Dissolution test device for open-loop or closed-loop configuration

Abstract

The invention relates to a dissolution testing device for testing a soluble substance dissolved in a dissolution medium, comprising at least one dissolution medium reservoir (15), at least one flow cell (4) for receiving the soluble substance to be tested, and at least one pump device (60) for pumping the dissolution medium through the at least one flow cell (4). Furthermore, the dissolution test device comprises at least two sampling containers (8.1, 8.2) connectable to a flow cell (4) for sampling a substance solution, an inlet fluid manifold (100) for selectively connecting the flow cell (4) to one of the at least two sampling containers (8.1, 8.2), an outlet fluid manifold (200) for selectively connecting the at least two sampling containers (8.1, 8.2) to the other of the at least two sampling containers (8.1, 8.2), and a flow cell (3) for selectively connecting the flow cell (4) to the other of the at least two sampling containers (8.1, 8.2). 8.1; 8.2) to an outlet fluid manifold (110) of the discharge line (140) for connecting one of the selected sampling containers (8.1; 8.2), and a switching valve system (150) for selectively connecting the discharge line (140) to the cell inlet line (27) or the extraction line (160) of the flow cell (4).

Description

Technical Field

[0001] This invention relates to a dissolution testing apparatus for drug release and dissolution testing, and more particularly to a flow cell instrument or apparatus having an open or closed operating mode module. This invention especially relates to the dissolution and testing of soluble substances. Background Technology

[0002] Dissolution testing is a pharmacopoeia-based in vitro test, used, for example, in drug research and development, to characterize the release rate of the active pharmaceutical ingredient (API) from the formulation, relating to its in vivo performance under reproducible conditions. Once an innovative drug product file receives approval from the target market regulatory agency, dissolution testing is used to assess batch-to-batch consistency of the manufactured product, based on the submitted specifications and general testing conditions described by the regulatory agency. Generic drug companies also use dissolution testing to establish the bioequivalence of their products without having to replicate the initial clinical studies conducted by the innovative drug company: doing so grants them a bioequivalence exemption.

[0003] Pharmaceutical formulations include granules, tablets, capsules, gels, creams, ointments, suspensions, suppositories, patches, microspheres, implants, and other long-acting injectables, such as microsuspensions and nanosuspensions. "Dissolution testing" is the term used for solid dosage forms, and more generally, "drug release testing" is used for other dosage forms, including coated medical devices. Outside of pharmaceuticals, dissolution testing devices are also used in other applications, such as the release of nicotine from smokeless tobacco products and the persistence testing of asbestos fibers in lung fluid. A primary advantage of flow-through cell dissolution testing instruments is their flexibility, as the cell and its internal arrangement can be adapted to the structure and challenges of the formulation being tested.

[0004] The general dissolution chapter is unified among the European, American, and Japanese pharmacopoeias (United States Pharmacopeia). <711> The dissolution test mode and the apparatus involved for solid dosage forms are described in [reference needed]. The Chinese Pharmacopoeia also describes flow-through cell dissolution as Method 6.

[0005] Standardized methods include, for example, using paddle apparatus to stir the substance in a container, as described in EP0746759A1; using basket apparatus to hold the substance in a basket, as described in US5816701A; or using flow-through apparatus to flow the dissolution medium through a pool containing the substance, as described in WO2013 / 003518A1. The dimensions and tolerances of such apparatus are precisely specified. Key test parameters that must be monitored periodically during use include, for example, the volume and temperature of the dissolution medium, the rotational speed, and the flow rate of the medium.

[0006] Flow-through apparatus is used for various test subjects. The principle of flow-through dissolution is to flow the dissolution medium onto a cell containing the dosage form to be tested at a defined temperature and flow rate. The total volume of the dissolution medium is based on the solubility of the active pharmaceutical ingredient (i.e., the corresponding substance) to be dissolved, and the test duration is ideally related to the in vivo performance of the product being tested.

[0007] Dissolution testing apparatuses typically consist of multiple channels to allow for simultaneous testing, for example, seven channels (six samples and one control). Therefore, before using the apparatus, all seven channels must be validated according to a documented process (installation validation, operational validation) to demonstrate that they allow for equivalent testing of all channels, as the final samples will all be compared to specifications since they represent the entire production batch. A flow-through dissolution testing apparatus includes a media reservoir, a multi-channel pump system, a dissolution module (containing the cell), and modules that allow for online partial collection, sampling, or direct analysis of samples.

[0008] The flow cell dissolution device can be used in two different configurations / modes.

