JP2010530542A - Equipment and methods for automatic insertion, bubble removal, cleaning and calibration of spectral probes during dissolution testing - Google Patents

Abstract

An improved fiber optic probe and associated apparatus and method for generating an accurate analytical signal from a liquid sample.
A dissolution test instrument includes an optical probe and an automated actuator. The probe performs an optical measurement in a dissolution medium contained in a test container and transmits this measurement to an analytical instrument located away from the container. The optical probe can be moved in and out of the container by an actuator. The dissolution test equipment is in communication with the optical probe and may include a bubble remover machine configured to transmit various vibration forces to the probe, in which case the bubbles are removed from the optical path gap of the probe. . In another dissolution test instrument, the bubble remover machine rotates the probe to remove bubbles. Another dissolution test instrument includes a movable cleaning mechanism, a movable calibration mechanism, or both mechanisms.
[Selection] Figure 1

Description

  The present invention relates generally to methods and apparatus for performing spectral analysis in pharmaceutical and medical device product testing. More particularly, the present invention detects bubbles from the probe's observation window or optical path gap when immersed in the dissolution medium to insert and remove the spectral probe from the medium when performing a dissolution test. And to an automated instrument and method for cleaning and calibrating a probe before, after and / or between spectral measurements and between spectral measurements.

This application claims priority to US Provisional Patent Application No. 60 / 936,257, filed June 20, 2007.
In general, dissolution tests are used to determine the rate at which a pharmaceutical solid dosage form, usually a tablet, capsule or transdermal dosage form, dissolves over time in a given medium. The The medium is generally used as a substitute for fluid in the human or animal gastrointestinal tract. The concentration of active pharmaceutical ingredient (API) released from the dosage form into the vehicle is measured over time. This release can be fast (eg, within 10-15 minutes) for immediate release dosage forms or can be quite long (eg, hours, weeks or months) with controlled / tuned release formulations ) There are cases. Often, the sample is physically removed from the dissolution medium, filtered, and then analyzed using an analytical instrument such as HPLC (High Performance Liquid Chromatography). Alternatively, in-situ measurements can be performed by using a fiber optic probe immersed in the dissolution medium for the entire dissolution test. Requirements for such dissolution test equipment are set forth in United States Pharmacopeia (USP) Section 711, Dissolution (2000). Dissolution tests and basic instrument processing to perform such tests are known in the art. For example, the following patent documents 1, 2 and 3 and the following non-patent document 1 all provide a general description of dissolution testing techniques.

  Conventionally configured equipment for dissolution testing of pharmaceutical products includes a dissolution unit having several dissolution containers each containing a medium and a drug to be tested. After placing the drug to be tested in the medium in the dissolution vessel, the stirring element is rotated (or reciprocated) in the test solution at a specific speed for a specific period. An example of such a conventional melting device is shown in Patent Document 4 below. Analytical measurements are performed in each container at specific points throughout the dissolution test. Each sample is measured by a spectrum analyzer attached to a fiber optic probe that is placed in the container at the start of the dissolution test. Each test solution is measured / analyzed using a spectral instrument that measures the concentration of API (active pharmaceutical ingredient) indicating the solubility at a given time. In order to make this spectral determination as a function of time in the test solution, such a lysis system incorporates both reflective and transmissive fiber optic probes. Many pharmaceutical APIs contain aromatic functional groups, but additives generally do not contain functional groups that have spectral properties in this region. The UV measurement is preferable because it can be performed almost immediately.

  As one skilled in the art understands, a typical fiber optic probe includes a long shaft or body that houses a light transmitter and receiver (light pipe or fiber optic) in optical communication with a spectrum analyzer, and 1 It includes one or more focusing lenses and, in some cases, one or more mirrors or prisms depending on the design or operating principle. The optical transmitter transmits light from a light source (often provided by an analytical instrument) to a liquid extraction (sampling) region formed in the body of the probe that receives the dissolution medium from the test container in which the probe is inserted. Provide a road. The light receiver provides an optical transmission path from the liquid extraction region to the detector of the analytical instrument. The liquid extraction area represents the optical path gap or observation window of the probe.

  While the existing principles and instruments used for spectral dissolution testing are well known, the art has several drawbacks to address.

