Dissolution test device with common heating channel

Abstract

The invention relates to a dissolution test device for dissolving a soluble substance in a dissolution medium, comprising at least one reservoir (15) for the dissolution medium, a plurality of dissolution units (4) each designed to receive the soluble substance to be tested, and a pump device for adding the dissolution medium to the units (4). A plurality of units (4) are arranged in a common heating channel (100), with a heater (101) connected to the heating channel (100) for heating a gaseous heating medium, such as hot air, in the heating channel (100).

Description

Dissolution test apparatus with a shared heating channel Technical Field

[0001] The present invention relates to a dissolution testing apparatus for drug release testing and dissolution testing, comprising a heating arrangement for one or more flow units, particularly flow unit instruments or devices, for tempering one or more test units. 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) in a formulation dosage form that is relevant to the in vivo performance of the formulation under reproducible conditions. After an innovator's product data is approved by the designated market authority, dissolution testing is used to assess batch-to-batch consistency of the manufactured product, based on the submitted specifications and the general testing conditions described by the authority. Companies also generally use dissolution testing to determine the bioequivalence of their products without having to repeat the innovator's initial clinical studies: doing so allows them to obtain bioassurance.

[0003] Pharmaceutical formulations include granules, tablets, capsules, gels, creams, ointments, suspensions, suppositories, patches, microspheres, implants, and other long-acting injectables, such as micro / nano suspensions. "Dissolution testing" is a term used for solid dosage forms; the more general term is "drug release testing" for other dosage forms, including coated medical devices. Outside the pharmaceutical field, dissolution testing devices are also used in applications such as nicotine release from smokeless tobacco products and for the persistence testing of rock wool fibers in lung fluid. The primary interest in dissolution testing devices in the form of flow-through unit dissolution apparatus lies in their flexibility, as the unit and its internal arrangement can be adapted to the formulation structure and challenges being tested.

[0004] The dissolution test modes for the solid dosage forms and devices involved are described in the unified general dissolution chapter of the European, American, and Japanese Pharmacopoes (USP < 711 >). Dissolution by unit is also described as Method 6 in the Chinese Pharmacopoeia.

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

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

[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 the unit in all channels and collected or analyzed after the unit. For example, open systems are recommended for insoluble drugs requiring large amounts of culture medium, or for applications such as mimicking gastrointestinal tract pH changes. In a closed system, the medium is pumped from a reservoir in each channel, through the unit, and back to the reservoir. For each channel, these separate loops allow for the accumulation of dissolved active ingredient in a sampleable or analyzable 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 defined in documented procedures (installation validation, operational validation) 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 (as a measure of the rate of medium entry) in each unit must be accurate and consistent throughout the testing process so that the test detects only variations in the samples.

[0009] Historically, heating systems that ensured proper unit temperatures were typically single water jackets immersed in a temperature-controlled water bath. The same heat source was used for temperature regulation of the incoming medium and the unit. Typically, the unit was equipped with a heating system, for example, comprising a single heating element or heating unit for each unit, as shown in WO 2010 / 059643. Further, a separate airflow or air bath could be applied to each unit to temper both the unit and the dissolving medium, as shown in US 2015 / 0358587 A1. The unit could be associated with a temperature sensing element, which was connected to a thermal control system for controlling the temperature in the control unit.

[0010] However, known dissolution testing apparatuses are slow or complex in regulating the temperature of the dissolution medium within the unit. In particular, water bath heating apparatuses are difficult to control over short periods. Furthermore, the heating elements disclosed in the art for each individual vessel require additional application and maintenance steps to prepare for and execute 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 apparatus for dissolving soluble substances in a dissolution medium, which can accurately and precisely adjust the temperature of the dissolution medium, reliably control the temperature of each dissolution unit, provide simple and flexible settings, and ensure rapid and repeatable testing. Summary of the Invention

[0012] These and other objectives, which will appear in the following description, are achieved by the dissolution testing apparatus described in the appended independent claims. Preferred embodiments are defined in the dependent claims.

[0013] The dissolution test apparatus according to the present invention for dissolving a soluble substance in a dissolution medium includes at least one reservoir for the dissolution medium, several dissolution units, each designed to contain the soluble substance to be tested, and a pump device for adding the dissolution medium to the dissolution units. The several units are arranged in a common heating channel. A heater is connected to the heating channel for heating a gaseous heating medium, such as air, within the heating channel. Therefore, all units in the heating channel are simultaneously tempered to the temperature level established by the heater in the common heating channel. The units interact directly with the tempering environment in the heating channel to rapidly transfer thermal energy to the units and the soluble substance and the dissolution medium within them. A separate heating jacket is not required for each unit.