[0009] In open mode, the channels simultaneously receive the dissolution medium from a single reservoir. The medium is flowed into flow cells by individual pump channels, filtered, and then the individual eluents (i.e., solutions) are collected or analyzed. Dosage forms are immersed in the medium, which is constantly refreshed in the cells at a rate defined by the pump flow rate setting. In the current system, a portion of the collected sample must be homogenized, and a smaller volume sample must be extracted from this portion for analysis. During the experiment, if different reservoirs are connected to the media selector, the source of the medium can be changed at defined intervals (for all cells). Because the media used can have different pH values, this media variation can be used to simulate pH changes occurring in the gastrointestinal tract. Therefore, the dosage forms in the cells can undergo pH changes comparable to those experienced in vivo.

[0010] In closed-loop mode, the media volume is stored in individual reservoirs in each channel. Each media reservoir is connected to a separate pump channel, which in turn connects to a separate flow tank and ultimately back to the media reservoir. This loop allows the media to flow onto the tank, be filtered, and return to the reservoir in an agitated manner. The dissolved active ingredient, released and dissolved from the formulation, passes through the filter and accumulates in the agitated reservoir, where it can be sampled. In the current system, testing is conducted only at a single pH.

[0011] For example, WO2021 / 076558A1 describes a dissolution testing apparatus with a closed-loop configuration. This apparatus includes a fluid reservoir for storing a medium comprising a solvent used to extract a substance from a pharmaceutical dosage form, and a substance solution for receiving the medium and the dissolved substance. The dosage form is placed in a flow cell connected to the fluid reservoir, and a pump delivers fluid from the reservoir to the flow cell. A multi-port manifold is used to circulate the fluid between the reservoir and the flow cell. A magnetic stirring mechanism is used to stir the substance solution in the fluid reservoir.

[0012] However, most devices are designed as either open or closed systems, and they are not configured to easily switch between open and closed modes. Current devices require unplugging and replugging tubing and sampling modules to switch from an open to a closed configuration.

[0013] The purpose of this invention is to provide a dissolution testing device and a dissolution testing method that allows for quick and easy switching between open-loop and closed-loop configurations, enhances the flexibility of device adjustment, improves the reliability and repeatability of test conditions and methods, and enables rapid and accurate testing of substance solution samples. Summary of the Invention

[0014] These and other objectives, which will appear in the following description, are achieved by the dissolution testing apparatus and dissolution testing method set forth in the appended independent claims. Preferred embodiments are defined in the dependent claims.

[0015] According to the present invention, a dissolution testing apparatus for testing soluble substances dissolved in a dissolution medium includes at least one dissolution medium reservoir, at least one flow cell connected to the dissolution medium reservoir for receiving the soluble substance to be tested, and at least one pump device for pumping the dissolution medium through the at least one flow cell. The at least one flow cell includes a cell inlet for the dissolution medium and a cell outlet for a solution containing the dissolution medium and the soluble substance. Furthermore, the at least one flow cell is designed to contain the soluble substance in a specific form, such as capsules or tablets. The flow cell may include a retaining structure to position the soluble substance within the cell.

[0016] According to the present invention, the dissolution testing apparatus includes two sampling containers for each flow cell, the two sampling containers being connectable to and disconnectable from the flow cell. The sampling containers sample a solution containing a dissolution medium and a dissolving substance. Furthermore, the dissolution testing apparatus includes an inlet fluid manifold for selectively connecting the flow cell to one of the at least two sampling containers, an outlet fluid manifold for selectively connecting one of the at least two sampling containers to an outlet line, at least one testing device for testing the solution in the selected sampling container, and a switching valve system for selectively connecting the outlet line to a pool inlet line or an extraction line of the flow cell. The dissolution testing apparatus may have multiple flow cells, for example, arranged in parallel with each other. Optionally, the dissolution testing apparatus may have more than two sampling containers per flow cell.

[0017] According to the present invention, the sampling container for sampling the substance solution ejected from the flow cell can be used to collect the substance solution and temporarily store it. The at least two sampling containers are integral components of the fluid flowing through the device, increasing the operational flexibility of the dissolution testing apparatus. Upon exiting the sampling container, the substance solution can be recycled back to the flow cell, extracted to a sample solution container for external treatment, or even disposed of as waste.

[0018] The inlet fluid manifold is designed to connect only one of the at least two sampling containers to the flow cell, and to switch between the sampling containers. Therefore, at any given time, only one sampling container is selected to be connected to the flow cell. Similarly, the outlet fluid manifold is designed to connect only one of the at least two sampling containers to the discharge line, and to switch between the sampling containers. Therefore, at any given time, only one sampling container is selected to be connected to the flow cell and filled with a substance solution, while one or the other of the at least two sampling containers can be connected to the discharge line.

