Heating module for heating dissolution medium of dissolution testing device

Abstract

The invention relates to a dissolution testing device and to a dissolution medium heating module (6) for a dissolution testing device for the dissolution of a dissolvable substance, in which the heating module (6) comprises a heating chamber in the form of a two-dimensional heating circuit structure (14), which is connected or connectable by means of a pump to a dissolution medium reservoir (15) for receiving a dissolution medium. At least one heater in the form of a planar heating surface (18) is arranged alongside the heating circuit structure (14) for heating the dissolution medium within the heating chamber. The heating circuit structure (14) includes a dissolution medium conduit that is annular in one plane in a serpentine pattern.

Description

Technical Field

[0001] This invention relates to a dissolution medium heating module for a dissolution testing apparatus, and more particularly to a dissolution medium heating module integrated into a flow cell instrument or apparatus for drug release testing and dissolution testing. Background Technology

[0002] Dissolution testing is a pharmacopoeia-based in vitro test, used, for example, in drug development, to characterize the release rate of the active pharmaceutical ingredient (API) from the dosage form. This test is performed under reproducible conditions and is correlated with its in vivo performance. Once an innovative product's filing is approved by the regulatory authority in the target market, dissolution testing is subsequently used to assess batch-to-batch consistency of the manufactured product against the submitted quality standards and general testing conditions prescribed by the regulatory authority. Generic drug companies also use dissolution testing to establish the bioequivalence of their products without having to replicate the innovator's initial clinical studies: in this way, they can obtain bioequivalence exemptions.

[0003] Pharmaceutical formulations include granules, tablets, capsules, gels, creams, ointments, suspensions, suppositories, patches, microspheres, implants, and other long-acting injectables, such as micron-sized and nano-sized suspensions. "Dissolution testing" is the term used for solid dosage forms; the more general term "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 nicotine release from smokeless tobacco products and the persistence testing of asbestos fibers in lung fluid. A primary advantage of dissolution testing devices is their flexibility, as the flow cell and its internal structure can be adapted to the dosage form structure and challenges being tested.

[0004] The dissolution testing methods and related equipment for solid dosage forms are described in detail in the harmonized General Dissolution section of the European, American, and Japanese Pharmacopoes, namely the USP. <711> The flow-through cell dissolution method is also described as Method 6 in the Chinese Pharmacopoeia.

[0005] Standardized methods include, for example, using paddle devices for stirring substances in containers as described in EP 0746759 A1, basket devices for containing substances in baskets as described in US 5816701 A, or flow devices that provide a dissolution medium flowing through a pool containing a substance as described in WO 2013 / 003518 A1. The dimensions and tolerances of these devices are precisely specified. Key test parameters that must be monitored regularly during use include the sample volume and temperature of the dissolution medium, the rotational speed and flow rate of the medium, etc.

[0006] Flow-through apparatuses are used for various test objects. The dissolution principle of a flow-through cell involves flowing the dissolution medium into a cell containing the test dosage form at a specified temperature and flow rate. The total volume of the dissolution medium depends on the dissolution rate of the corresponding active pharmaceutical ingredient to be dissolved, and the test time is ideally related to the in vivo performance of the test product. Therefore, the temperature of the medium flowing into the cell must be controlled throughout the testing process (32°C for transdermal products, 37°C for oral products, and higher temperatures can be achieved within the range of accelerated testing). Cell temperature control and its efficiency are related to two processes: the temperature control of the medium flowing into the cell (at different possible flow rates, since flow rate is a method parameter) and the ambient temperature of the chamber containing the cell.

[0007] The flow-through device can be implemented as an open or closed system, for example, as shown in EP 0049293 A1. An open system uses a dissolution medium that is pumped from a reservoir through a pool in all channels and subsequently collected or analyzed in the pool. Open systems are recommended, for example, for poorly soluble drugs requiring large amounts of medium, or for, for example, to simulate pH changes in the gastrointestinal tract. In a closed system, the medium is pumped from a single reservoir in each channel, through the pool, and back to the reservoir. For each channel, these separate loops allow for the accumulation of the dissolved active ingredient in a sampleable or analytical reservoir.

[0008] Typically, dissolution testing apparatuses consist of multiple channels to allow for the simultaneous testing of at least seven channels (six samples and one reference). Therefore, before the apparatus is used, the seven channels must be qualified through documented procedures (installation qualification, operational qualification) to demonstrate that they allow for equivalent testing of all channels, as the final samples will be compared to specifications representing the entire production batch. Consequently, the temperature in each cell (as a measure of the medium's entry rate) must be accurate and consistent throughout the testing process so that the test detects only variations in the sample.

[0009] Historically, the heating system of dissolution testing apparatuses, which ensured the medium entered at a suitable temperature, was, for example, a single heating coil located in a water bath with sole temperature control. Individual channels could not be individually calibrated or adjusted. Typically, the pool was a heating system, for example, equipped with a separate heating element or heating unit for each pool, as shown in WO 2010 / 059643. Further, a gas flow or gas bath could be applied separately to each pool to separately regulate the temperature of the pool and the dissolution medium, as shown in US2015 / 0358587 A1. The pool could be associated with a temperature sensing element, which was connected to a thermal control system for controlling the temperature within the pool.