[0014] In one embodiment of the dissolution testing apparatus, a ventilator is disposed within the heating channel to generate heated air or airflow along the units. The ventilator can be positioned before or after the heater to direct heated air toward the units within the heating channel. The heated airflow generated by the ventilator ensures uniform heat distribution along the units within the common heating channel. Preferably, the dissolution units are aligned along the longitudinal axis of the heating channel in the direction of the heating medium flow. This arrangement supports efficient interaction with the tempering flow and allows for a compact design.

[0015] In one embodiment of the dissolution testing apparatus, the heating channel is implemented as a heating channel loop, the heating channel loop including a first elongated portion accommodating the plurality of units and a second elongated portion accommodating the heater and the ventilator. The plurality of units can be aligned along the longitudinal axis of the first elongated portion of the heating channel. The heater and the ventilator can be aligned along the longitudinal axis of the second elongated portion of the heating channel. The heating channel loop provides a closed space for the gaseous heating medium to be heated. The ventilator provides circulation of the heating medium within the heating channel. The loop design reduces the energy required to heat the heating channel to the desired temperature level, facilitating the maintenance of the temperature level.

[0016] Advantageously, the heating channel includes an opening along the elongated portion and a cover for closing the opening, providing access to the plurality of units, the elongated portion accommodating the dissolution units. The opening is used for inserting and removing the dissolution units.

[0017] In one embodiment of the dissolution testing apparatus, the heater includes a plurality of flat heating elements, such as heating plates or heating meshes, arranged along the longitudinal axis of the heating channel. The flat surfaces of the heating elements extend along the length of the heating channel. This avoids interference with the heating flow and prolongs the contact time between the heating medium and the heating elements, thereby achieving effective heating of the heating medium.

[0018] In another embodiment of the dissolution testing apparatus of the present invention, guide plates are located upstream of several units in the heating channel to support laminar flow along the units. For example, the guide plates are disposed in front of curved portions and / or unit portions of the heating channel. The guide plates are arranged parallel or concentrically with respect to the radius of the curved portions. Preferably, a group of guide plates are equally spaced along the width of the heating channel. For example, depending on the size of the channel, 3 to 8 guide plates are distributed on the heating channel.

[0019] In another embodiment of the dissolution testing apparatus, the heating channel includes a fluid channel for a dissolution medium conduit, the fluid channel being fluidly connected to the unit inlet for supplying the dissolution medium to the unit. Therefore, the dissolution unit can be placed within the heating channel, and the dissolution medium can be added to the unit as needed.

[0020] Advantageously, the dissolution medium heating module is configured as a flow module connected in series with a dissolution medium reservoir outside the heating channel and the dissolution unit inside the heating channel. The dissolution medium heating module preheats the dissolution medium before it is applied to the dissolution unit. Therefore, the dissolution medium can be heated to a desired temperature outside the dissolution unit and the heating channel. When the heated dissolution medium is passed into the dissolution unit in the heating channel, the heated gaseous medium flow maintains the dissolution medium at the preheated temperature, and the temperature can be rapidly adjusted if necessary.

[0021] In one embodiment of the dissolution testing apparatus according to the invention, the dissolution medium heating module includes a heating chamber, which is connected to or can be connected to the dissolution medium reservoir, for example via a pump, for receiving the dissolution medium. At least one planar heating surface is provided in the heating chamber for heating the dissolution medium therein. The heating chamber is advantageously implemented as a two-dimensional heating loop structure, which includes a medium inlet at one end of the heating loop structure and a medium outlet at the other end of the heating loop structure for receiving and distributing the dissolution medium. At least one planar heating surface is disposed adjacent to the heating loop structure for emitting and transferring thermal energy to the heating loop structure. The dissolution medium heating module allows for rapid and precise heating of the dissolution medium while it continuously flows into the dissolution unit in the heating channel.

[0022] Preferably, the dissolution testing apparatus is designed for closed-loop and / or open-loop configurations, as known from USP 4 devices, wherein the dissolution unit is a flow-through unit comprising a unit inlet for the dissolution medium and a unit outlet for a sample solution containing the dissolution medium and the dissolved substance. In a closed-loop configuration, the sample solution can be returned to the flow-through unit as the dissolution medium to collect the dissolved active ingredient in a reservoir. In an open-loop configuration, the sample solution is extracted in partial form and then transferred to a vial for analytical testing or online analysis.