[0019] In the context of this invention's description, the term "connected to" should be understood as meaning that two components, such as the pool, the sampling container, the discharge line, the inlet line, etc., are in fluid communication, such as the dissolution medium, the substance solution, the cleaning medium, etc., can flow from one component to the other and through the components. Accordingly, the terms "connectable" and "disconnectable" should be understood as meaning that the fluid communication can be established or interrupted, for example, by a valve, a fluid separator, a liquid distributor, etc.

[0020] According to the dissolution testing method of the present invention for testing soluble substances dissolved in a dissolution medium, the inlet fluid manifold, the outlet fluid manifold, and / or the switching valve system establish a selective fluid connection such that the dissolution testing apparatus operates in open-loop mode by connecting the discharge line to the extraction line, or alternatively, the apparatus operates in closed-loop mode by connecting the discharge line to the pool inlet line. The switching valve system coordinates with the inlet and outlet fluid manifolds to guide the substance solution leaving the selected sampling container back to the flow pool for closed-loop testing via fluid circulation, or to guide the fluid flow extracting the substance solution for open-loop testing.

[0021] The dissolution testing apparatus according to the invention expands the range of options for flexibly adapting the apparatus to in vivo conditions by customizing the flow of the dissolution medium through the soluble substance and ensuring consistent flow conditions when needed. The dissolution testing apparatus provides consistent dissolution quality for dissolving various forms of substances, particularly pharmaceutical substances. The dissolution testing apparatus enables multifunctional and automated dissolution testing and supports accurate and predictive test results. The dissolution testing apparatus according to the invention is modularized based on two sampling containers per flow cell, allowing for easy switching from open to closed configurations, direct conversion from partial collection to sampling processes, and pH variations also available in closed systems.

[0022] In one embodiment of the dissolution testing apparatus, at least the inlet manifold, the outlet manifold, and the switching valve system are connected to a controller to control the selective fluid connections between the flow cell, the sampling container, the discharge line, the cell inlet line, and the extraction line. For example, the controller is implemented by an electronic control system designed to electronically command the operation of the inlet manifold, the outlet manifold, and the switching valve system, which are further configured with electronic steering components that communicate with the electronic control system. Furthermore, the controller may include a processing unit for processing test protocols defining the test procedure, an input device for inputting test information data, a display device for displaying test information, test results, etc., and a storage unit for storing test protocols, information data, test results, etc.

[0023] In one embodiment of the dissolution testing apparatus according to the invention, at least one testing device is arranged at the discharge line and / or the at least one sampling container to test the substance solution in the discharge line and / or the sampling container. Therefore, the substance solution can be tested quickly even after it has dissolved in the dissolution medium, while still being processed in the dissolution testing apparatus. For example, the testing device can be an optical testing device, such as a UV spectrophotometer. Alternatively, as is well known, the substance solution can be extracted from the fluid flow and stored in a sample solution container for further sample analysis.

[0024] In an exemplary embodiment of the dissolution testing apparatus according to the invention, the inlet fluid manifold includes an inlet end in fluid communication with the substance solution conduit of the flow cell and an outlet end of each of the sampling containers, wherein the outlet end is in fluid communication with the sampling container inlet line. The outlet fluid manifold includes an inlet end of each of the sampling containers and an outlet end in fluid communication with the discharge line, the inlet end being in fluid communication with the sampling container outlet line of the corresponding sampling container. The substance solution enters the inlet fluid manifold through the inlet end and is directed to the outlet end associated with the selected sampling container to connect the flow cell to the selected sampling container. Once the first selected sampling container is filled, for example, according to test requirements, the inlet fluid manifold switches to another outlet end to select another sampling container, namely a second sampling container. The outlet fluid manifold opens the manifold inlet end of one of the sampling containers to receive, for example, the substance solution from the first sampling container, while the second sampling container is filled and directed to the outlet end or another outlet end of the discharge line. Once the substance solution in the first sampling container has been processed, the outlet fluid manifold can process the second sampling container.

[0025] The switching valve system is, for example, a valve unit, wherein the discharge line, the extraction line, and the pool inlet line are connected to the valve unit. Furthermore, the switching valve system may include multiple switching valves and at least one recirculation line or bypass line to redirect the substance solution from the discharge line back to the pool inlet line. The inlet fluid manifold, the outlet fluid manifold, and the switching valve system can be used to control the flow rate into and out of the sampling container, for example, according to standard test protocols.

[0026] In another embodiment of the dissolution testing apparatus according to the invention, a stirring loop is provided at the sampling container outlet line. This stirring loop includes a pump to pump the substance solution through the stirring loop and back into the sampling container. For example, the stirring loop may be a fluid line including the pump and merging back into the sampling container. The stirring loop allows for flexible and uniform mixing of the substance solution in the sampling container. Advantageously, the stirring loop may be connected to the outlet fluid manifold. The outlet fluid manifold may include a stirring end to connect the at least one sampling container to the stirring loop.