[0010] However, known dissolution testing apparatuses are slow or complex in controlling the temperature of the dissolution medium in the conditioning tank. In particular, heating equipment using water baths is difficult to control over short periods. Furthermore, the heating elements disclosed in the art for each individual container require additional application and maintenance steps to prepare and perform the test. Most apparatuses are designed as open or closed systems and are not configured for easy switching between open and closed configurations. These drawbacks impact effective quality control, compliance monitoring, and product optimization.

[0011] The purpose of this invention is to provide a dissolution testing device and a dissolution medium heating module for the dissolution testing device, which can realize rapid and accurate temperature adjustment of the dissolution medium, realize individual temperature control of a single dissolution tank, provide simple and flexible settings, and ensure accurate and repeatable testing. Summary of the Invention

[0012] These and other objectives, as described below, can be achieved by the dissolution medium heating module and dissolution testing device as described in the appended independent claims. Preferred embodiments are defined in the dependent claims.

[0013] The dissolution medium heating module of the dissolution testing apparatus for dissolving soluble substances in a dissolution medium according to the present invention includes a heating chamber connected to or connectable (e.g., via a pump device) to a dissolution medium reservoir for receiving the dissolution medium, and at least one planar heating surface disposed in the heating chamber for heating the dissolution medium therein. The heating chamber is implemented as a two-dimensional heating loop structure, including a medium inlet at one end of the heating loop structure and a medium outlet at the opposite end of the heating loop structure for receiving and dispensing the dissolution medium.

[0014] Advantageously, the medium outlet can be directly connected to the dissolution tank of the dissolution testing device, the dissolution tank being configured to contain the soluble substance to be tested. At least one planar heating surface of the dissolution medium heating module is configured to be adjacent to the heating circuit structure for emitting and transferring thermal energy to the heating circuit structure.

[0015] Compared to traditional dissolution medium containers, the two-dimensional loop design of the heating circuit structure provides a very large surface area for the interaction between the dissolution medium and thermal energy, while maintaining a narrow heating space. This design accelerates heat exchange and reduces energy loss. When the dissolution medium flows from the medium storage container to the dissolution tank of the dissolution testing device, the dissolution medium can be rapidly heated to a predetermined temperature within the heating circuit structure by at least one planar heating surface. The flow or circulation of the medium to the tank is uninterrupted to heat the dissolution medium, and the dissolution medium can be continuously supplied to the tank at a predetermined temperature. The dissolution medium heating module of this invention allows for the rapid and flexible supply of precisely temperature-controlled dissolution media.

[0016] The dissolution medium reservoir is connected to the heating circuit structure via a dissolution medium conduit that supplies the medium to the heating circuit structure. The dissolution medium reservoir may be part of a dissolution testing system, for example, located in the dissolution module, extraction module, or sample module of the device, and may be connected to the dissolution medium conduit of the heating module.

[0017] Advantageously, the heating circuit structure is designed as a medium conduit or conduit circulating within a coordinate plane. The extension of the heating circuit structure preferably covers the entire area of ​​the at least one planar heating surface. The medium conduit / conduit, for example, has a coiled, twisted, or serpentine annular layout, which optimizes the use of the planar area corresponding to the at least one planar heating surface. In an alternative to the heating module, there may be two parallel planar heating surfaces surrounding the heating circuit structure on both sides. The planar heating surfaces may be implemented by a single heating element, or multiple adjacent heating elements may be used on one side of the heating circuit structure to cover an area of ​​the structure.

[0018] The medium outlet of the heating circuit structure can be connected to the inlet of the dissolution tank, for example, by using a medium outlet line and / or an inlet conduit to supply the tank with a temperature-controlled dissolution medium. Advantageously, the medium outlet of the heating circuit structure is located at a short distance from the inlet of the dissolution tank to avoid any heat loss as the dissolution medium flows through the medium outlet line and / or the inlet conduit.

[0019] In one embodiment of the leaching medium heating module according to the invention, the planar heating surface is achieved by a heating plate, preferably a ceramic plate, including an internal heating coil. For example, the heating coil is electrically operated. The ceramic plate has a low coefficient of thermal expansion and high thermal conductivity, enabling repeatable and rapid heat transfer.

[0020] Furthermore, the media selector can be connected to the media inlet of the heating module, for example, via a pump. The media selector provides varying amounts of different types of solvents, for example, specifying in the test protocol a particular soluble substance to be tested corresponding to in vivo conditions. The media selector delivers the specified solvent and its quantity to the dissolution media conduit, for example, by supplying the media to the heating circuit structure via the pump, with the media outlet line leading to the pool.