[0023] As described above, in embodiments of the dissolution testing apparatus, the heating channel includes a fluid channel for a dissolution medium conduit, which is fluidly connected to an inflow conduit entering the unit and an outflow conduit leaving the unit. For example, the lower and upper walls of the heating channel, located below and above the flow unit, include connection ports for establishing fluid communication with the inflow and outflow conduits. Outside the heating channel, the fluid passageway can be connected to the aforementioned dissolution medium reservoir or dissolution medium heating module, and to a sample solution conduit for transporting sample solution for extraction or testing.

[0024] In the heating channel, the flow unit is preferably configured such that the dissolution medium flow through the unit is perpendicular to the heating medium flow in the heating channel. This simplifies the positioning of the heating channel in the dissolution testing apparatus and the positioning of the flow unit within the channel.

[0025] However, the heating channel is also suitable for heating the dissolution medium used in other unit configurations of the dissolution test apparatus, such as filled containers rather than flow-through units.

[0026] In another embodiment of the dissolution testing apparatus according to the invention, at least one temperature sensor is provided in the heating channel and / or at one or more locations in the dissolution unit. For example, the temperature sensor may be located at the beginning and / or the end of an elongated portion accommodating the dissolution unit. The temperature sensor can provide real-time temperature monitoring of the temperature conditions in the heating channel and directly monitor the temperature in the dissolution unit, thereby enabling accurate dissolution testing.

[0027] Preferably, the dissolution testing apparatus according to the invention includes a control unit connected to at least one temperature sensor for controlling, for example, the heater and / or ventilator based on temperature measurements from the temperature sensor. Further, the control unit can control the dissolution medium heating module to adjust the input temperature of the dissolution medium to the dissolution unit. The control unit also controls the flow rate of the dissolution medium to ensure a constant and continuous input of the medium to the dissolution unit.

[0028] The dissolution testing apparatus according to the present invention improves the repeatability of dissolution quality assessment of soluble substances by ensuring compliance with testing requirements. The dissolution testing apparatus helps to provide consistent dissolution quality for dissolved substances, especially pharmaceuticals. Furthermore, due to the precise temperature setting of the dissolution medium, it provides predictive measurements of the effectiveness of API substances and other drug-based applications. Attached Figure Description

[0029] 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:

[0030] Figure 1: Overview of the operation modules of the dissolution test apparatus according to the present invention.

[0031] Figure 2: Internal view of the dissolution module of the dissolution test apparatus of Figure 1, including the dissolution medium heating module according to the present invention.

[0032] Figure 3: A three-dimensional view of the leaching medium heating module according to the present invention.

[0033] Figure 4a: Longitudinal view through the leaching medium heating module in Figure 3.

[0034] Figure 4b: The BB line in Figure 4a of the leaching medium heating module in Figure 3.

[0035] Figure 5: A schematic top view of the heating arrangement of the unit heating channel for the heating dissolution test apparatus according to the present invention.

[0036] Figures 6a to 6c: Schematic diagrams of three operating modes of the dissolution test apparatus: test mode, bypass mode, and cleaning mode.

[0037] Figures 7a and 7b: a side view and a schematic inner view of the flow unit used in the dissolution test apparatus of the present invention;

[0038] Figures 8a and 8b: Schematic diagrams of the open-loop and closed-loop configurations of the dissolution test apparatus according to the present invention. Detailed Implementation

[0039] Figure 1 illustrates the setup of the dissolution testing apparatus used in this invention. 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 described below. The dissolution module 1 houses several dissolution units designed as flow-through units 4, arranged in unit chambers 11 of the dissolution module 1. Each unit is filled with a soluble substance 5 (see Figures 7a and 7b). The dissolution medium is supplied to the flow-through units 4 via a dissolution medium heating module 6 located below the units in the dissolution module 1, as shown in Figure 2. After passing through the flow-through units 4, the dissolution medium, including the dissolved substance, leaves the flow-through units 4 as a sample solution containing the dissolution medium and the dissolved substance. The sample solution is transferred to the extraction module 2 via a sample solution conduit 7. In the extraction module 2, a defined small portion of the sample solution is extracted from the sample solution conduit 7 into a sample vial 8. Depending on the operating mode, the sample portion in the sample vial can be tested and returned to its respective unit, or the sample vial can be transferred to the sample module 3 for testing.