U.S. Pat.No. 4,279,860 U.S. Pat.No. 4,335,438 U.S. Patent 6,948,389 U.S. Pat.No. 5,589,649

R. Hanson and V. Gray, Handbook of Dissolution Testing, 3rd Edition, Dissolution Technologies, Inc. (2004) 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)

  Special issues addressed by the present invention are: 1) minimizing turbulent laminar fluid flow turbulence in the test vessel due to the continuous inherent probe, 2) spectral probe optical path gap with air or gas bubbles Or effective removal from the observation area, 3) automatic standardization and normalization of the probe, and 4) effective cleaning of the spectral probe between tests.

  Accordingly, there is a continuing need for improved fiber optic probes and associated instruments and methods that generate accurate analytical signals from liquid samples.

In order to address all or part of the above problems and / or other problems that would have been observed by one skilled in the art, the present disclosure provides methods, as illustrated by examples in the embodiments described below, Providing treatments, systems, equipment, instruments and / or devices.
According to one embodiment, a dissolution test instrument is provided. The dissolution test instrument includes an optical probe and an automated actuator. The optical probe is configured to perform an optical measurement in a dissolution medium contained in a test container and to transmit the optical measurement to an analytical instrument disposed away from the test container. The optical probe includes a main body and an optical path gap formed in the main body for receiving the dissolution medium. The automated actuator is coupled to the optical probe and is movable along at least one dimension, and the optical probe is alternately movable in and out of the test vessel by the automated actuator. Yes.

  The optical probe may include an optical transmitter and light receiver disposed within the body with the optical path gap disposed in optical communication with the optical transmitter and light receiver. As the optical probe is moved into the test container by an automated actuator, the optical path gap is submerged in the dissolution medium. When the optical probe is moved out of the test container by an automated actuator, the optical path gap is removed from the dissolution medium. The optical probe may be left out of the dissolution medium between optical measurements.

According to another embodiment, the dissolution test instrument further includes a foam remover configured to contact the optical probe to transmit various vibrational (oscillating) forces to the probe, wherein the foam is removed from the optical path gap. The
According to another embodiment, the dissolution test apparatus further includes an elastomeric coupling member attached to the probe and configured to return the probe to a set / registered position after deactivation of the foam remover machine.

According to another embodiment, the bubble remover machine is configured to transmit oscillating forces to the probe at various frequencies, various amplitudes, or both at various frequencies and various amplitudes.
According to another embodiment, the bubble remover machine is further configured to rotate the probe at an angle relative to the nominal axis of the probe.

According to another embodiment, the bubble remover machine changes the angle at which the probe is rotated, changes the speed at which the probe is rotated relative to the nominal axis, or changes both the angle and speed. It is configured to let you.
According to another embodiment, the dissolution test instrument further includes an automated cleaning mechanism that includes a bath for containing a cleaning solution. The automated cleaning mechanism is movable to and from a position below the optical probe, and the optical probe is movable in and out of the bath by an automated actuator.

According to another embodiment, the dissolution test instrument further includes an automated calibration mechanism that includes a calibration bath for containing a calibration medium. The automated calibration mechanism is made movable to and from the position below the optical probe, and the optical probe is made movable in and out of the bath by an automated actuator.
According to another embodiment, a dissolution test instrument is provided. The dissolution test instrument includes an optical probe, an automated actuator, and an automated cleaning mechanism. The optical probe is configured to perform an optical measurement in a dissolution medium contained in a test container and to transmit the optical measurement to an analytical instrument disposed away from the container. The optical probe includes a main body and an optical path gap formed in the main body for receiving the dissolution medium. An automated actuator is coupled to the optical probe and is movable along at least one dimension, and the optical probe is movable into and out of the test container by the automated actuator. The automated cleaning mechanism includes a tank for containing a cleaning solution. The automated cleaning mechanism is movable to and from a position below the optical probe, and the optical probe is movable in and out of the cleaning tank by an automated actuator.