[0021] In another embodiment of the dissolution medium heating module according to the invention, a fluid pump is arranged in the flow direction upstream of the heating circuit structure for controlled discharge of the dissolution medium into the heating circuit structure and the dissolution tank. Advantageously, the fluid pump is arranged between the medium reservoir and the heating circuit structure to ensure precise distribution of the dissolution medium volume. The fluid pump can also be designed as a pressure gauge to provide information about the fluid pressure in the heating circuit structure or any blockage in the dissolution medium conduit.

[0022] In another embodiment of the leaching medium heating module according to the invention, at least one temperature sensor is provided at the heating circuit structure, for example at the medium outlet and / or medium inlet. The temperature sensor monitors the temperature of the leaching medium immediately before it enters the leaching tank, allowing for accurate dissolution rate testing if release is temperature-dependent.

[0023] Preferably, the dissolution medium heating module according to the invention includes a control unit for controlling the temperature of the planar heating surface, for example, based on temperature measurements from a temperature sensor. Further, the control unit can control pump operation and pressure in the heating circuit structure and / or dissolution medium conduits, such as the medium outlet line and the inflow conduit to the dissolution tank. The control unit can also control the flow rate of the dissolution medium to ensure a constant and continuous medium input to the dissolution tank. Further, the control unit can control the type and amount of solvent provided by the medium selector.

[0024] According to another aspect of the invention, a dissolution testing apparatus includes at least one reservoir for a dissolution medium in fluid communication with at least one dissolution tank containing the soluble substance to be tested, a pump device for adding the dissolution medium from the at least one reservoir to the at least one dissolution tank, and at least one dissolution medium heating module as described above. The at least one reservoir is connected or can be connected to the pump device, and then to the medium inlet of the heating circuit structure, and the medium outlet of the heating circuit structure is connected or can be connected to at least the dissolution tank. For example, the connection is achieved via a simple fluid conduit, or by means of, for example, a valve or manifold establishing fluid communication. Advantageously, each tank of the dissolution testing apparatus is provided with a dissolution medium heating module. Due to the narrow structural design of the dissolution medium heating modules, several modules can be stacked adjacently in a small space to serve several adjacent tanks.

[0025] Advantageously, the dissolution testing apparatus includes several dissolution cells for simultaneously testing several units of soluble substance, thereby enabling rapid and reproducible dissolution testing. The dissolution cells are arranged in parallel, and multiple heating modules associated with each cell are arranged in parallel below the cells to provide upward flow. Similarly, the narrow structure of the heating modules allows for independent heating of the dissolution medium supplied to each cell.

[0026] Preferably, the dissolution testing device is designed for closed-loop and / or open-loop configurations, such as the known USP 4 device, wherein the at least one cell is a flow-through cell, including a cell inlet for the dissolution medium and a unit outlet for a sample solution containing the dissolution medium and the dissolved substances. In the closed-loop configuration, the sample solution can be returned to the flow-through cell as the dissolution medium to accumulate the dissolved substances in a reservoir. In the open-loop configuration, the sample solution is extracted in component form and then transferred to a sample vial for analysis or online analysis.

[0027] Advantageously, the heating circuit structure of the at least one heating module is arranged in the dissolution medium flow provided by a pumping device between the at least one reservoir and the at least one pool. That is, the heating module and the associated pool are arranged in series along the flow direction, and the heating circuit structure establishes the cross-section of the medium conduit from the reservoir to the pool. This avoids the need for additional fluid branches or fluid compartments that need to be incorporated into the medium conduit.

[0028] In one embodiment of the dissolution testing apparatus of the present invention, the at least one heating module is detachably connected to the pool. Furthermore, it can also be detachably connected to the storage tank if desired. For example, the two-dimensional heating circuit structure and the at least one planar heating surface can be disposed within a heating module housing including a fluid connector. The fluid connector of the housing connects the medium inlet of the heating circuit structure to a fluid connector communicating with the medium storage tank, and connects the medium outlet of the heating circuit structure to a fluid connector communicating with the inlet of the dissolution pool. The fluid connectors can be connected to each other, for example, by press-fit, form-fit, threaded connection, bayonet connection, etc., and can be separated by loosening or reconnecting the fit. Therefore, the heating module can be easily removed from the dissolution testing apparatus, for example, providing access to the interior of the apparatus for maintenance or replacement of components.

[0029] In another embodiment of the dissolution testing apparatus according to the invention, a bypass conduit is provided between the medium outlet of the heating module and the outlet of the pool to bypass the pool. The bypass conduit may be arranged parallel to the dissolution pool and connected via a valve to an inflow conduit entering the pool, and via another valve to an outflow conduit leaving the unit. The bypass conduit facilitates the adjustment of dissolution conditions in the dissolution pool, replacing the pool channel for medium flow. Therefore, even without a dissolution pool, the dissolution medium can circulate through the dissolution testing apparatus. This bypass facilitates pre-test temperature control or UV-Vis online analysis baseline, as well as cleaning of system piping at the end of the test.