[0027] In another embodiment of the dissolution testing apparatus, the outlet fluid manifold may include a waste liquid end to connect the at least two sampling containers to a waste liquid line. For example, when the apparatus is operated in open-loop mode, the waste liquid line is useful for discarding excess solution. Furthermore, a cleaning system may be provided to clean the at least two sampling containers. The cleaning system may include a cleaning medium reservoir outside the at least two sampling containers and a container inlet, such as a nozzle, at each of the sampling containers. The cleaning medium may be, for example, water or any other suitable cleaning fluid. The cleaning system is connected to the inlet fluid manifold to connect the cleaning system to the at least two sampling containers or their nozzles. The cleaning medium may be circulated by the stirring loop and discarded from the sampling containers via the waste liquid line.

[0028] Advantageously, the dissolution medium reservoir can be connected to and disconnected from the flow cell by the switching valve system. The switching valve system can connect the dissolution medium reservoir to the inflow conduit leading to the cell inlet. Therefore, the dissolution medium can be supplied to the flow cell as needed for dissolution. In one example, the dissolution medium reservoir includes a medium selector and a medium manifold, the medium selector providing multiple different solvents, and the medium manifold being connectable to the flow cell by the switching valve system, or even as an integral part of the switching valve system. Therefore, different solvents or additives can be added to the dissolution medium before it enters the flow cell, and the conditions of the dissolution medium can be flexibly adjusted to suit specific experimental conditions. In particular, the pH value of the dissolution medium in the cell can be adjusted as needed.

[0029] In another example embodiment, the dissolution testing apparatus may include a heating module to heat the dissolution medium at the inflow conduit leading to the flow cell. Therefore, the dissolution medium can be heated according to the requirements of the testing protocol or as required by in vitro conditions. Furthermore, the at least one flow cell and / or the at least two sampling containers may be arranged in a heating channel to heat the substance solution in the cell or container, respectively. Therefore, the dissolution medium and / or the substance solution can be heated according to the requirements of the testing protocol or as required by in vitro conditions.

[0030] As mentioned above, the dissolution testing apparatus can advantageously operate in open-loop or closed-loop mode by switching the connection of the at least two sampling containers between the extraction line and the pool inlet line. In a variant of the dissolution testing method according to the invention, the at least two sampling containers are alternately connected to the flow cell and the discharge line, such that a continuous flow of substance solution exits the flow cell. The continuous flow of substance solution flows through the substance solution conduit connecting the flow cell and the inlet fluid manifold. The fluid manifold connected to the sampling containers controls the inflow and outflow of the substance solution, such that the first sampling container is filled while a portion of the substance solution in the second sampling container is processed for analysis and emptied to receive subsequent portions of the substance solution. The second container buffers the substance solution while the continuous flow of substance solution is directed to the first sampling container. Conversely, the portion in the first sampling container is processed for analysis while the second container is filled. Thus, the at least two sampling containers alternately receive the substance solution from the flow cell and alternately discharge it. This process is particularly useful for open-loop mode and allows for rapid substance solution processing. If necessary, more than two sampling containers may be used to process and prepare the substance solution for analysis or extraction by the device.

[0031] In an advantageous variant of the dissolution testing method, a portion of the substance solution is tested within the sampling container. For example, a photodetector can analyze the substance solution within the sampling container while the solution remains in the container or is stirred in the stirring loop. This process accelerates the testing of the substance solution. Alternatively, the portion of the substance solution can be tested by a testing device arranged in the discharge line while the substance solution flows through the discharge line. Alternatively, the portion can be extracted from the discharge line and then tested.

[0032] In an example variant of the dissolution testing method operating in closed-loop mode, the flow cell is connected to one of the at least two sampling containers, and the discharge line is connected to the cell inlet line, with multiple samples being continuously sampled and tested by the testing equipment. In closed-loop mode, the sampling container can serve as a dissolution medium reservoir, wherein the dissolution volume can be larger than the cell volume. Advantageously, the substance solution is tested before entering the cell inlet line. For example, the testing equipment is arranged in the discharge line or the recirculation line of the switching valve system. Thus, for the closed-loop mode, only one of the sampling containers is used. The invention allows switching between the two containers to allow for changes in the medium (and therefore pH) within the closed system.

[0033] The dissolution testing apparatus and method according to the present invention realize a multifunctional and automated flow cell dissolution test, and support accurate and repeatable test results. Operability between different configurations is enhanced and ensured, and the transfer from part to sample is automated and therefore traceable. Attached Figure Description

[0034] Preferred embodiments of the invention will be described in the accompanying drawings, which illustrate the principles of the invention but should not limit its scope. The drawings show:

[0035] Figure 1 An overview of the operating modules of the dissolution testing apparatus according to the present invention,

[0036] Figure 2 A schematic diagram of the substance solution flow in the sampling module of the dissolution test apparatus.