  According to another embodiment, a dissolution test instrument is provided. The dissolution test instrument includes an optical probe, an automated actuator, and an automated calibration mechanism. The optical probe is configured to perform an optical measurement in a dissolution medium contained in a test container and to transmit the optical measurement to an analytical instrument disposed away from the container. The optical probe includes a main body and an optical path gap formed in the main body for receiving the dissolution medium. An automated actuator is coupled to the optical probe and is movable along at least one dimension, and the optical probe is movable into and out of the test container by the automated actuator. The automated calibration mechanism includes a calibration bath for containing calibration media. The automated calibration mechanism is movable to and from the position below the optical probe, and the optical probe is moved into and out of the calibration chamber by an automated actuator.

According to another embodiment, a dissolution test instrument 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 integral mechanism that is movable relative to the optical probe.
According to another embodiment, a method is provided for operating an optical probe within a test container of a dissolution test instrument. By actuating the automated actuator, the optical probe is inserted into the test container along the nominal axis of the optical probe until the optical path gap of the optical probe sinks into the dissolution medium contained in the test container. By vibrating (oscillating) the optical probe with respect to the nominal axis, bubbles present in the optical path gap are removed.

According to another embodiment, the optical probe is automatically returned to the set / registered position by using an elastomeric coupling member attached to the optical probe.
According to another embodiment, bubbles are removed by vibrating the optical probe at different frequencies, different amplitudes, or both at different frequencies and different amplitudes.

According to another embodiment, the method further includes removing bubbles by rotating the optical probe at an angle relative to the nominal axis of the optical probe.
According to another embodiment, bubbles are removed by rotating the optical probe at various angles, various speeds relative to the nominal axis of the optical probe, or both at various angles and various speeds.

According to another embodiment, the method cleans the optical probe by moving the cleaning mechanism to a position below the optical probe and inserting the optical probe into a cleaning tank of a cleaning mechanism containing a cleaning solution. It further includes steps.
According to another embodiment, the method moves the calibration mechanism to a position below the optical probe and inserts the optical probe into the calibration chamber of the calibration mechanism containing the calibration material. The method further includes calibrating the probe.

According to another embodiment, the method includes activating a probe to perform an optical measurement of a dissolution medium present in the optical path gap and activating an automated actuator to activate the optical probe. And removing from the test container.
According to another embodiment, the method includes adjusting the height of the optical probe relative to the test container so that the optical probe is accurately positioned at the desired test location of the probe where the optical measurement of the dissolution medium is performed. The method further includes actuating an actuator to adjust.

According to another embodiment, the method further includes automatically detecting the presence and / or absence of bubbles in the optical path gap. In one example, software is used for such detection.
According to another embodiment, a method is provided for operating an optical probe within a test container of a dissolution test instrument. The optical probe is cleaned by moving the cleaning mechanism to a position below the optical probe and inserting the optical probe into the cleaning tank of the cleaning mechanism containing the cleaning solution. The optical probe is then inserted into the test container.

According to another embodiment, a method is provided for operating an optical probe within a test container of a dissolution test instrument. The optical probe is calibrated by moving the calibration mechanism to a position below the optical probe and inserting the optical probe into a calibrated calibration bath containing calibration material or unused media. The optical probe is then inserted into the test container.
According to another embodiment, a method is provided for operating an optical probe within a test container of a dissolution test instrument. The optical probe is inserted into the test container until the optical path gap of the optical probe sinks into the dissolution medium contained in the test container. The optical probe is actuated to make an optical measurement of the dissolution medium present in the optical path gap. After making an optical measurement and before making another optical measurement, the optical probe is removed from the test container by actuating an automated actuator.

  According to another embodiment, the method comprises the steps of (a) removing bubbles present in the optical path gap by vibrating the optical probe prior to optical measurement; (b) The step of cleaning the optical probe by moving the cleaning mechanism to a position below the optical probe while it is outside the dissolution medium and inserting the optical probe into the cleaning tank of the cleaning mechanism, (c) the optical probe is dissolved Calibrating the optical probe by moving the calibration mechanism to a position below the optical probe while being out of the medium and inserting the optical probe into the calibration tank of the calibration mechanism; and (d) 2 of the above steps The method further includes performing a step selected from the group consisting of a combination of two or more.