[0030] In another embodiment of the dissolution testing apparatus according to the invention, a controller controls the operating conditions of the dissolution testing apparatus. The controller includes, for example, a processing unit, a user interface, and a control display. The controller receives, for example, measurement data from temperature sensors of the heating module, measurement data from other temperature sensors arranged in the dissolution tank or the chamber containing the tank, or arranged in the medium reservoir, measurement data from pressure sensors or meters arranged in the dissolution medium conduit (especially in the outflow conduit of the heating module and the tank), measurement data from sample solution testing equipment (e.g., a UV-Vis spectrophotometer), or any other sensors or devices used in the dissolution testing apparatus. The control unit of the dissolution medium heating module can be integrated into the controller or controlled by the controller. For example, the controller receives a test plan for testing a specific soluble substance and controls the operation of the dissolution testing apparatus according to the requirements of the test plan.

[0031] In another embodiment of the dissolution testing apparatus of the present invention, the dissolution tank is disposed in a chamber serving as a heating channel. A heater is connected to the heating channel and is used to heat the air or other gas in the heating channel, while the soluble substance is exposed to the dissolution medium. The heating channel and the heater prevent the temperature of the dissolution medium from changing after it is heated and injected into the dissolution tank from the heating circuit structure. Therefore, the test conditions in the dissolution tank can remain stable during the dissolution process.

[0032] Dissolution medium heating modules and dissolution testing apparatuses incorporating such modules improve the repeatability of dissolution quality assessments of soluble substances by enhancing compliance with testing requirements. They contribute to providing consistent dissolution quality for soluble substances, particularly pharmaceutical ingredients. Furthermore, they provide a predictive measure of effectiveness for API substances and other drug-based applications. Attached Figure Description

[0033] Preferred embodiments of the present invention will be described in the accompanying drawings, which illustrate the principles of the invention but should not limit its scope. Brief Description of the Drawings:

[0034] Figure 1 Overview of the operation module of the dissolution testing apparatus according to the present invention.

[0035] Figure 2 The present invention provides a heating module for a dissolution medium. Figure 1 An internal view of the dissolution module of the dissolution testing device;

[0036] Figure 3 A three-dimensional diagram of the leaching medium heating module provided by the present invention.

[0037] Figure 4a : Figure 3 A longitudinal view of the leaching medium heating module.

[0038] Figure 4b : Figure 3 The dissolution medium heating module Figure 4a The BB line in the middle.

[0039] Figure 5 A schematic top view of a heating device for heating the pool heating channel of a dissolution test apparatus according to the present invention.

[0040] Figures 6a-6c Schematic diagram of three working modes of the dissolution testing device: test mode, bypass mode, and cleaning mode.

[0041] Figure 7a &7b: A side view and a schematic inner view of the flow cell used in the dissolution testing apparatus of the present invention. And...

[0042] Figure 8a &8b: Schematic diagrams of the open-loop and closed-loop configurations of the dissolution testing apparatus according to the present invention. Detailed Implementation

[0043] Figure 1 The construction of the dissolution testing apparatus used in this invention is illustrated. The dissolution testing apparatus includes a dissolution module 1, an extraction module 2, and a sample module 3. The dissolution testing apparatus can operate in a closed mode configuration or an open mode configuration, as will be explained below. The dissolution module 1 houses several dissolution cells designed as flow cells 4, arranged in the cell chambers 11 of the dissolution module 1. Each cell is filled with a soluble substance 5 (see...). Figure 7a and 7b ).like Figure 2 As shown, the dissolution medium is supplied to the flow cell 4 via the dissolution medium heating module 6 located below the cell in 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 sample solution containing both the dissolution medium and the dissolved substances. The sample solution is transferred to the extraction module 2 via the sample solution conduit 7. In the extraction module 2, the defined components of the sample solution are extracted from the sample solution conduit 7 into sample vials 8. Depending on the operating method, the sample components in the sample vials can be tested and returned to their respective cells, or the sample vials can be transferred to the sample module 3 for testing.

[0044] like Figure 2The diagram shows the interior of the dissolution module 1 of the dissolution testing apparatus according to the present invention. A heating chamber 11 is implemented above the dissolution medium heating module 6 for heating the dissolution medium before it enters the pool 4. An assembly structure 90 in the form of a mounting plate is provided inside the dissolution module 1. On the front side, the assembly structure 90 includes a pool holder 91 for keeping the flow pool 4 upright and arranged along a longitudinal axis, a connector rod 92 including a connector port for connecting the pool outlet 13 to the sample solution conduit 7, and a connector platform 93 for supporting the dissolution medium heating module 6 below the platform and the flow pool 4 above the platform. The connector platform 93 includes a connector port for connecting the medium outlet line 28 of the heating module 6 to the pool inlet 12 (see [link to connector port]). Figure 3 The connector rod 92 and the connector platform 93 extend from each other and are substantially perpendicular to the assembly structure 90. Therefore, the assembly structure 90, the connector rod 92, and the connector platform 93 form the pool chamber 11.

