated cleaning mechanism and an automated calibration mechanism. In one example, the cleaning mechanism and the calibration mechanism are integrated into a single or unitary mechanism that is movable to and from the optical probe.

[0020] According to another implementation, a method is provided for operating an optical probe in a test vessel of a dissolution test apparatus. The optical probe is inserted into the test vessel along a nominal axis of the optical probe by operating an automated actuator, until a light path gap of the optical probe is submerged in dissolution media contained in the test vessel. Any bubbles residing within the light path gap are removed by oscillating the optical probe relative to the nominal axis.

[0021] According to another implementation, the optical probe is automatically returned to a set/registered position by utilizing an elastomeric coupling attached to the optical probe. [0022] According to another implementation, the bubbles are removed by oscillating the probe at a variable frequency, a variable amplitude, or both a variable frequency and a variable amplitude.

[0023] According to another implementation, the method further includes removing any bubbles by rotating the optical probe at an angle to a nominal axis of the optical probe. [0024] According to another implementation, the bubbles are removed by rotating the optical probe at a variable angle, at a variable speed relative to the nominal axis, or at both a variable angle and a variable speed.

[0025] According to another implementation, the method further includes cleaning the optical probe by moving a cleaning mechanism into a position below the optical probe, and inserting the optical probe into a cleaning bath of the cleaning mechanism that contains a cleaning solution.

[0026] According to another implementation, the method further includes calibrating the optical probe by moving a calibrating mechanism into a position below the optical probe, and inserting the optical probe into a calibrating bath of the calibrating mechanism that contains a calibrant.

[0027] According to another implementation, the method further includes operating the probe to take an optics-based measurement of the dissolution media residing in the light path gap, and removing the optical probe from the test vessel by operating the automated actuator. [0028] According to another implementation, the method includes operating the actuator to adjust the height of the optical probe relative to the test vessel, such that the optical probe is accurately positioned at a desired test position of the probe at which optics-based measurements of the dissolution media are taken. [0029] According to another implementation, the method includes automatically detecting the presence and/or absence of bubbles in the light path gap. In one example, software is utilized for such detection.

[0030] According to another implementation, a method is provided for operating an optical probe in a test vessel of a dissolution test apparatus. The optical probe is cleaned by moving a cleaning mechanism into a position below the optical probe, and inserting the optical probe into a cleaning bath of the cleaning mechanism that contains a cleaning solution. The optical probe is then inserted into the test vessel.

[0031] According to another implementation, a method is provided for operating an optical probe in a test vessel of a dissolution test apparatus. The optical probe is calibrated by moving a calibrating mechanism into a position below the optical probe, and inserting the optical probe into a calibrating bath of the calibrating that contains a calibrant or blank medium. The optical probe is then inserted into the test vessel.

[0032] According to another implementation, a method is provided for operating an optical probe in a test vessel of a dissolution test apparatus. The optical probe is inserted into the test vessel until a light path gap of the optical probe is submerged in dissolution media contained in the test vessel. The optical probe is operated to take an optics-based measurement of the dissolution media residing in the light path gap. After taking the optics-based measurement and prior to taking another optics-based measurement, the optical probe is removed from the test vessel by operating the automated actuator. [0033] According to another implementation, the method further includes performing a step selected from the group consisting of (a) before taking the optics-based measurement, removing any bubbles residing within the light path gap by oscillating the optical probe; (b) while the optical probe is outside of the dissolution media, cleaning the optical probe by moving a cleaning mechanism into a position below the optical probe, and inserting the optical probe into a cleaning bath of the cleaning mechanism; (c) while the optical probe is outside of the dissolution media, calibrating the optical probe by moving a calibrating mechanism into a position below the optical probe, and inserting the optical probe into a calibrating bath of the calibrating mechanism; and (d) combinations of two or more of the foregoing steps.

[0034] According to various implementations, the cleaning step, the calibration step, or both the cleaning and calibration steps may be performed prior to the initiation of a dissolution test run, after the completion of the dissolution test run, and/or in between each iteration of taking an optics-based measurement during the course of the dissolution test run. [0035] Other devices, apparatus, systems, methods, features and advantages of the invention will be or will become apparent to one with skill in the art upon examination of the following figures and detailed description. It is intended that all such additional systems, methods, features and advantages be included within this description, be within the scope of the invention, and be protected by the accompanying claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0036] The invention can be better understood by referring to the following figures. The components in the figures are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention. In the figures, like reference numerals designate corresponding parts throughout the different views.