In various embodiments, the cleaning step, the calibration step, or both the cleaning step and the calibration step can be optical before the start of the dissolution test operation, after the dissolution test operation ends, and / or during the course of the dissolution test operation. It may be performed between each iteration of performing the measurement.
Other devices, instruments, systems, methods, features and advantages of the present invention will become apparent to those skilled in the art upon review of the following drawings and detailed description. All such additional systems, methods, features and advantages are included in this detailed description, are within the scope of the claims of the invention, and are intended to be protected by the accompanying claims.

It is a typical elevational view of an example of a dissolution tester including an optical probe and a mechanism for vibrating the optical probe. FIG. 2 is a schematic elevation view of an example dissolution tester machine that includes an optical probe and a mechanism for cleaning, cleaning, calibrating and / or standardizing the optical probe.

The present invention can be better understood with reference to the above drawings. The components in the figure are not necessarily isometric (the scale ratio is constant), and emphasis is added when explaining the principle of the present invention. In the figures, like reference numerals designate corresponding parts throughout the different views.
The present disclosure addresses the challenges and problems associated with prior art optical fiber (spectral) dissolution tests. In the prior art, the probe is inherent in the test vessel throughout the dissolution test, causing undesirable fluid turbulence in the test vessel. Continuing disturbances in the mixed fluid dynamics caused by the underlying probe can significantly affect the dissolution profile of the drug formulation. For example, it has been reported that when an endogenous rod-like probe is used, a dissolution rate of 3-5% has been observed compared to manual extraction methods. In prior art systems, the spectral probe is left in the test solution for the entire test, which can increase or change the dissolution rate of the API. The reason for including the probe in prior art systems is that as the probe is raised and lowered from the medium, bubbles are trapped in the spectral window, which can interfere with accurate measurement of the sample. In addition, the probe remains internal to prevent the material from drying on the spectral window and interfering with the absorption measurement.

  Prior art systems require the probe to be calibrated offline before starting the experiment, and generally recalibrated between lysis operations or between sample and sample (offline) There is. In addition, to avoid cross-contamination between samples and to clean the probe observation window and optics for the next measurement, between or between lysis operations or extraction After (sampling), it is necessary to clean the probe offline. Regardless of the shape of the probe, it has been found that insoluble particulate matter often accumulates in the probe window, blocking the optical path and preventing proper spectroscopic measurements. Therefore, incorporating an automated dissolution tester, automated probe insertion and removal, automated bubble removal, automated built-in (online) probe cleaning, and automated built-in calibration into a fiber optic probe, It is necessary to solve the drawbacks of the prior art.

  In accordance with an example of the present invention, the system has an automated mechanism for inserting and removing a spectral probe from a test vessel immediately at a particular point in time, thereby providing fluid dynamics within the vessel. Any perturbation due to the probe is reduced. Immediate insertion of the fiber optic probe only disturbs the fluid dynamics of the container for a short time compared to using a conventional cannula (Non-Patent Document 2 and Non-Patent Document 3).

  In accordance with another example of the present invention, to remove gas or air bubbles from the spectral probe optical path gap or viewing region, apply vibrational forces at various amplitudes and frequencies, and rotational motion at various angles and velocities. The system incorporates a mechanism designed to do this. Bubbles may be entrained when the probe is inserted into the container medium or during the time that the probe is present in the container medium. In addition, a self-centering elastomeric or flexible mechanical coupling that allows the probe body to move and rotate during the bubble removal process and return the probe to its set / registered position after the bubble is removed This device may be incorporated. Software that can inspect and determine if and when bubbles are present can be coupled to the bubble remover machine. Prior art systems do not have a means to automatically detect and remove bubbles from the spectral probe optical path, which often results in indeterminate or invalid test results because the bubbles interfere with spectral transmission. I came.

  According to another example of the present invention, the system incorporates automated built-in means to effectively clean the spectral probe between tests or between experiments. This new system incorporates one or more fixed (static) and / or recirculation vessels per probe. One or a series of cleaning and / or cleaning solutions to remove debris, insoluble or hydrophobic materials, etc. that accumulate in the spectral probe optical path gap or observation area while immersed in a dissolution vessel or calibration standard (standard) This tank may contain. In addition, this bath is used to clean the outer surface of the probe to reduce or prevent any residue and cross-contamination. This cleaning process ensures that the collected dissolution profile data represents the tested sample.