[0045] like Figure 2 As shown, seven flow cells 4 are arranged in cell chamber 11, resulting in a cell volume of 10 (see Figure 10). Figure 7b The flow cell 4 is fully exposed and accessible from all sides through its walls, for example, for visual inspection and interaction with the environmental conditions present in the cell chamber 11. The cell includes a cell inlet 12 at the bottom and a cell outlet 13 at the top. The cell outlet 13 is in fluid communication with a sample solution conduit 7, which delivers the sample solution to the extraction module 2. The bottom of the flow cell 4 is located on a connector platform 93 for fluid connection to a dissolution medium heating module 6 disposed below the connector platform 93 in the dissolution module 1. Each flow cell 4 is associated with a dissolution medium heating module 6, which are arranged adjacent to each other below the cell.

[0046] Figure 3 Figure 4 illustrates a dissolution medium heating module 6 according to the present invention. The heating module includes a heating chamber implemented as a two-dimensional heating loop structure 14. For example, the heating loop structure 14 is designed as a ring-shaped medium conduit in a plane, for example, in a serpentine pattern. The heating loop structure 14 is connected to a dissolution medium reservoir 15 (see Figure 4) via a pump device 60. Figure 8a and 8b The heating circuit structure 14 includes a medium inlet 16 at one end and a medium outlet 17 at the opposite end, for receiving and dispensing the dissolving medium.

[0047] A planar heating surface, in the form of a heating plate 18, is disposed near the heating circuit structure 14 for heating the dissolution medium in the heating circuit structure 14. For example, the heating plate 18 includes dimensions covering the area of ​​the two-dimensional heating circuit structure.

[0048] Alternatively, two or more heating plates or other flat heating elements or plates can be used to cover the heating circuit area. Heating plate 18 is, for example, a ceramic plate including an internal heating coil. Furthermore, silica material or metal can be used for the planar heating surface.

[0049] The heating module receives the dissolution medium from an external dissolution medium storage 15, which is located, for example, in the dissolution module 1 or the extraction module 2 of the dissolution test device.

[0050] exist Figure 3 In the exemplary embodiment shown in FIG4, the leaching medium heating module 6 includes two housing halves that surround the heating circuit structure 14 and the heating plate 18 in an assembled state. One or both housing halves may include recessed structures corresponding to the two-dimensional heating circuit structure 14 for accommodating the heating circuit structure therein.

[0051] Furthermore, the housing half-shell has an inlet through-hole 21 and first and second outlet through-holes 22 and 22', which serve as medium conduits for the medium inlet 16 and medium outlet 17 of the heating circuit structure 14. The two housing half-shells can be screwed together to realize the heating block 23 of the heating module 6.

[0052] The dissolution medium heating module 6 includes a pressure sensor 26 in the medium inlet line 27 for monitoring the pressure in the heating circuit structure 14. The medium inlet line 27 is formed by a through-passage of through-hole 21 and is detachably connected to an external dissolution medium reservoir 15 via, for example, an input port at through-hole 21. The medium outlet 17 is incorporated into the medium outlet line 28, which enters the valve unit 30 (see...). Figures 6a-6c Valve unit 30 can be attached to the housing. Valve unit 30 switches between parallel through passages provided by the first through-hole 22 and the second through-hole 22'. The first through-hole 22 can be connected to the pool inlet 12 to provide a temperature-controlled dissolution medium to the flow pool 4. The second through-hole 22' can be connected to the bypass conduit 31 for bypassing the pool. Each through-hole 22 and 22' includes temperature sensors 33 and 34, respectively, for monitoring the temperature of the dissolution medium leaving the heating loop structure 14. Temperature sensors 33 / 34 and pressure sensor 26 can be placed in the medium inlet line 27 and through-holes 22 / 22' when assembling the two housing halves to realize the heating block 23.

[0053] In the assembled state of the dissolution medium heating module 6, the shell halves are assembled together to form the heating block 23. The heating module includes a thin design, wherein the thickness measured on the two halves is only about half the length or height of the heating module. Preferably, the thickness is only 1 / 3 of the length or height, more preferably only 1 / 4 of the length or height. The thin design allows for a separate dissolution medium heating module 6 for each flow cell 4 of the dissolution testing device without occupying a large space.

[0054] like Figure 8a In more detail, the media selector 80 can be connected to the media inlet line 27 for selectively adding solvent to the dissolving medium before it enters the heating circuit structure, as described above. The medium can be supplied to the inlet line 27 by the pump unit 60.

[0055] Furthermore, the dissolution medium heating module 6 may include control sensors for monitoring and controlling the operation of the heating module 6 and the dissolution testing apparatus. For example, at least one temperature sensor may be provided to monitor the temperature of the dissolution medium flowing through the heating module. The temperature sensor may, for example, be located at the medium inlet line 27. Temperature sensors 33 and 34 are located in through-holes 22, 22'. Furthermore, at least one pressure gauge, such as pressure sensor 26, may be located, for example, in the medium inlet line 27 and / or the medium outlet line 28, to provide pressure measurement for controlling the medium input. The control unit controls the operation of at least one heating plate 18 and the pump, as explained below.