[0037] Figure 1 is a schematic/elevation view of an example of a dissolution test apparatus including an optical probe and a mechanism for vibrating the optical probe. [0038] Figure 2 is a schematic/elevation view of an example of a dissolution test apparatus including an optical probe and a mechanism for cleaning, rinsing, calibrating and/or standardizing the optical probe.

DETAILED DESCRIPTION OF THE INVENTION

[0039] The present disclosure addresses issues and problems with the prior art of fiber-optic (spectral) dissolution testing. In the prior art, probes remain resident in the test vessels throughout the dissolution test causing unwanted fluid disturbances within the test vessel. The continuous disruption of mixing hydrodynamics, caused by a resident probe, can have a marked impact on the dissolution profile of a drug formulation. For example, it has been reported when resident rod probes were used compared with manual sampling methods, a 3 - 5% increase in dissolution rate has been observed. In prior art systems, the spectral probes are kept resident within the testing solution for the entire test, thereby potentially accelerating or altering the dissolution rate of an API. The reason for the resident probes in prior art systems is that the raising and lowering of the probe in and out of the media risks capturing a bubble within the spectral window, which in turn inhibits accurate measurement of the sample. Additionally, probes are left resident so as to prevent material from drying on the spectral viewing window which abrogates absorption measurements.

[0040] In prior art systems, probes need to be calibrated off-line before starting an experiment and generally need to be re-calibrated (off-line) between dissolution runs or between samples. In addition, probes need to be cleaned off-line between dissolution runs or after sampling in order to eliminate cross-contamination between samples and to clean the probe viewing window and optics in preparation for the next measurement. It has been found that regardless of probe geometry, insoluble particulate matter frequently collects on probe windows, which occludes the light path and inhibits a proper spectroscopic measurement. Therefore, in order to incorporate fiber-optic probes with automated dissolution testers, automated probe insertion and removal, automated bubble removal, automated online probe cleaning, and automated online calibration become a necessity to reconcile short-comings with the prior art. [0041] According to one example of the present invention, the system has an automated mechanism for momentarily inserting and removing the spectral probes into and out from the testing vessels, at specific time points, which in turn reduces any disruption to the fluid dynamics within the vessel due the probe. The momentary insertion of the fiber-optic probes is comparable with the use of a conventional canula, which only disturbs the hydrodynamics of the vessel for a brief moment (Schatz et al., Thoughts on Fiber Optics in Dissolution Testing, Dissolution Technologies, 8(2): 1-5 (2001); Schatz et al., Shaft Sampling with Fiber Optics, Dissolution Technologies, 7(1): 20-21 (2000)).

[0042] According to another example of the present invention, the system incorporates a mechanism designed to apply a vibration force at varying amplitudes and frequencies, and a rotating motion at varying angles and speeds, to remove gas or air bubbles from the spectral probe light path gap or viewing area. Bubbles may be captured as the probe is inserted into the vessel media or during the time that the probe is resident in the vessel media. Furthermore, this apparatus may incorporate a self-centering, elastomeric or compliant mechanical coupling that allows the probe body to move and rotate during the bubble removal process and returns the probe to its set/registered position after the bubble is removed. This bubble removal apparatus can be coupled with software which is able to check and determine if and when a bubble is present and when it is removed. Prior art systems did not have a means for automatically detecting and removing bubbles from the spectral probe light path, which has frequently resulted in inconclusive or invalid testing results, due to the interference of the bubbles with the spectral transmission.

[0043] According to another example of the present invention, the system incorporates an automated online means of effectively cleaning the spectral probes in between testing points or experiments. The novel system incorporates one or more static and/or re-circulating baths for each probe. The baths may contain one, or a series, of cleaning and/or rinsing fluids for removing any debris, insoluble or hydrophobic materials, etc. that collected on the spectral probe light path gap or viewing area during the time that it was immersed in the dissolution vessel or calibration standards. Furthermore, the baths are used to clean the outer surfaces of the probes, thereby reducing or eliminating any carryover and cross contamination. This cleaning process ensures that the data for the dissolution profiles collected are representative of the sample that was tested.