  According to another example of the present invention, the system incorporates automated built-in means for calibrating the fiber optic probe to a known reference standard. The system incorporates one or more fixed and / or recirculating vessels per probe. These vessels contain APIs and / or unused (blank) media used to calibrate probes and associated spectral instruments at known concentrations. The probe is automatically inserted into the calibration tank (if necessary, bubbles are removed by the bubble remover machine as described above) and spectra are collected to calibrate the probe. This automated method allows several dissolution tests to be performed in succession, allowing calibration to be performed automatically (online) as it is incorporated between each test run. .

  Therefore, there is a need for an automated spectral dissolution tester that overcomes the above disadvantages associated with the prior art. In addition, 1) Minimize turbulent fluid flow turbulence in the test vessel by automatically inserting a spectral probe only when test measurements are needed, and 2) remove air or gas bubbles from the spectral probe optical path gap or An automated dissolution tester that effectively removes from the observation area, 3) automatically cleans the spectral probe between tests, and 4) automatically provides probe standardization and normalization is needed.

  In accordance with the present invention, several novel devices and methods are provided for implementation in a dissolution tester. Various embodiments of the present invention include: 1) an automated mechanism for lowering and raising the spectral probe into and from the test vessel and fluid; 2) air or gas bubbles to the spectral probe optical path gap or viewing region Automated means for removal from, 3) automated mechanisms including a plurality of fixed or recirculating tanks (rack) for cleaning of spectral probes, and / or 4) spectral probes and related It may include an automated mechanism that includes a platform that holds a plurality of fixed or recirculating vessels for standardization and standardization of analytical instruments.

  FIG. 1 illustrates an example of a dissolution test apparatus 100 according to one or more embodiments taught herein. The dissolution test apparatus 100 generally includes a spectral probe (eg, fiber optic probe or optical probe) 104 that may be configured as described above. The probe 104 may be lowered and raised from the dissolution vessel 108 containing the dissolution medium 112. A stirrer or other USP type device 116 may operate in the dissolution medium 112 in a manner understood by those skilled in the art. As the test is being performed, the automated actuator 120 moves the probe 104 vertically from a position above and outside the dissolution medium 112 to a test position within the dissolution medium 112 (as indicated by arrow 124). An actuator 120 is coupled to the probe 104 so that it can be moved. FIG. 1 shows in detail the probe 104 in the test position. Probe 104 includes an optical path gap or observation window 124 as described above, which is typically located near the end of probe 104. The optical path gap 124 is immersed in the dissolution medium 112 at the test location of the probe 104 to allow optical measurements to be made. The actuator 120 may be actuated to remove the probe 104 from the dissolution medium 112 after the measurement point is acquired, as described above, so that the probe 104 is in the dissolution medium 112 only during the test. . In order to remove any fluid turbulence in the container 108, the probe 104 may thus be removed from the fluid 112 when not in use for testing. In the test position, the probe 104 is positioned along a nominal longitudinal (ie, vertical) axis 128. The height of the probe 104 and other position coordinates of the probe 104 with respect to the test container 108 may be indicated by a standard (guideline) such as the USP described above. In order to promote compliance with such position conditions, the actuator 120 may be operated to adjust the position (especially the height) of the probe 104.

  As further shown in FIG. 1, the dissolution test apparatus 100 may further include a foam remover machine 132 attached to the actuator 120 or any other suitable structure of the dissolution test apparatus 100. Foam remover machine 132 may include, for example, a vibration source or vibration generator 136 in communication with probe 104 via a suitable coupling member 140. As an example, the vibration mechanism 136 of the foam remover machine 132 may be a solenoid type device. As an example, the vibration source 136 may be fixed at a predetermined position, while the coupling member 140 is movable with respect to the vibration source 136. The coupling member 140 transmits vibration energy to the probe 104 by contact with the probe 104. Oscillation of coupling member 140 is indicated by arrow 144 in FIG. 1 and the resulting oscillation or vibration of probe 104 is indicated by arrow 148. Contact with the probe 104 may be made by any suitable means. As an example, the coupling member 140 may be in intermittent contact with the probe 104, such as by “striking” the probe 104, thereby displacing the probe 104 in response to an impact from the coupling member 140. As another example, the coupling member 140 may be coupled to the probe 104 generally continuously so that the probe 104 moves in direct response to movement from the coupling member 140. In one embodiment, the vibration of the probe 104 is characterized by the movement of the probe 104 back and forth depending on the angle of the probe 104 with respect to the pivot point 152. The pivot point 152 may be realized by connecting the probe 104 to any suitable structure (eg, actuator 120) of the dissolution test apparatus 100. In one embodiment, the probe 104 is held in a flexible or elastomeric coupling member 156 that performs self-centering, as shown in FIG. The connecting member 156 allows the probe 104 to move in the lateral direction in response to stimulation by the vibration mechanism 136 of the bubble removing device 132. When the bubble removal device 132 is deactivated (ie, after the bubble removal procedure is complete), the coupling member 156 returns the probe 104 to its set / registered position collinear with its nominal axis 128.