[0056] like Figure 2 As shown, the leaching medium heating module 6 is detachably installed in the leaching module 1, and the medium outlet pipeline 28 of the heating circuit structure 14 is detachably connected to the pool inlet 12. Therefore, the heating module 6 can be easily replaced for maintenance.

[0057] Figure 5 The diagram illustrates a heating device for heating several dissolution pools 4 housed in a pool chamber 11 of a dissolution module 1. In the illustrated example, the pool chamber 11 is part of a heating channel 100 shared by all the pools 4. A heater 101 is disposed in the heating channel 100 for heating air or other gases within the heating channel 100. A ventilator 104 is disposed adjacent to the heater 101 in the heating channel 100 for generating a heated airflow along the flow pools 4 within the heating channel. In the illustrated example, the heating channel 100 is implemented as a heating channel loop, comprising a first elongated section 102 accommodating the pool chamber 11 with several flow pools 4 and a second elongated section 103 accommodating the heater 101 and the ventilator 104. The first elongated section 102 and the second elongated section 103 are connected by a curved section to realize the heating channel loop. Several flow pools 4 are arranged along the longitudinal axis of the first elongated section 102.

[0058] The heater 101 includes a plurality of flat heating elements, such as heating plates, arranged along the longitudinal axis of the heating channel 100. Airflow also flows along the longitudinal axis, allowing it to easily pass through the flat heating elements for heating. A set of guide plates 105 are located upstream of several pools 4 to support laminar flow in the pools along the first elongated section 102 of the heating channel 100. Further guide plates may be located at bends in the heating channel to support laminar flow along the heater 101 and the ventilator 104.

[0059] Furthermore, the heating channel 100 includes a fluid passage ( Figure 5 (Not shown in the image) For fluid connection with the flow cell 4, there are eluent conduits, such as a medium outlet line 28 for connecting to the heating module 6 at the cell inlet 12 to transfer the eluent to the cell 4, and a sample solution conduit 7 for transferring the sample solution from the cell outlet 13 to the extraction module 2.

[0060] The common heating channel includes at least one temperature sensor 106 in the first elongated section 102 of the heating channel 100 that houses several flow pools 4 (see [link]). Figures 6a-6b Further temperature sensors may be located at or near at least one of the locations in the flow cell 4, and in the area of ​​the heating channel housing the ventilator 104. The control unit and / or the controller of the dissolution testing device at the heating channel may receive information data from the temperature sensors used to control the heater 101 and / or the ventilator 104, based on the desired temperature in the heating chamber 11.

[0061] like Figure 2 The diagram shows the interior of the dissolution module 1 of the dissolution testing apparatus of the present invention. The heating chamber 11 of the heating channel 100 is located above the dissolution medium heating module 6 for heating the dissolution medium before it enters the pool 4. The assembly structure 90, connector rod 92, and connector platform 93 respectively create the pool chamber 11 and the heating channel 100. The heater and ventilator may be located on the back side of the assembly structure 90. The assembly structure 90, having the above-described assembled components, is installed in the housing of the dissolution module 1.

[0062] In the region representing the sample chamber 11 of the elongated section 102 of the heating channel 100, the housing includes an opening along the length of the sample chamber 11 and a cover (not shown) for closing the opening. The opening and cover provide access to the cell chamber 11 for positioning flow cells therein and connecting them to connection ports. The cells are surrounded by a heated gas flow, and the flow of the dissolution medium through the cells is perpendicular to the heat flow in the heating channel, which allows for uniform exposure to the heated air.

[0063] In the dissolution testing apparatus of the present invention, the dissolution medium is rapidly and effectively heated to the desired temperature by the heating module 6, while the dissolution medium flows into the flow cell 4. The heating circuit structure 14 of the heating module 6 is arranged between the dissolution medium reservoir 15 and the flow cell 4 along the dissolution medium flow path. That is, the heating module 6 and its associated cell 4 are arranged in series. The heating channel 100 is mainly used to maintain the temperature of the dissolution medium at the temperature reached by the heating module, while the medium flows through the cell 4. This arrangement ensures the precise and continuous flow of the medium through the cell at a predetermined constant temperature, and enables flexible and predictable dissolution testing of soluble substances.

[0064] Figures 6a to 6c Different operations of the dissolution testing apparatus according to the present invention are described, schematically illustrating the flow of the dissolution medium provided by the dissolution medium heating module 6 and the chamber 11. As previously described, the dissolution medium is provided by the medium inlet line 27 and enters the heating loop structure 14, where it is heated by the heating plate 18 as it flows through the structure. A temperature sensor 33 measures the temperature, and a pressure gauge 35 measures the pressure of the dissolution medium in the medium outlet line 28. A bypass valve 30 arranged in the medium outlet line 28 distributes the dissolution medium to the inflow conduit 40 or bypass conduit 31 connected to the chamber inlet 12. A temperature sensor 34 measures the temperature in the bypass conduit 31. In the chamber 11, in the corresponding heating channel 100, the dissolution medium, heated by the heating module 6, flows through the flow cell 4 and dissolves the soluble substance 5 therein, thereby forming a sample solution containing the dissolution medium and a portion of the dissolved substance. The sample solution leaves the flow cell 4 through the chamber outlet 13 and enters the outflow conduit 41. The outflow conduit 41 and the bypass conduit 31 converge at the bypass valve 32, and the medium flow continues from the bypass valve 32 into the sample solution conduit 7, flowing towards the extraction module 2 and / or the sample module 3.