[0044] According to another example of the present invention, the system incorporates automated online means to calibrate the fiber-optic probes to a known reference standard. The system incorporates one or more static and/or re-circulating baths for each probe. These baths contain known concentrations of API and/or blank media that are used to calibrate the probe and the associated spectral instrument. The probes are automatically inserted into the calibration bath(s) (and bubbles are removed, with the bubble removal apparatus as described above, as necessary), and spectra are collected in order to calibrate to probe. The automated method allows several dissolution tests to be performed consecutively, with the ability to perform a calibration automatically, on-line between each test performed. [0045] Accordingly, there is a need for an automated spectral dissolution testing apparatus that overcomes the shortcomings identified above related to the prior art. Further, there is a need for an automated dissolution testing apparatus that 1) minimizes disturbance of laminar fluid flow in the test vessels by automatically inserting the spectral probes only when test measurements are required, 2) effectively removes air or gas bubbles from the spectral probe light path gap or viewing area, 3) performs automatic cleaning of the spectral probes between testing points, and 4) automatically provides standardizing and normalization of the probes. [0046] In accordance with the present inventions, several novel devices and methods for implementation within a dissolution testing apparatus are provided. Various implementations of the invention may include 1) an automated mechanism for lowering and raising the spectral probes into and out of the testing vessel and fluid, 2) an automated means to remove air or gas bubbles from the spectral probe light path gap or viewing area, 3) an automatic mechanism, including a rack which will hold a plurality of static or re-circulating baths for the cleaning of the spectral probes, and/or 4) an automatic mechanism including a rack which will hold a plurality of static or re-circulating baths for the standardization and normalization of the spectral probes and associated analytical instrument.

[0047] Figure 1 illustrates an example of a dissolution testing apparatus 100 according to one or more implementations taught herein. The dissolution testing apparatus 100 generally includes a spectral probe (e.g., a fiber-optic probe or optical probe) 104 that may be structured as described above. The probe 104 may be lowered into and raised out from a dissolution test vessel 108 containing dissolution media 112. A stirring device or other USP-type device 116 may operate within the dissolution media 112 in a manner appreciated by persons skilled in the art. An automated actuator 120 is coupled to the probe 104 so as to enable the actuator 120 to move the probe 104 vertically (as indicated by an arrow 124) from a position above and outside of the dissolution media 112 to a testing position within the dissolution media 112 when a test is being performed. Figure 1 specifically illustrates the probe 104 at the testing position. The probe 104 includes a light path gap or viewing window 124 as described above, which is typically located near a distal end of the probe 104. The light path gap 124 is submerged in the dissolution media 112 at the testing position of the probe 104 to enable optics-based measurements to be taken. As described above, the actuator 120 may be operated to remove the probe 104 from the dissolution media 112 after a measurement point has been acquired, such that the probe 104 resides in the dissolution media 112 only during testing. The probe 104 may thus be removed from the fluid 112 when not being used for testing to eliminate any fluid disturbance in the vessel 108. At the testing position, the probe 104 is positioned along a nominal longitudinal (i.e., vertical) axis 128. The height of the probe 104, and other positional coordinates of the probe 104 relative to the test vessel 108, may be dictated by guidelines such as the above-mentioned USP. The actuator 120 may be operated to make adjustments to the position of the probe 104 (in particular, height) to facilitate compliance with such positional requirements.