  In addition to the periodic movement along one dimension, such as the lateral movement shown by the arrows in FIG. 1, the vibration mechanism 136 of the bubble remover machine 132 moves back and forth (inside May be configured to activate the probe 104 to movement along another dimension, such as exiting, i.e., orthogonal to arrow 144). In addition or alternatively, the vibration mechanism 136 is configured to drive the probe 104 to rotate or pivot at an angle relative to the nominal axis 128 and relative to the pivot point 152 of the probe 104. Also good. The elastomeric coupling member 156 is configured to allow these other types of movement of the probe 104 and return the probe 104 to its set / registered position when vibration stimulation is stopped, as described above. Also good. The displacement of the probe 104 along one or more dimensions or axes and / or rotation or pivoting of the probe 104 at an angle with respect to the nominal axis 128 of the probe 104 may be achieved by any suitable means. . In one example, the coupling member 140 may be disposed at an angle relative to the probe 104, that is, at an angle other than the horizontal direction of the coupling member 140 as shown in detail in FIG. In another example, the coupling member 140 can rotate and / or rotate via a connection with the vibration generating component 136 of the foam removal device 132, and this movement can be probed via the coupling of the coupling member 140. 104 (ie, yoke, ring, etc.). In another example, the foam removal device 132 may include one or more vibration generating components 136 and associated coupling members 140. For example, one vibration generating component 136 and associated coupling member 140 may be positioned / oriented as shown in FIG. 1, while another vibration generating component 136 and associated coupling member 140 are arranged in the illustrated lateral direction. May be arranged / orientated orthogonally to add back-and-forth motion.

  In some embodiments, the vibration mechanism 132 is configured to apply vibration forces of various amplitudes and / or frequencies, which are programmable and fully adjustable to allow for different probe shapes and fluids. May be enabled. In embodiments that provide rotational motion, the vibration mechanism 132 may further change the angle at which the probe 104 pivots or rotates relative to the nominal axis 128 and / or the probe 104 rotates or pivots about the nominal axis 128. It may be configured to change the speed at which it is performed.

  FIG. 2 illustrates another example of a dissolution test apparatus 200 according to one or more embodiments taught herein. Dissolution test instrument 200 may include features and components similar to those shown in FIG. 1, and thus like reference numerals indicate like features. The dissolution test instrument 200 includes a mechanism 260 for cleaning or washing the probe 204. For example, the illustrated mechanism 260 includes a platform (rack) 264 that holds one or more reservoirs 268 and 272 that contain cleaning or cleaning fluids. As described above, the vessels 268 and 272 may be fixed or recirculated (components that provide circulation are not shown). As indicated by arrow 276, mechanism 260 can be moved to a position above test container 208 and below probe 204 by a suitable actuator (not shown). The actuator 220 coupled to the probe 204 may then be actuated to lower the probe 204 into the selected reservoir 268 or 272 of the mechanism 260. With this configuration, the probe 204 can be cleaned between tests, or between sample readings and sample readings (ie, between optical and optical measurements), if desired. Also good. Thus, the probe 204 may be lowered into the dissolution medium 212 by the actuator 220 and pulled up from the dissolution medium 212 after performing the measurement. The probe 204 may be pulled up sufficiently to provide a clearance for the cleaning mechanism 260. As a result, the cleaning mechanism 260 is moved to a position below the probe 204 and the probe 204 is lowered into one of the tanks 268 and 272 for cleaning / washing. The cleaning mechanism 260 is then moved out of the vertical travel path of the probe 204, and the probe 204 may be lowered back into the dissolution medium 212 to obtain the next test point. This process may be repeated one or more times according to the desired test procedure. A cleaning step may also be performed before the start of the melting operation (after a series of data points are acquired to generate a dissolution rate curve) and after the completion of the melting operation.