[0065] exist Figure 6a In the dissolution testing device, operating in test mode, a heated dissolution medium is delivered from the dissolution medium heating module 6 to the flow cell 4 in the heating channel 100. The temperature in the flow cell 4 is maintained or adjusted within the heating channel, allowing soluble substances to dissolve in the dissolution medium. A sample solution is injected into the sample solution conduit 7. The sample solution can be tested while flowing through the sample solution conduit 7, for example, using optical analysis, or it can be guided to the extraction module 2 to be extracted into a sample vial 8 for testing.

[0066] exist Figure 6bIn this dissolution testing apparatus, the dissolution medium operates in bypass mode, wherein a diversion valve 30 directs the dissolution medium from the medium outlet line 28 and the through-hole 22' of the heating module 6 to the bypass conduit 31. This can be, for example, if the flow cell is blocked, or in the event of any other malfunction of the dissolution testing apparatus. A bypass valve 32 guides the dissolution medium from the bypass conduit 31 into the sample solution conduit 7, from which the dissolution medium can be discarded or returned to the dissolution medium circulation system.

[0067] exist Figure 6c In this dissolution testing apparatus, the dissolution tester operates in cleaning mode, with the flow cell removed from chamber 11. Dissolution medium or cleaning medium is used to clean the conduits of the dissolution tester. The medium passes through heating module 6, and bypass valve 30 guides the medium through bypass conduit 31 and replacement conduit 42, replacing the inflow conduit 40, flow cell 4, and outflow conduit 41. Bypass valve 32 guides the medium into sample solution conduit 7.

[0068] Figure 7a and 7b A flow-through cell 4 is shown because it can be used for the assembly top view and schematic internal view of the present invention. The flow-through cell 4 includes a cell volume 10 having a generally cylindrical shape and predefined dimensions. The cell volume 10 tapers towards its bottom end, which includes a cell inlet 12, and opens at its top. A soluble substance 5 is placed in the cell volume 10. Within the dissolution cup volume, the soluble substance can be placed at a position relative to the bottom using a basket, bead bed, or similar structure, depending on the test method used or the shape requirements of the soluble substance. A closure ring 50 having a central through passage and a holder for a filter 51 are 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 closure ring 50 to close the cell volume 10 and hold the filter 51 in place. Alternatively, the closure ring 50 and cap 52 can be implemented as a single piece, wherein the filter 51 can be set in a single piece before the single piece is mounted on the cell volume.

[0069] The pool volume 10 is made of, for example, glass or plastic material, which is inert relative to the soluble substance, and includes transparent walls for observing the dissolution process. The pool volume 10 does not require placement within an additional container as known in the art for providing heating elements at the pool. The flow-through pool 4 features a simple design and facilitates the preparation of the soluble substance for testing.

[0070] Advantageously, the closed loop 50 or cover 52 may include an electronic chip, a temperature sensor, a positioning sensor, a flow meter, and other sensor devices. The electronic chip is designed to communicate wirelessly with the controller of the dissolution testing apparatus and transmit information such as the temperature at the dissolution volume, the pool position, and the flow rate through the pool. This data can be used to control the dissolution medium heating module 6, the heater 101 in the heating channel 100, the pump of the apparatus, and other functions of the dissolution testing apparatus, as well as to record test conditions.

[0071] Figure 8a and 8b The dissolution testing apparatus of the present invention provides testing methods using open-loop and closed-loop configurations of the flow cell 4.

[0072] exist Figure 8a In the open-loop configuration shown, fresh dissolution medium is supplied by one or more medium reservoirs 15 provided by a medium selector 80 and pumped into the flow cell 4 by a medium pump 60. The dissolution medium flows through the heating module 6, is heated to a preselected temperature, and enters the flow cell 4 in the heating channel 100. The dissolution medium flows through the flow cell 4, passing through the soluble substance 5 to form a sample solution. The sample solution flows from the flow cell to a bypass valve 32, which directs the sample solution to the extraction module 2 or the waste conduit 61. In the extraction module, two portions of the sample solution are extracted into sample vials 8 for testing. The total amount of dissolution medium is determined by the flow rate generated by the medium pump. In the open-loop configuration, the total amount of medium is unlimited. The dissolution medium heating module 6 and the heating channel 100 provided according to the invention can be advantageously used to heat the flow of fresh dissolution medium. Over time, the soluble substance decreases, and less substance dissolves into the medium. Therefore, the measured dissolution rate is represented as a differential curve over time, showing a decreasing dissolution rate.