[0048] As further illustrated in Figure 1, the dissolution testing apparatus 100 may further include a bubble removal apparatus 132 that may be mounted to the actuator 120 or any other suitable structure of the dissolution testing apparatus 100. The bubble removal apparatus 132 may include, for example, a vibration source or generator 136 that communicates with the probe 104 via a suitable linkage 140. As an example, the vibrating mechanism 136 of the bubble removal apparatus 132 may be a solenoid-type device. As an example, the vibration source 136 may be fixed in position while the linkage 140 is movable relative to the vibration source 136. The linkage 140 transfers the vibrational energy to the probe 104 through contact with the probe 104. Oscillation of the linkage 140 is represented by an arrow 144 in Figure 1 and the resulting oscillation or vibration of the probe 104 is represented by an arrow 148. Contact with the probe 104 may be effected by any suitable means. As one example, the linkage 140 may intermittently come into contact with the probe 104 such as by "tapping" the probe 104 whereby the probe 104 is displaced in response to impact by the linkage 140. As another example, the linkage 140 may be generally continuously coupled to the probe 104 such that the probe 104 moves in direct response to movement by the linkage 140. In one implementation, the vibration of the probe 104 is characterized by movement of the probe 104 back and forth through an angle relative to a pivot point 152 of the probe 104. The pivot point 152 may be realized through coupling of the probe 104 to any suitable structure of the dissolution test apparatus 100 such as the actuator 120. In one implementation, the probe 104 is held in a self-centering, compliant or elastomeric coupling 156 as illustrated in Figure 1. This coupling 156 allows the probe 104 to move in a side-to-side motion in response to stimulation by the vibrating mechanism 136 of the bubble removal device 132. Upon de-activation of the bubble removal device 132 (i.e., after completion of the bubble removing procedure), the coupling 156 allows the probe 104 to return to its set/registered position collinear with its nominal axis 128.

[0049] In addition to cyclical translation along one dimension such as the side-to- side motion depicted by the arrow in Figure 1, the vibrational mechanism 136 of the bubble removal apparatus 132 may be configured to excite the probe 104 into movement along other dimensions such as front- to-back (into and out from the drawing sheet, i.e., orthogonal to the arrow 144). Additionally or alternately, the vibrational mechanism 136 may be configured to drive the probe 104 into rotational or gyrating motion at an angle relative to the nominal axis 128 and relative to the pivot point 152 of the probe 104. The elastomeric coupling 156 may be configured to accommodate these other types of movements of the probe 104 and, as noted above, return the probe 104 to its set/registered position upon cessation of the vibrational stimulus. Displacement of the probe 104 along more than one dimension or axis, and/or rotation or gyration of the probe 104 at an angle to the nominal axis 128 of the probe 104, may be effected by any suitable means. In one example, the linkage 140 may be positioned at an angle relative to the probe 104, i.e., some angle other the horizontal orientation of the linkage 140 specifically shown in Figure 1. In another example, the linkage 140 is able to pivot and/or rotate through its connection to the vibration generating component 136 of the bubble removal device 132, and this motion is transferred to the probe 104 via the coupling of the linkage 140 to the probe 104 (e.g., a yoke, ring or the like). In another example, the bubble removal device 132 may include more than one vibration generating component 136 and associated linkage 140. For instance, one vibration generating component 136 and associated linkage 140 may be positioned/oriented as shown in Figure 1, and another vibration generating component 136 and associated linkage 140 may be positioned/oriented orthogonally so as to add a front-to-back motion to the illustrated side-to- side motion.

[0050] In some implementations, the vibrating mechanism 132 is configured to exert a vibration force of varying amplitude and/or frequency, which may be programmable and fully adjustable to accommodate different probe geometries and fluids. In implementations providing rotational motion, the vibrating mechanism 132 may additionally be configured to vary the angle at which the probe 104 gyrates or rotates relative to the nominal axis 128, and/or vary the speed of rotation or gyration of the probe 104 about the nominal axis 128.

[0051] Figure 2 illustrates another example of a dissolution testing apparatus 200 according to one or more implementations taught herein. The dissolution testing apparatus 200 may include features or components similar to those illustrated in Figure 1, and accordingly like reference numerals designate like features. The dissolution testing apparatus 200 includes a mechanism 260 for cleaning or rinsing the probe 204. By way of example, the illustrated mechanism 260 includes a rack 264 that holds one or more baths 268 and 272 containing cleaning or rinsing fluids. As noted above, the bath(s) 268 and 272 may be static or recirculating (the components effecting circulation not being shown). As illustrated by an arrow 276, the mechanism 260 is movable by a suitable actuator (not shown) into a position above the test vessel 208 and below the probe 204. The actuator 220 coupled to the probe 204 may then be operated to lower the probe 204 into a selected bath 268 or 272 of the mechanism 260. By this configuration, the probe 204 may be cleaned between testing points or sample readings (i.e., between the taking of optics-based measurements) if desired. Thus, the probe 204 may be lowered into the dissolution media 212 by the actuator 220 and, after the taking a measurement, raised out from the dissolution media 212. The probe 204 may be raised far enough upward to provide clearance for the cleaning mechanism 260. Subsequently, the cleaning mechanism 260 is moved into position below the probe 204 and the probe 204 is lowered into one of the baths 268 or 272 for cleaning/rinsing. The cleaning mechanism 260 may then be moved out of the vertical travel path of the probe 204, and the probe 204 lowered back into the dissolution media 212 for acquiring the next testing point. This process may be repeated one or more times in accordance with the desired testing procedure. The cleaning step may also be performed before the initiation of a dissolution run (in which a series of data points are acquired to generate a dissolution rate curve) and after completion of the dissolution run.