[0037] Figure 3 A schematic diagram of the open-loop / closed-loop configuration of the dissolution testing apparatus according to the present invention.

[0038] Figure 4 A schematic diagram of the closed-loop configuration of the dissolution testing apparatus according to the present invention, and

[0039] Figure 5a and Figure 5b Assembly diagram and exploded view of the flow cell used in the dissolution testing apparatus of the present invention. Detailed Implementation

[0040] Figure 1The setup of the dissolution testing apparatus used in this invention is shown. The dissolution testing apparatus includes a dissolution module 1, a sampling module 2, and an extraction module 3. As will be explained below, the dissolution testing apparatus can be configured to operate in a closed mode or an open mode. The dissolution module 1 houses multiple dissolution cells designed as flow-through cells 4, which are arranged in the cell chamber 11 of the dissolution module 1. Each cell is filled with a soluble substance 5 (see [reference]). Figure 5a and Figure 5b ).like Figure 3 As shown, a dissolution medium is supplied to the flow cell 4 by a dissolution medium reservoir 15 arranged in or next to the dissolution module 1. After passing through the flow cell 4, the dissolution medium, including the dissolved substances, leaves the flow cell 4 as a substance solution containing the dissolution medium and the dissolved substances. The substance solution is transferred to the sampling module 2 via a substance solution conduit 7. In the sampling module 2, a defined portion of the substance solution is dispensed from the substance solution conduit 7 into a sampling container 8. As will be explained below, depending on the operating mode, the portion of the substance solution in the sampling container can be tested and returned to its corresponding cell, or the substance solution can be discharged to the extraction module 3 for testing or further processing.

[0041] Figure 2 This is a schematic diagram of the sampling module 2 of the dissolution testing apparatus. The sampling module 2 includes two sampling containers 8.1 and 8.2, which can be connected to one of a plurality of flow cells 4; an inlet fluid manifold 100 for selectively connecting the flow cell 4 to one of the two sampling containers 8.1 and 8.2; and an outlet fluid manifold 110 for selectively discharging the selected sampling container 8.1 or 8.2 to an outlet line 140. The sampling module 2 may include testing equipment for testing the substance solution in the selected sampling container. Alternatively, at least one testing device 70 may be arranged externally to the sampling module 2 within the dissolution testing apparatus (see [link to diagram]). Figure 3 and Figure 4 In addition, the dissolution testing apparatus includes a switching valve system 150 for selectively connecting the discharge line 140 to the inlet line 27 or the extraction line 160 of the flow cell 4.

[0042] The inlet fluid manifold 100 includes an inlet end 101 in fluid communication with the substance solution conduit 7 of the flow cell 4, and outlet ends 102.1 and 102.2 of each of the sampling containers 8.1 and 8.2, which are in fluid communication with sampling container inlet lines 103.1 and 103.2 leading to the respective sampling containers 8.1 and 8.2. Furthermore, the inlet fluid manifold 100 includes a cleaning end 104 connected to a cleaning media reservoir 170 located outside at least two of the sampling containers 8.1 and 8.2. The outlet ends can be used to supply cleaning media to nozzles 171 located inside each of the sampling containers 8.1 and 8.2. The cleaning media reservoir 170 and nozzles 171 provide a cleaning system connected to the inlet fluid manifold to connect the cleaning system to at least two sampling containers 8.1 and 8.2. The cleaning system can be connected to both sampling containers simultaneously, or selectively clean the sampling containers sequentially. Finally, the inlet fluid manifold 110 includes a waste liquid end 105 to discard the substance solution before it reaches the sampling container.

[0043] The outlet fluid manifold 110 includes inlet ends 111.1 and 111.2 for each of sampling containers 8.1 and 8.2, which are in fluid communication with sampling container outlet lines 112.1 and 112.2. The outlet fluid manifold 110 includes an outlet end 113 in fluid communication with discharge line 140. Furthermore, the outlet fluid manifold 110 includes a waste end 114 for connecting sampling containers 8.1 and 8.2 to waste line 141 to discard the substance solution from the sampling containers. Additionally, the outlet fluid manifold 110 includes stirring ends 115.1 and 115.2 for each sampling container for connecting sampling containers 8.1 and 8.2 to a stirring loop. The stirring loop includes sampling container outlet lines 112.1 / 112.2 and loop lines 116.1 / 116.2. Loop lines 116.1 / 116.2 include pumps 117.1 / 117.2 for pumping the substance solution back into the sampling containers 8.1 / 8.2 via the stirring loop. The stirring loop provides a continuous stirred flow of the substance solution in the sampling containers and allows for thorough mixing of the contents of the substance solution within the sampling containers. Using this arrangement, a portion of the substance solution collected in the sampling containers can be advantageously stirred in the stirring loop before testing by at least one test device 70.