[0073] like Figure 8b The closed-loop configuration shown is used in conjunction with a fixed volume of dissolution medium provided by dissolution medium reservoir 15. The dissolution medium is recirculated through flow cell 4 and passes through the soluble substance several times. A test device 70, such as a UV spectrophotometer, can be set up online to test the sample solution while it circulates within the device. Alternatively, a small, limited sample can be extracted for testing, while the majority of the sample solution is recirculated within the closed-loop system. The measured dissolution is expressed as a cumulative curve over time, where the dissolved substances accumulate in a fixed volume of medium over several cycles.

[0074] In summary, the dissolution testing apparatus according to the present invention facilitates accurate and reproducible temperature conditions to simulate the in vivo conditions of all forms of soluble substances listed at the outset. The dissolution testing apparatus allows for easy modification of the cell type without altering the heating system. The heating modules for the dissolution medium and the heating channels within the dissolution module can be used for various types of dissolution cells. The dissolution testing apparatus enables universal and automated dissolution testing, supporting accurately predictable test results.

[0075] The dissolution testing apparatus according to the present invention allows for accurate and repeatable measurement of the dissolution rate and amount of soluble substances in formulations, which is crucial for product safety and efficacy. The dissolution testing apparatus facilitates quality control and formulation optimization, accurately predicts in vivo drug release profiles, and provides reliable batch-to-batch consistency assessments. It plays a vital role in product compliance and market launch decisions.

[0076] Reference tag list

[0077]

Claims

1. A dissolution medium heating module for a dissolution testing device for dissolving soluble substances in a dissolution medium, wherein the heating module (6) includes a heating chamber connected to or connectable to a dissolution medium storage device (15) for receiving the dissolution medium, and a heater device for heating the dissolution medium in the heating chamber; Its features are: The heating chamber is implemented as a two-dimensional heating circuit structure (14), including a medium inlet (16) at one end of the heating circuit structure (14) and a medium outlet (17) at the opposite end of the heating circuit structure (14), for receiving and dispensing the dissolution medium, and The heater device includes at least one planar heating surface (18) adjacent to the heating circuit structure (14).

2. The dissolution media heating module of claim 1, wherein, The heating circuit structure (14) is designed as a medium conduit circuit in a plane along the at least one planar heating surface (18).

3. The dissolution medium heating module according to claim 1 or 2, characterized in that, The at least one planar heating surface (18) covers the entire area of ​​the two-dimensional heating circuit structure (14).

4. Dissolution medium heating module according to one of the preceding claims, characterized in that The at least one planar heating surface (18) is a heating plate including an internal heating coil, preferably a ceramic plate.

5. Dissolution medium heating module according to one of the preceding claims, characterized in that The medium selector (80) is connected to the medium inlet (16) of the heating circuit structure (14) for selectively adding dissolution medium.

6. Dissolution medium heating module according to one of the preceding claims, characterized in that The pressure sensor (26) is installed in the medium inlet pipeline (27) of the heating circuit structure (14) to control the discharge of the leaching medium into the heating circuit structure (14).

7. Dissolution medium heating module according to one of the preceding claims, characterized in that At least one temperature sensor (33, 34) and a control unit for controlling the heater device are provided at and / or within the heating circuit structure (14).

8. Dissolution testing apparatus characterized in that, The device includes at least one dissolution tank (4) arranged to contain the soluble substance to be tested, a pump device (60) for adding a dissolution medium to the at least one tank, and at least one dissolution medium heating module (6) as described in any of the preceding claims, wherein at least one reservoir (15) is fluidly connected to the medium inlet (16) of the heating circuit structure (14), and the medium outlet (17) of the heating circuit structure (14) is fluidly connected to the at least one tank (4).

9. The dissolution testing apparatus of claim 8, wherein, Each dissolution pool (4) of the dissolution test device is provided with a dissolution medium heating module (6).

10. The dissolution testing apparatus according to one of the preceding claims 8 or 9, characterized in that, The heating circuit structure (14) of the at least one heating module (6) is disposed in the dissolution medium flow between the at least one reservoir (15) and the at least one pool (4).

11. The dissolution testing apparatus according to any one of claims 8 to 10, characterized in that, The at least one heating module (6) is detachably connected to the pool inlet (12) and the storage outlet (15).

12. The dissolution testing apparatus of any of the preceding claims 8 to 11, characterized in that, A bypass conduit (31) is arranged between the heating module medium outlet (17) and the outlet (13) of the pool (4), bypassing the pool.

13. The dissolution testing apparatus of any of the preceding claims 8 to 12, characterized in that, The at least one pool (4) is a flow pool, including a pool inlet (12) for the dissolution medium and a pool outlet (13) for the dissolution medium containing the dissolution substance.

14. The dissolution testing apparatus of any of the preceding claims 8-13, characterized in that, A pressure gauge is arranged in the leaching medium conduit to provide pressure measurements to the control unit that controls the pump.

15. The dissolution testing apparatus of any of the preceding claims 8-14, characterized in that, The at least one pool is arranged in a heating channel (100), and a heater (101) is connected to the heating channel (100) for heating the gas heating medium in the heating channel (100).

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