[0040] Figure 2 shows the interior of the dissolution module 1 of the dissolution testing apparatus of the present invention. A heating chamber 11 is formed above the dissolution medium heating module 6 for heating the dissolution medium before it enters the unit 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 unit holder 91 for keeping the flow unit 4 upright and aligned along the longitudinal axis, a connector rod 92 including a connector port for connecting the unit 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 unit 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 unit inlet 12 (see Figure 3). The connector rod 92 and the connector platform 93 extend spaced apart 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 create the unit chamber 11.

[0041] As shown in Figure 2, seven flow units 4 are located in unit chamber 11, such that the unit volume 10 (see Figure 7b) is fully exposed and accessible from each side through the walls of the flow unit, for example, for visual inspection and interaction with the environmental conditions present in unit chamber 11. Each unit includes a unit inlet 12 at the bottom and a unit outlet 13 at the top. The unit outlet 13 is in fluid communication with a sample solution conduit 7, delivering the sample solution to extraction module 2. The bottom of each flow unit 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 dissolution module 1. Each flow unit 4 is associated with a dissolution medium heating module 6, which are aligned adjacent to each other below the unit.

[0042] According to the present invention, multiple units are typically arranged in the heating channel 100, and the heater 101 is connected to the heating channel 100 to heat the gaseous heating medium in the heating channel, which will be described in more detail in FIG5.

[0043] Figures 3 and 4 illustrate the dissolution medium heating module 6 of 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 medium conduit circulating in a plane, for example, in a serpentine pattern. The heating loop structure 14 is connected to a dissolution medium reservoir 15 (see Figures 8a and 8b) via a pump device 60 for receiving the dissolution medium. The heating loop structure 14 includes a medium inlet 16 at one end and a medium outlet 17 at the other end for receiving and dispensing the dissolution medium.

[0044] A planar heating surface, in the form of a heating plate 18, is disposed near the heating circuit structure 14 for heating the dissolving medium within the heating circuit structure 14. For example, the heating plate 18 may have dimensions covering an area of ​​the two-dimensional heating circuit structure. Alternatively, two or more heating plates or other flat heating elements or plates may be used to cover the heating circuit area. The heating plate 18 may be, for example, a ceramic plate including an internal heating coil. Furthermore, silica or metal may be used for the planar heating surface.

[0045] 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 extraction module 2 of the dissolution test apparatus.

[0046] In the exemplary embodiments shown in Figures 3 and 4, 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 receiving the heating circuit structure therein. Further, the housing halves have an inlet through-hole 21 and a first outlet through-hole 22 and a second outlet through-hole 22', serving as medium conduits for media inlet 16 and media outlet 17 traveling to and from the heating circuit structure 14. The two housing halves can be screwed together to form the heating block 23 of the heating module 6.

[0047] 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 disposed through a through-hole 21 and is detachably connected to an external dissolution medium reservoir 15, for example, through an input port of the through-hole 21. The medium outlet 17 is incorporated into the medium outlet line 28, which enters the valve unit 30 (see Figures 6a to 6c), which can be attached to the housing. The valve unit 30 switches between parallel through-holes provided by a first through-hole 22 and a second through-hole 22'. The first through-hole 22 can be connected to the unit inlet 12 to supply tempering dissolution medium to the flow unit 4. The second through-hole 22' can be connected to a bypass conduit 31 to bypass the unit. Each through-hole 22 and 22' includes temperature sensors 33 and 34, respectively, for monitoring the temperature of the dissolution medium leaving the heating circuit structure 14. When the two housing halves are assembled to realize the heating block 23, the temperature sensor 33 / 34 and the pressure sensor 26 can be placed in the medium inlet line 27 and the through hole 22 / 22'.

[0048] 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 has a thin design, with the thickness measured on the two halves being 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 unit 4 of the dissolution testing apparatus without occupying a large space.

[0049] As explained in more detail in Figure 8a, the media selector 80 can be connected to the media inlet line 27 for selectively adding solvent to the dissolution media before the media enters the heating circuit structure, as described above. The media can be supplied to the inlet line 27 by the pump unit 60.

[0050] As shown in Figure 2, 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 unit inlet 12. Therefore, the heating module 6 can be easily replaced for maintenance.