[0044] When the switching valve system connects the discharge line 140 to the extraction line 160, the dissolution testing apparatus is in an open-loop configuration. In open-loop mode, for example, the first sampling container 8.1 of the two sampling containers is connected to the flow cell 4 via the inlet end 101 and the outlet end 102.1 of the inlet fluid manifold 100 and is filled with a first portion of the substance solution. Then, by closing the outlet end 102.1, sampling container 8.1 is disconnected from the flow cell 4, allowing the first portion to be tested, for example, by the testing equipment. Simultaneously, the inlet fluid manifold 100 connects the second sampling container 8.2 of the two sampling containers to the flow cell 4 via the outlet end 102.2, and sampling container 8.2 is filled with a second portion of the substance solution. The two sampling containers 8.1 and 8.2 are alternately connected to the flow cell 4 and the discharge line 140, such that while one sampling container is filled with the substance solution, the substance solution in the other sampling container is tested and / or discharged, and vice versa. For example, the first sampling container 8.1 is discharged from the outlet fluid manifold 110 using the inlet end 111.1 and the outlet end 113 to discharge a portion of the sampling container 8.1 into the discharge line 140. Thus, after the test, the first portion in the sampling container 8.1 can be discharged to the extraction line 160 by the switching valve system 150, while another sampling container 8.2 is filled with a second portion of the substance solution for testing.

[0045] Advantageously, the flow rate of the solution and the timing of the alternating connection between the two sampling containers 8.1 and 8.2 and the flow cell 4 and the discharge line 140 are controlled so that a continuous flow of the substance solution leaves the flow cell 4. Furthermore, if necessary, the flow rate of the substance solution can be modulated.

[0046] The dissolution testing apparatus includes a controller that controls the operating conditions of the apparatus. The controller includes, for example, a processing unit, a user interface, and a control display. Specifically, the controller is configured to control the inlet fluid manifold 100, the outlet fluid manifold 110, and the switching valve system 150 to redirect the selective fluid connection of the flow cell 4 to the two sampling containers 8.1 and 8.2. The controller receives, for example, measurement data from pumping equipment that pumps the dissolution medium and substance solution within the dissolution testing apparatus, measurement data from pressure sensors or meters arranged in the dissolution medium and substance solution lines, measurement data from sample solution testing equipment (such as a UV spectrophotometer), or measurement data from any other sensors used in the dissolution testing apparatus. For example, the controller receives a test protocol for testing a specific soluble substance and controls the operation of the dissolution testing apparatus according to the requirements of the test protocol.

[0047] Figure 3 and Figure 4The arrangement of the dissolution module 1 and sampling module 2 of the dissolution testing apparatus is schematically shown. A flow-through cell 4, having a cell inlet 12 and a cell outlet 13, contains the soluble substance 5. The cell inlet 12 is connected to a cell inlet line 27, which is connected by a first valve unit 151 to a dissolution medium reservoir 15 to receive the dissolution medium. The dissolution medium reservoir 15 includes a medium selector 80 and a medium manifold 81. The medium selector 80 provides multiple different solvents, and the medium manifold 81 is connectable to the flow-through cell 4 by the valve unit 151. The cell inlet line 27 includes a pump device 60 and a dissolution medium heating module 6. The heating module 6 is arranged as part of the inlet line and advantageously heats the dissolution medium before it enters the flow-through cell 4. The cell outlet 13 is connected to a substance solution conduit 7, which transfers a substance solution containing the dissolution medium and the soluble substance from the flow-through cell 4 to the sampling module 2.

[0048] As relative to Figure 2 As described, in sampling module 2, the substance solution is alternately supplied to two sampling containers 8.1 and 8.2. According to... Figure 3 and Figure 4 In the illustration, the ports of the inlet fluid manifold 100 and the outlet fluid manifold 110 are depicted as switching valves to illustrate the optional connection of the fluid lines. The substance solution delivered by the substance solution conduit 7 is transferred to one of sampling containers 8.1 and 8.2, which is selected by the inlet fluid manifold 110. Alternatively, the substance solution can be transferred directly to the waste line 141 from port 105 of the inlet fluid manifold 100. In this example, a portion of the substance solution exiting the discharge line 140 from sampling containers 8.1 and 8.2 leaves the sampling module 2 and is tested by the test equipment 70. After that, the substance solution enters the second valve unit 152. Both the first valve unit 151 and the second valve unit 152 are components of the switching valve system 150.