  FIG. 2 also shows an embodiment in which mechanism 260 is a calibration or standardization mechanism. In this case, the stationary or recirculating tanks 268 and 272 of the platform 264 contain calibrators or unused media. In one example, one tank 268 may contain calibration media and the other tank 272 contains unused media. As with cleaning / washing, the mechanism 260 and associated components of the dissolution test instrument 200 allow the probe 204 (and spectrum analyzer) to be calibrated / standardized between tests, if desired. It may be manipulated to do. A cleaning step may also be performed before the start of the melting operation (after a series of data points are acquired to generate a dissolution rate curve) and after the completion of the melting operation.

In all these cases, the dissolution test instrument 200 allows all cleaning, cleaning, calibration and similar procedures to be performed while incorporated (online), while conventional instruments and methods do such a procedure. Can be implemented independently (offline).
In one embodiment, the dissolution test instrument 200 includes a mechanism for cleaning the probe 204 and a second mechanism for calibrating the probe 204. In another embodiment, the same mechanism 260 may be used for both cleaning and calibration, in which case different tanks 268 and 272 may contain cleaning fluid and calibration fluid, respectively. Good.

  As further shown in FIG. 2, the dissolution test apparatus 200 may include the foam removal device 232 described above in connection with FIG. Therefore, if desired, the bubble removal device 232 may be activated before each measurement is repeated. The timing, duration, and order of operation of each of the foam removal device 232, the cleaning and / or calibration mechanism 260, the actuator 220, and associated components may be determined or programmed in a manner desired by the user.

  1 and 2, the dissolution test apparatus 100, 200 includes a single assembly (eg, probe, actuator, bubble remover, cleaning / calibration mechanism, etc.) that operates in a single test vessel 108, 208. Those skilled in the art will appreciate that the dissolution test apparatus 100, 200 typically includes a series of test vessels 108, 208. Accordingly, it will be further appreciated that the dissolution test apparatus 100, 200 shown in FIGS. 1 and 2 may include multiple assemblies associated with a similar number of test vessels 108, 208. Furthermore, additional modifications are easily devised. For example, in the case of a multi-container dissolution test instrument, a single cleaning / calibration mechanism 260 or a single pair of cleaning and calibration mechanisms 260 may be moved sequentially from one probe 204 to another.

  Overall, “in communication (connection, communication)” and “in communication (connection, communication) with” (for example, the first component is in communication (connection, communication) with the second component. ) "Or" in communication (coupled, communicated) "), etc., as used herein are structural, functional, mechanical, electrical, between two or more components or elements It is used to suggest dynamic, signal, optical, magnetic, electromagnetic, ionic or fluid relationships. In this way, one component is said to be in communication (coupled or communicated) with the second component because the additional component is between the first component and the second component. And / or is not intended to exclude the possibility of operatively related or associated with the first component and the second component.

  It should be understood that various aspects or details of the invention may be changed without departing from the scope of the claims of the invention. Furthermore, the above description is for illustrative purposes only and is not intended to be limiting, and the present invention is defined by the claims.

Claims (20)