[0052] Figure 2 also represents an implementation in which the mechanism 260 is a calibration or standardization mechanism. In this case, the static or recirculating baths 268 and 272 of the rack 264 contain calibrant or blank media. In one example, one bath 268 may contain a calibration medium while the other bath 272 contains a blank medium. As in the case of cleaning/rinsing, the mechanism 260 and associated components of the dissolution testing apparatus 200 may be operated to perform calibration/standardization of the probe 204 (and spectral analyzer) between testing points if desired. The cleaning step may also be performed before the initiation of a dissolution run (in which a series of data points are acquired to generate a dissolution rate curve) and after completion of the dissolution run.

[0053] In all such cases, it can be seen that the dissolution apparatus 200 enables all cleaning, rinsing, calibration and like procedures to be perform on-line, whereas conventional apparatus and methods have required such procedures to be performed off-line. [0054] In one implementation, the dissolution testing apparatus 200 includes a mechanism for cleaning the probe 204, and a second mechanism for calibrating the probe 204. In another implementation, the same mechanism 260 may be utilized for both cleaning and calibration, in which case different baths 268 and 272 may contain respective cleaning and calibration fluids. [0055] As further illustrated in Figure 2, the dissolution testing apparatus 200 may include the bubble removing device 232 described above in conjunction with Figure 1. Hence, the bubble removing device 232 may be operated prior to each measuring iteration if desired. The timing, duration and sequence of the respective operations of the bubble removing device 232, the cleaning and/or calibration mechanism 260, the actuator 220, and associated components may be determined or programmed in any manner desired by the user. [0056] While in Figures 1 and 2 the dissolution testing apparatus 100, 200 is schematically depicted as including a single assembly (e.g., probe, actuator, bubble removing device, cleaning/calibration mechanism, etc.) operating at a single test vessel 108, 208, it is well appreciated by persons skilled in the art that the dissolution testing apparatus 100, 200 will typically include an array of testing vessels 108, 208. Accordingly, it will further be understood that the dissolution testing apparatus 100, 200 illustrated in Figures 1 and 2 may include a plurality of assemblies associated with a like number of test vessels 108, 208. Moreover, additional variations are readily envisioned. For instance, in the case of a multi-vessel dissolution testing apparatus, a single cleaning/calibration mechanism 260 or a single pair of cleaning and calibration mechanisms 260 may be sequentially moved from one probe 204 to another.

[0057] In general, terms such as "communicate" and "in . . . communication with" (for example, a first component "communicates with" or "is in communication with" a second component) are used herein to indicate a structural, functional, mechanical, electrical, signal, optical, magnetic, electromagnetic, ionic or fluidic relationship between two or more components or elements. As such, the fact that one component is said to communicate with a second component is not intended to exclude the possibility that additional components may be present between, and/or operatively associated or engaged with, the first and second components. [0058] It will be understood that various aspects or details of the invention may be changed without departing from the scope of the invention. Furthermore, the foregoing description is for the purpose of illustration only, and not for the purpose of limitation — the invention being defined by the claims.

Claims

WHAT IS CLAIMED IS:

1. A dissolution test apparatus comprising: an optical probe configured for taking an optics-based measurement in dissolution media contained in a test vessel and transmitting the optics-based measurement to an analytical instrument situated remotely from the test vessel, the optical probe comprising a body and a light path gap formed in the body; and an automated actuator coupled to the optical probe and movable along at least one dimension, wherein the optical probe is alternately movable by the automated actuator into and out from the test vessel.

2. The dissolution test apparatus of claim 1, further comprising a bubble removal apparatus communicating with the optical probe and configured for transmitting a variable oscillating force to the probe, wherein bubbles are removed from the light path gap.