[0049] In open-loop mode, the second valve unit 152 connects the discharge line 140 to the extraction line 160, which transfers the substance solution to the sample manager 180 for collecting the substance solution discharged from sampling containers 8.1 and 8.2 in sample solution container 181. As previously discussed, the at least two sampling containers of the dissolution testing apparatus, such as sampling containers 8.1 and 8.2, provide flexible testing conditions and increase the throughput through the apparatus.

[0050] exist Figure 4In this diagram, the dissolution testing apparatus operates in closed-loop mode. For simplicity, components not necessarily involved in closed-loop dissolution operation are omitted. Specifically, the second sampling container is not shown because it is not required in closed-loop mode. However, physical removal of the second sampling container from sampling module 2 is not necessary, as it can also be used for pH changes. In closed-loop mode, the sampling container advantageously serves as a dissolution medium reservoir. The dissolution volume can be larger than the pool volume. The sampling container can be filled, for example, with 0.25, 0.5, or 1 liter, and in this example, it is used as a bottle-type reservoir. As previously mentioned, no additional dissolution medium reservoir is required. In the second valve unit 152 of the switching valve system, the substance solution is redirected to the recirculation line 153 for transferring the substance solution back to the first valve unit 151, which redirects the substance solution back to the flow cell 4. In closed-loop mode, the same sampling container 8.1 can be used to sample all the substance solution samples required for the test. The discharge line 140 is connected to the pool inlet line 27 via the recirculation line 153 and the switching valve system 150. Multiple samples can be continuously sampled in a single sampling container and tested using testing equipment.

[0051] The same dissolution testing apparatus can be used for both open-loop and closed-loop operation. Switching between modes requires no modification to the system's physical settings. Switching between different operating modes can be easily controlled by the apparatus's controller via a directional switching valve system. Therefore, the dissolution testing apparatus according to the invention saves time and resources and facilitates various testing procedures.

[0052] Figure 5a and Figure 5b The flow-through cell 4, which can be used in this invention, is illustrated in exploded and assembled views. The flow-through cell 4 comprises a cell volume 10 having a generally cylindrical shape and predefined dimensions (depending on the cell) as described in the pharmacopoeia. The dissolution cell volume 10 tapers towards its bottom, which includes a cell inlet 12, and is open at its top. A soluble substance 5 is placed in the cell. If required by the test method used or the shape of the soluble substance, a retaining structure, bead bed, or similar device can be used inside the cell volume to position the soluble substance at a distance from the bottom. A closing ring 50 with a central through-hole and a filter 51 is placed over the upper opening of the cell volume 10. The filter 51 can be selected according to the test requirements of the soluble substance being tested. A cap 52 including a cell outlet 13 is mounted on the closing ring 50 to close the cell volume 10 and hold the filter 51 in place.

[0053] The dissolution testing apparatus according to the present invention can be further modified by implementing a heating module 6 for heating the dissolution medium at the medium inlet line 27 leading to the flow cell 4, as described in the applicant's parallel patent application entitled "Heating Module for Heating the Dissolution Medium in a Dissolution Testing Apparatus". Furthermore, the dissolution testing apparatus according to the present invention can be further modified by implementing a heating channel in the flow cell for heating the dissolution medium, as described in the applicant's parallel patent application entitled "Dissolution Testing Apparatus with a Common Heating Channel". The heating module and heating channel allow uninterrupted fluid flow in the dissolution testing apparatus while the dissolution medium is heated to the desired temperature. Therefore, the testing process can be simplified and adjusted to suit in vivo conditions. Both patent applications should be fully incorporated into the description of the present invention.

[0054] List of reference numerals

[0055]

Claims

1. A dissolution testing apparatus for testing soluble substances dissolved in a dissolution medium, comprising: At least one dissolution medium storage container (15). At least one flow cell (4) for receiving the soluble substance to be tested, the at least one flow cell (4) being connected to the dissolution medium reservoir (15). Sampling containers (8.1, 8.2) for sampling solutions containing dissolution media and dissolution substances, and At least one pump device (60) for pumping the dissolution medium through the at least one flow cell (4). The feature is that the dissolution testing device further includes: At least two sampling containers (8.1, 8.2) can be connected to a flow cell (4). An inlet fluid manifold (100) for selectively connecting the flow cell (4) to one of the at least two sampling containers (8.1, 8.2). An outlet fluid manifold (110) for selectively connecting one of the at least two sampling containers (8.1, 8.2) to an outlet line (140). as well as A switching valve system (150) for selectively connecting the discharge line (140) to the pool inlet line (27) or the extraction line (160) of the flow pool (4).