[0051] Figure 5 illustrates the heating arrangement for heating several dissolution units 4 housed in unit chamber 11 of dissolution module 1. Unit chamber 11 is part of a heating channel 100 shared by all units 4. A heater 101 is disposed in the heating channel 100 for heating a gaseous medium, such as air or other gas, within the heating channel 100. A ventilator 104 is disposed adjacent to the heater 101 in the heating channel 100 for generating a flow of heated medium along the flow units 4 in the heating channel. In the example shown, the heating channel 100 is implemented as a heating channel loop, comprising a first elongated portion 102 and a second elongated portion 103. The first elongated portion 102 houses the unit chamber 11, which has multiple flow units 4, and the second elongated portion 103 houses the heater 101 and the ventilator 104. The first elongated portion 102 and the second elongated portion 103 are connected by a bend to realize the heating channel loop. Several flow units 4 are aligned along the longitudinal axis of the first elongated portion 102.

[0052] 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 and readily passes over the flat heating elements to be heated. A set of guide plates 105 are located upstream of several units 4 to support laminar flow in the units along the first elongated portion 102 of the heating channel 100. Further guide plates may be located at curved portions of the heating channel to support laminar flow along the heater 101 and the ventilator 104.

[0053] Furthermore, the heating channel 100 includes a fluid channel (not shown in FIG. 5) for a dissolution medium conduit, which is used to fluidly connect to the flow unit 4, for example, a medium outlet line 28 for the heating module 6 or an inflow conduit 40 connected to the unit inlet 12 to transfer the dissolution medium into the unit 4, and an outflow conduit 41 or a sample solution conduit 7 for transferring the sample solution from the unit outlet 13 to the extraction module 2.

[0054] Figure 2 shows the interior of the dissolution module 1 of the dissolution testing apparatus according to the present invention. A heating chamber 11 of the heating channel 100 is realized above the dissolution medium heating module 6 for heating the dissolution medium before it enters the unit 4. The unit chamber 11 and the heating channel 100 are formed on the assembly structure 90, connector rod 92, connector platform 93, and housing side of the dissolution module 1, respectively. The heater and ventilator can be located on the back of the assembly structure 90.

[0055] In the region of the elongated portion 102 of the heating channel 100 representing the sample chamber 11, the dissolution module 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 unit chamber 11 to position the flow unit therein and connect it to the connection port. The unit is surrounded by a flow of heated medium, and the flow of the dissolution medium through the unit is perpendicular to the heat flow in the heating channel 100, thereby enabling uniform exposure to heated air.

[0056] Initially, the dissolution medium is rapidly and efficiently heated to the desired temperature by the heating module 6, while simultaneously flowing to the flow unit 4. The heating circuit structure 14 of the heating module 6 is arranged in series with the dissolution medium flow between the dissolution medium reservoir 15 and the flow unit 4, wherein the medium flow is generated by a pump device. That is, the heating module 6 and its associated unit 4 are arranged in series. The dissolution medium is then maintained at the temperature reached by the heating module 6 while the heated medium flow passes through the unit 4 via the heating channel 100. This setup ensures a precise and continuous flow of the medium through the unit at a predetermined constant temperature, enabling flexible and predictable dissolution tests for soluble substances.

[0057] However, the dissolution testing apparatus of the present invention does not depend on the heating module 6. Once the dissolution medium enters the dissolution unit, the heating medium flow in the heating channel 100 provided by the present invention can easily heat the dissolution medium. Several units are typically exposed to the heated flow, and the dissolution medium in all units is uniformly heated.

[0058] Figures 6a to 6c illustrate different operations of the dissolution test apparatus of the present invention, schematically showing the flow of the dissolution medium through the dissolution medium heating module 6 and the heating channel 100.

[0059] The common heating channel includes at least one temperature sensor 106 in a first elongated portion 102 of the heating channel 100, the first elongated portion 102 accommodating several flow units 4. Further temperature sensors may be located, for example, at or near at least one flow unit 4, and within the area of ​​the heating channel accommodating the ventilator 104. The control unit of the heating channel and / or the controller of the dissolution testing apparatus can 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.

[0060] 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 test apparatus. For example, at least one temperature sensor may be provided to monitor the temperature of the dissolution medium as it flows through the heating module. The temperature sensor may be located, for example, at the medium inlet line 27. The temperature sensor 33 may be located, for example, at the medium outlet line 28. Furthermore, at least one pressure gauge 35 or pressure sensor may be provided, for example, in the medium inlet line 27 and / or the medium outlet line 28, to provide pressure measurement for controlling the pump 60. The control unit 29 controls the operation of at least one heating plate 18 of the heating module 6 and the pump, as described below.