3. The dissolution test apparatus of claim 2, further comprising an elastomeric coupling attached to the probe and configured to return the probe to a set position after the bubble removal apparatus is deactivated.

4. The dissolution test apparatus of claim 3, wherein the automated actuator is connected to the elastomeric coupling.

5. The dissolution test apparatus of claim 2, wherein the bubble removal apparatus is configured for transmitting an oscillating force to the probe with a variable frequency, a variable amplitude, or both a variable frequency and a varying amplitude.

6. The dissolution test apparatus of claim 2, wherein the bubble removal apparatus is further configured for rotating the probe at an angle to a nominal axis of the probe.

7. The dissolution test apparatus of claim 6, wherein the bubble removal apparatus is configured for varying the angle at which the probe is rotated, varying the speed at which the probe is rotated relative to the nominal axis, or varying both the angle and the speed.

8. The dissolution test apparatus of claim 1, further comprising an automated cleaning mechanism having a bath for containing a cleaning solution, the automated cleaning mechanism movable to and from a position, which is below the optical probe, wherein the optical probe is movable by the automated actuator into and out from the bath.

9. The dissolution test apparatus of claim 8, wherein the bath is a recirculating bath.

10. The dissolution test apparatus of claim 1, further comprising an automated calibration mechanism having a bath for containing a calibration medium, the automated calibration mechanism movable to and from a position, which is below the optical probe, wherein the optical probe is movable by the automated actuator into and out from the bath.

11. The dissolution test apparatus of claim 1, further comprising an automated cleaning mechanism having a cleaning bath for containing a cleaning solution, the automated cleaning mechanism movable to and from a position below the optical probe, and an automated calibration mechanism including a calibration bath for containing a calibration medium, the automated cleaning mechanism and the automated calibration mechanism movable to and from a position below the optical probe, wherein the optical probe is movable by the automated actuator into and out from the cleaning bath and the calibration bath.

12. A method for operating an optical probe in a test vessel of a dissolution test apparatus, the method comprising: inserting the optical probe into the test vessel along a nominal axis of the optical probe by operating an automated actuator, until a light path gap of the optical probe is submerged in dissolution media contained in the test vessel; and removing any bubbles residing within the light path gap by oscillating the optical probe relative to the nominal axis.

13. The method of claim 12 further comprising, after oscillating the optical probe, automatically returning the optical probe to a set position by utilizing an elastomeric coupling attached to the optical probe.

14. The method of claim 12, wherein removing any bubbles comprises oscillating the optical probe at a variable frequency, a variable amplitude, or both a variable frequency and a variable amplitude.

15. The method of claim 12, wherein removing any bubbles further comprises rotating the optical probe at an angle to a nominal axis of the optical probe.

16. The method of claim 15, wherein removing any bubbles comprises rotating the optical probe at a variable angle, at a variable speed relative to the nominal axis, or at both a variable angle and a variable speed.

17. The method of claim 12, further comprising cleaning the optical probe by moving a cleaning mechanism into a position below the optical probe, and inserting the optical probe into a cleaning bath of the cleaning mechanism that contains a cleaning solution.

18. The method of claim 12, further comprising calibrating the optical probe by moving a calibrating mechanism into a position below the optical probe, and inserting the optical probe into a calibrating bath of the calibrating mechanism that contains a calibrant.

19. A method for operating an optical probe in a test vessel of a dissolution test apparatus, the method comprising: inserting the optical probe into the test vessel until a light path gap of the optical probe is submerged in dissolution media contained in the test vessel; operating the probe to take an optics-based measurement of the dissolution media residing in the light path gap; and after taking the optics-based measurement and prior to taking another optics-based measurement, removing the optical probe from the test vessel by operating the automated actuator.

20. The method of claim 19, further comprising performing a step selected from the group consisting of (a) before taking the optics-based measurement, removing any bubbles residing within the light path gap by oscillating the optical probe; (b) while the optical probe is outside of the dissolution media, cleaning the optical probe by moving a cleaning mechanism into a position below the optical probe, and inserting the optical probe into a cleaning bath of the cleaning mechanism; (c) while the optical probe is outside of the dissolution media, calibrating the optical probe by moving a calibrating mechanism into a position below the optical probe, and inserting the optical probe into a calibrating bath of the calibrating mechanism; and (d) combinations of two or more of the foregoing steps.