2. The dissolution testing apparatus according to claim 1, characterized in that, The inlet fluid manifold (100), the outlet fluid manifold (110), and the switching valve system (150) are connected to the controller to control the selective fluid connection.

3. The dissolution testing apparatus according to claim 1 or 2, characterized in that, The test equipment (70) is arranged at the emission line and / or at least one sampling container (8.1, 8.2) to test the substance solution in the emission line (140) and / or the sampling container (8.1, 8.2).

4. The dissolution testing apparatus according to any one of the preceding claims, characterized in that, The inlet fluid manifold (100) includes an inlet end (101) in fluid communication with the substance solution conduit (7) of the flow cell (4) and an outlet end (102.1, 102.2) of each of the sampling containers (8.1, 8.2), the outlet end (102.1, 102.2) being in fluid communication with the sampling container inlet line (112.1, 112.2).

5. The dissolution testing apparatus according to any one of the preceding claims, characterized in that, The outlet fluid manifold (110) includes an inlet end (111.1, 111.2) of each of the sampling containers (8.1, 8.2) and an outlet end (113) in fluid communication with the discharge line (140), the inlet end (111.1, 111.2) being in fluid communication with the sampling container outlet line (112.1, 112.2) of the corresponding sampling container (8.1, 8.2).

6. The dissolution testing apparatus according to any one of the preceding claims, characterized in that, A stirring loop is provided at the sampling container outlet line (112.1, 112.2), the stirring loop including a pump (117.1, 117.2) to pump the substance solution through the stirring loop and back into the sampling container (8.1, 8.2).

7. The dissolution testing apparatus according to any one of the preceding claims, characterized in that, The outlet fluid manifold (110) includes stirring ends (115.1, 115.2) to connect the at least one sampling container (8.1, 8.2) to the stirring loop.

8. The dissolution testing apparatus according to any one of the preceding claims, characterized in that, The outlet fluid manifold (110) includes a waste liquid end (141) for connecting the at least one sampling container (8.1, 8.2) to the waste liquid line (141).

9. The dissolution testing apparatus according to any one of the preceding claims, characterized in that, The cleaning system includes a cleaning medium reservoir (170) outside the at least two sampling containers (8.1, 8.2) and a nozzle (171) located in the sampling containers (8.1, 8.2), wherein the cleaning system is connected to the inlet fluid manifold (100) to connect the cleaning system to the at least two sampling containers (8.1, 8.2).

10. The dissolution testing apparatus according to any one of the preceding claims, characterized in that, The dissolution medium reservoir (15) can be connected to the flow cell (4) via the switching valve system (150).

11. The dissolution testing apparatus according to any one of the preceding claims, characterized in that, The dissolution medium reservoir (15) includes a medium selector (80) and a medium manifold (81), the medium selector (80) providing a variety of different solvents, and the medium manifold (81) being connectable to the flow cell (4) by the switching valve system (150).

12. A dissolution testing method for testing soluble substances dissolved in a dissolution medium using a dissolution testing apparatus according to any one of the preceding claims, characterized in that, The inlet fluid manifold (100), the outlet fluid manifold (110), and / or the switching valve system (150) are selectively connected such that: The device operates in open-loop mode by connecting the discharge line (140) to the extraction line (160), or in closed-loop mode by connecting the discharge line (140) to the pool inlet line (27).

13. The dissolution test method according to claim 12, characterized in that, The at least two sampling containers (8.1, 8.2) are alternately connected to the flow cell (4) and the discharge line (140) so that a continuous flow of material solution leaves the flow cell (4).

14. The dissolution test method according to any one of claims 12 to 13, characterized in that, In the open-loop mode, the at least two sampling containers (8.1, 8.2) are alternately connected to the flow cell (4) and the discharge line (140), such that one sampling container (8.1) is filled with a substance solution while the substance solution in the other sampling container (8.2) is tested and / or discharged.

15. The dissolution test method according to any one of claims 12 to 14, characterized in that, In the open-loop mode, one of the at least two sampling containers (8.1, 8.2) containing a first portion of the substance solution is disconnected from the flow cell and the first portion is tested by the test equipment, while the other sampling container (8.2) of the at least two sampling containers (8.1, 8.2) is connected to the flow cell (4) and contains a second portion of the substance solution.

16. The dissolution test method according to any one of claims 12 to 15, characterized in that, In closed-loop mode, the flow pool (4) is connected to one of the at least two sampling containers (8.1), and the discharge line (140) is connected to the pool inlet line (27), and multiple portions are continuously sampled in one sampling container (8.1) and tested by the test equipment (70).

17. The dissolution test method according to any one of claims 12 to 16, characterized in that, The portion is stirred in the stirring loop before being tested by the at least one test device (70).

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