[0061] As previously described, the dissolution medium is supplied by the medium inlet line 27 and enters the heating circuit 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, located in the medium outlet line 28, distributes the dissolution medium to either the inflow conduit 40 or the bypass conduit 31 connected to the unit inlet 12. A temperature sensor 34 measures the temperature in the bypass conduit 31. In the heating channel 100, the dissolution medium, heated by the heating module 6, flows through the flow unit 4 and dissolves the soluble substances 5 therein, resulting in a sample solution containing the dissolution medium and a portion of the dissolved substances. The sample solution exits the flow unit 4 through the unit outlet 13 and enters the outflow conduit 41. The outflow conduit 41 and the bypass conduit 31 terminate at the bypass valve 32, from which the medium flow continues into the sample solution conduit 7 towards the extraction module 2 and / or the sample module 3.

[0062] In Figure 6a, the dissolution testing apparatus operates in test mode, wherein the heated dissolution medium is transferred from the dissolution medium heating module 6 to the flow unit 4 in the heating channel 100. The temperature in the flow unit 4 is maintained or regulated in the heating channel while the soluble substance dissolves into the dissolution medium. The 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 tests, or it can be guided to the extraction module 2 to extract the sample solution into the sample container 8 for testing.

[0063] In Figure 6b, the dissolution test apparatus operates in bypass mode, where a diversion valve 30 directs the dissolution medium from the medium output 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 unit is blocked, or in the event of any other malfunction of the dissolution test apparatus. A bypass valve 32 directs the dissolution medium from the bypass conduit 31 into the sample solution conduit 7, from where the dissolution medium can be discarded or returned to the dissolution medium circulation system.

[0064] In Figure 6c, the dissolution test apparatus is operating in cleaning mode, where the flow unit has been removed from unit chamber 11. Dissolution medium or cleaning medium can be used to clean the conduits of the dissolution test apparatus. 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 unit 4, and outflow conduit 41. Bypass valve 32 guides the medium into sample solution conduit 7.

[0065] Figures 7a and 7b show the flow unit 4, which can be used as an assembly top view and schematic internal view of the present invention. The flow unit 4 includes a unit volume 10 having a generally cylindrical shape and predefined dimensions. The unit volume 10 tapers towards its bottom end, which includes a unit inlet 12, and opens at its top end. Soluble material 5 is placed in the unit volume 10. When required by the test method used or the shape of the soluble material, a holding structure such as a basket, bead bed, or the like can be used within the unit volume to space the soluble material from the bottom. A closing ring 50 with a central through-channel and a holder for a filter 51 is placed at the top opening of the unit volume 10. The filter 51 can be selected according to the test requirements of the soluble material being tested. A cover 52 including a unit outlet 13 is mounted on the closing ring 50 to close the unit volume 10 and hold the filter 51 in place. Alternatively, the closing ring 50 and the cover 52 can be implemented as a single piece, wherein the filter 51 can be set in the single piece before the single piece is mounted on the unit volume.

[0066] The unit volume 10 is made of, for example, glass or plastic material, which is inert relative to the soluble substance, and includes a transparent wall for observing the dissolution process. The unit volume 10 does not require placement in an additional container known in the art for providing a heating device on the unit. The flow unit 4 has a simple design and facilitates the preparation of soluble substances for testing.

[0067] 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 temperature at the dissolution volume, cell position, and flow through the cell. 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.

[0068] Figures 8a and 8b illustrate the test methods using the open-loop and closed-loop configurations of the dissolution test apparatus of the present invention.

[0069] In the open-loop configuration shown in Figure 8a, fresh dissolution medium is supplied by one or more medium reservoirs 15 provided by a medium selector and pumped to flow unit 4 by a medium pump 60. The dissolution medium flows through heating module 6, is heated to a preselected temperature, and enters flow unit 4 in heating channel 100. The dissolution medium flows through flow unit 4, passing through soluble substance 5 to form a sample solution. The sample solution flows from flow unit to bypass valve 32, which guides the sample solution to extraction module 2 or waste conduit 61. In extraction module 2, a portion of the sample solution is extracted into sample vial 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 medium volume is infinite. The dissolution medium heating module 6 and heating channel 100 provided by the present invention can be advantageously used to heat the flow of fresh dissolution medium. Over time, soluble substance decreases, and less substance dissolves into the medium. Therefore, the measured dissolution rate is represented by a differential curve over time, showing a decreasing dissolution rate.