An optical probe configured to perform an optical measurement in a dissolution medium contained in a test container and to transmit the optical measurement to an analytical instrument disposed away from the test container; An optical probe including a main body and an optical path gap formed in the main body;
An automated actuator coupled to the optical probe and movable along at least one dimension, wherein the optical probe is alternately movable in and out of the test container by the automated actuator. Dissolution testing equipment with automated actuators.   The dissolution test of claim 1, further comprising a bubble remover in communication with the optical probe and configured to transmit various oscillating forces to the probe, wherein bubbles are removed from the optical path gap. machine.   3. The dissolution test apparatus according to claim 2, further comprising an elastomeric coupling member attached to the probe and configured to return the probe to a set position after the operation of the bubble remover is stopped.   4. A dissolution test apparatus according to claim 3, wherein the automated actuator is connected to the elastomeric coupling member.   The dissolution test apparatus of claim 2, wherein the bubble remover machine is configured to transmit an oscillating force to the probe at various frequencies, various amplitudes, or both at various frequencies and various amplitudes. .   The dissolution testing apparatus of claim 2, wherein the foam remover machine is further configured to rotate the probe at an angle relative to a nominal axis of the probe.   The bubble remover machine is further configured to change the angle at which the probe is rotated, to change the speed at which the probe is rotated relative to the nominal axis, or to both the angle and the speed. 7. The dissolution test apparatus of claim 6, wherein the dissolution test apparatus is configured to change.   A tank for containing a cleaning solution, and further comprising an automated cleaning mechanism movable to and from a position below the optical probe, the optical probe being driven by the automated actuator; The dissolution test apparatus according to claim 1, wherein the dissolution test apparatus is movable in and out.   9. The dissolution test apparatus according to claim 8, wherein the tank is a circulating tank.   Further comprising an automated calibration mechanism that is movable to and from a position below the optical probe, the optical probe comprising a reservoir for containing a calibration medium, the optical probe being driven by the automated actuator; The dissolution test apparatus according to claim 1, wherein the dissolution test apparatus is movable in and out.   Automated calibration with an automated cleaning mechanism having a cleaning tank for containing a cleaning solution, movable to and from the position below the optical probe, and a calibration tank for containing a calibration medium And wherein the automated cleaning mechanism and the automated calibration mechanism are movable to and from a position below the optical probe, the optical probe comprising the automated actuator The dissolution test apparatus according to claim 1, wherein the dissolution test apparatus is configured to be movable in and out of the cleaning tank and the calibration tank. A method for operating an optical probe in a test container of a dissolution test instrument comprising:
By actuating an automated actuator, the optical probe is inserted into the test container along the nominal axis of the optical probe until the optical path gap of the optical probe sinks into the dissolution medium contained in the test container. And steps to
Oscillating the optical probe with respect to the nominal axis to remove bubbles present in the optical path gap.   13. The method according to claim 12, further comprising the step of automatically returning the optical probe to a set position by using an elastomer connecting member attached to the optical probe after the optical probe is vibrated. The method described.   13. The method of claim 12, wherein removing bubbles comprises oscillating the optical probe at various frequencies, various amplitudes, or both various frequencies and various amplitudes.   13. The method of claim 12, wherein removing bubbles further comprises rotating the optical probe at an angle relative to a nominal axis of the optical probe.   16. The method of claim 15, wherein removing bubbles comprises rotating the optical probe at various angles, various speeds relative to the nominal axis, or both various angles and various speeds.   13. The method further comprises the step of cleaning the optical probe by moving a cleaning mechanism to a position below the optical probe and inserting the optical probe into a cleaning tank of the cleaning mechanism containing a cleaning solution. The method described in 1.   Further comprising calibrating the optical probe by moving a calibration mechanism to a position below the optical probe and inserting the optical probe into a calibration chamber of the calibration mechanism containing a calibration substance. 13. The method according to claim 12. A method for operating an optical probe in a test container of a dissolution test instrument comprising:
Inserting the optical probe into the test container until the optical path gap of the optical probe sinks into a dissolution medium contained in the test container;
Activating the probe to make an optical measurement of the dissolution medium present in the optical path gap;
Removing the optical probe from the test vessel by actuating an automated actuator after making the optical measurement and before making another optical measurement.   (A) removing bubbles present in the optical path gap by vibrating the optical probe before performing the optical measurement; (b) while the optical probe is outside the dissolution medium. (C) cleaning the optical probe by moving the cleaning mechanism to a position below the optical probe and inserting the optical probe into a cleaning tank of the cleaning mechanism; and (c) the optical probe is the dissolution medium Calibrating the optical probe by moving a calibration mechanism to a position below the optical probe and inserting the optical probe into a calibration tank of the calibration mechanism while outside 20. The method of claim 19, further comprising performing a step selected from the group consisting of a combination of two or more of the steps.

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