[0070] The closed-loop configuration shown in Figure 8b is used in conjunction with a fixed volume of dissolution medium provided by dissolution medium reservoir 15. The dissolution medium is recirculated several times through flow unit 4 and the soluble substance. A test apparatus 70, such as a UV spectrophotometer, can be set online for testing the sample solution while it circulates within the apparatus. 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 rate is represented by a cumulative curve over time, where the dissolved substance accumulates in a fixed volume of medium over several cycles.

[0071] In summary, the dissolution testing apparatus according to the present invention provides accurate and reproducible temperature conditions for simulating in vivo conditions of all forms of soluble substances listed at the outset. The dissolution testing apparatus allows for easy modification of unit types without altering the heating system. The dissolution medium heating module and heating channel within the dissolution module can be used for various types of dissolution units. The dissolution testing apparatus enables universal and automated dissolution testing and supports accurately predictable test results.

[0072] The dissolution testing apparatus according to the present invention allows for precise and repeatable measurement of the dissolution rate and amount of soluble substances in a component, 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 reliably assesses batch-to-batch consistency. Furthermore, it plays a significant role in product compliance and market launch decisions.

[0073] Reference Number List

[0074]

Claims

1. A dissolution testing apparatus for dissolving a soluble substance in a dissolution medium, the dissolution testing apparatus comprising at least one reservoir (15) for the dissolution medium, a plurality of dissolution units (4), each designed to contain the soluble substance to be tested, and a pump device for adding the dissolution medium to the units (4), characterized in that, The plurality of units (4) are arranged in a common heating channel (100), wherein a heater (101) is connected to the heating channel (100) and is used to heat the gas heating medium in the heating channel (100).

2. The dissolution testing apparatus according to claim 1, characterized in that, A ventilator (104) is provided in the heating channel (100) for forming a heating medium flow along the unit (4).

3. The dissolution testing apparatus according to claim 1 or 2, characterized in that, The heating channel (100) is implemented as a heating channel loop, which includes a first elongated portion (102) accommodating the plurality of units (4) and a second elongated portion (103) accommodating the heater (101).

4. The dissolution testing apparatus according to any one of the preceding claims, characterized in that, The heater (101) includes a plurality of flat heating elements arranged along the longitudinal axis of the heating channel (100) in the heating channel (100).

5. The dissolution testing apparatus according to any one of the preceding claims, characterized in that, The guide plate (105) is located at least upstream of the plurality of units (4) to support laminar flow along the units.

6. The dissolution testing apparatus according to any one of the preceding claims, characterized in that, The control unit is connected to at least one temperature sensor (106) in the heating channel (100) and / or at least one unit (4) for controlling the heater (101) and / or the ventilator (104).

7. The dissolution testing apparatus according to any one of the preceding claims, characterized in that, The plurality of units (4) are aligned along the longitudinal axis of the elongated portion of the heating channel (100).

8. The dissolution testing apparatus according to any one of the preceding claims, characterized in that, The unit (4) is implemented as a flow unit, which includes a unit inlet (12) for a dissolution medium and a unit outlet (13) for a dissolution medium containing a dissolved substance, wherein the flow unit is arranged in the heating channel (100) such that the dissolution medium flow through the unit (4) is perpendicular to the heated medium flow in the heating channel (100).

9. The dissolution testing apparatus according to any one of the preceding claims, characterized in that, The heating channel (100) includes a fluid channel for a dissolution medium conduit, the fluid channel being fluidly connected to the unit inlet (12) for supplying the dissolution medium to the unit (4).

10. The dissolution testing apparatus according to the preceding claims, characterized in that, The dissolution medium heating module (6) is configured as a flow module connected in series with the dissolution medium storage (15) outside the heating channel (100) and the dissolution unit (4) inside the heating channel (100).

11. The dissolution testing apparatus according to any one of the preceding claims, characterized in that, The elongated portion of the heating channel (100) includes an opening along the length of the elongated portion and a cover for closing the opening to provide access to the plurality of units (4).

12. The dissolution testing apparatus according to any one of the preceding claims, characterized in that, The heating channel (100) is integrated into the dissolution module (1) of the dissolution test device.

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