EP2217920A1

EP2217920A1 - Device and method for automatically releasing and measuring active ingredients of a pharmaceutical preparation

Info

Publication number: EP2217920A1
Application number: EP08858072A
Authority: EP
Inventors: Werner G. Müller; Levent Bozkurt
Original assignee: Erweka GmbH
Current assignee: Erweka GmbH
Priority date: 2007-12-06
Filing date: 2008-10-15
Publication date: 2010-08-18
Also published as: DE102007058718A1; WO2009071380A1

Abstract

The invention relates to release test device and a method for automatically releasing and measuring active ingredients of a pharmaceutical preparation, comprising one or more release unit(s), each comprising one or more test station(s) having test containers for accommodating release samples, stirrers that are associated with the test stations for stirring the release samples, and one or more means for heating the test containers, and a computer unit, wherein the release test device further comprises at least one program-controlled industrial robot having at least one gripper, and the release unit(s) and means for storing the release samples to be tested and/or the tools of the industrial robot are disposed within reach of the industrial robot.

Description

Apparatus and method for the automatic release and measurement of drugs from a drug preparation

The invention relates to an automatic release test device and to a method for measuring the release of active substances from a pharmaceutical preparation.

With the help of release test devices, the release of a substance from a drug preparation in a solution is measured. Substances to be dissolved out of medicaments in question which can be present, for example, in tablet form, as a capsule, granule or dragee, are particularly suitable substances to be dissolved out.

Analytical methods for evaluating the release (dissolution, dissolution) of drug formulations have been introduced by the regulatory authorities of the pharmaceutical industry to describe release profiles of some specific formulations. Today, for quality control and regulatory purposes, such methods are used in most formulations. Furthermore, release tests are used in the development of new formulations to determine the rate of release of the active compound from the formulation and other parameters related to efficacy, to establish optimal dosage forms, and to produce in vitro / in vivo correlations.

As a rule, several tablets are tested simultaneously, so that release test devices have a plurality of test vessels, in each of which one tablet is dissolved.

In order to replicate the dissolution of a tablet, as is done, for example, in the stomach as realistically as possible, the test vessels are filled with a gastric fluid and heated to body temperature. The heating can be done by placing the test vessels in a water bath the desired temperature can be introduced. The water bath is usually controlled by means of an external water pump and a heater.

Previously known release test devices have a flushing station, a test stand and a movable device which contains a plurality of measuring containers in a water bath. The rinse has a paddle for each test container, which is drivable in the direction of rotation and raised and lowered in the vertical direction, all paddles are also driven in the direction of rotation and for stirring the liquid in the containers, the substance to be examined in terms of its dissolution behavior contain, can be lowered into the measuring container. Furthermore, in such a known release test device, a suction tube is provided for each measuring container which, together with the provided paddle, can be immersed in the liquid containing the substance to be examined. The paddles are lowered into the measuring containers in order to uniformly stir a liquid into which the substance to be investigated is introduced at a certain time. After a certain stirring time, the liquid is sucked out of the measuring containers by means of the suction tubes. After such a cycle, it is necessary to replace the filters at the tips of the suction tubes with new filters. As a further development, EP 0 343 261 B1 discloses a device with a filter wiper device, with which the changing of filters between different measuring cycles is facilitated and also automated.

On the other hand, it was still necessary, in the case of devices for testing release samples, in particular, to carry out the removal and recycling of volume fractions of the release samples with the help of an operator. This operator is responsible, for example, for the required positioning of sampling tubes of a sampling device in each test container of a release test device, the positioning of the sampling tubes of the sampling device depending on the type of stirring tool and the liquid level of the release sample. Therefore, EP 0 779 506 B1 has described a release test device with a plurality of test containers for receiving release samples, wherein a frame is attached to the Housing is arranged adjustable in height and a motor is provided in the housing, which moves the frame and thus the removal tubes on the input data on the level and the stirring element programmatically in the respective working position. EP 1 373 859 B1 also describes an apparatus for testing the dissolution of products having a multiplicity of test vessels with stirring elements and a dose delivery mechanism.

In the above-mentioned known release testing apparatus, a plurality of operations must continue to be performed by an operator. This fact adversely affects the repeatability and comparability of the analyzes carried out.

It was therefore the object to provide a release test device, which allows an automatic, yet flexible release test and guarantees a continuous and reproducible process.

This object is achieved by a release test device for the automatic release and measurement of active ingredients from a drug preparation, the device comprising one or more release units, comprising in each case one or more test stations with test containers for receiving release samples, agitators assigned to the test stations for stirring the release samples, and one or more means for heating the test containers and a computer device, preferably for storing measurement data and predetermined parameters, wherein the release test device further at least one program-controlled handling device, preferably a program-controlled industrial robot having, the industrial robot at least has three degrees of freedom and at least one gripper, and within range of the industrial robot, the release unit (s) and means for storage for the release samples to be tested and / or are arranged for storing tools of the industrial robot. The terms release test device, dissolution test device and dissolution test device are used interchangeably for the purposes of the present invention, as are the terms release sample, dissolution sample and dissolution sample, which are the pharmaceutical preparations to be tested.

For the purposes of the present invention, a release sample can be any preparation of a drug. In particular, solid and semisolid dosage forms, such as, for example, powders, powders, granules, tablets, dragees, capsules, effervescent tablets, pills or suppositories, can be tested as release samples.

For the purposes of this invention, a basket is a stirring element in the form of a cylindrical basket, for example of stainless steel or other inert material, which may be provided with a gold coating. The lateral and lower part of the basket is designed as a sieve.

For the purposes of this invention, paddles are blade stirrers made of stainless steel or other inert material, which may be provided with a gold coating.

For the purposes of this invention, a sinker is understood to mean an agent which is deposited at the bottom of a test vessel and with the aid of which the release sample to be examined is held in the test medium. This is especially necessary if the release sample would otherwise float due to its physical properties. As a sinker, for example, Japsinker or Spidersinker can be used.

In an advantageous embodiment, within reach of the handling device, which is thus preferably designed as an industrial robot, one or more removal device / s for taking samples from the test containers, at least one means for medium filling the test container and / or one or more suction and / or cleaning nozzle / s arranged for emptying and / or cleaning the test container. It is particularly advantageous if the industrial robot preferably has four to six degrees of freedom. This achieves high flexibility and flexibility. Furthermore, it is advantageous if the gripper is a pneumatic gripper. Special stability can be achieved by attaching the industrial robot to a pedestal anchored in the ground. Alternatively, the industrial robot can also be attached to a stable frame.

The release test device according to the invention thus represents a fully automatic robot release system which, if required, can also meet the quality standards for medicaments according to the United States Pharmacopeia (USP), European Pharmacopoeia (EP) and Japanese Pharmacopoeia. The corresponding pharmacopoeias are largely harmonized, so that the USP methods herein are each representative of all quality standards.

This device can integrate several, preferably up to two, dissolution test devices each having eight test sites and, in particular, process the USP methods 1 and 2 fully automatically and enable the fully automatic use of sinkers. The system can work with the USP method 2, ie with a paddle, or according to USP method 1, ie with a basket. Any other methods can be processed with the device mentioned. In particular, the programmability of the industrial robot makes it possible to adapt the device and the method to new or changed methods if necessary. The industrial robot can take over one, several or all working steps and thus guarantee a continuous and repeatable process. In order to ensure the safety of the operating personnel, the complete system is preferably housed in a frame, for example an aluminum profile frame. The accessibility of the devices can be ensured via side hinged doors. For this purpose, the industrial robot can preferably have a hardware interface, in particular a suitable interface for Ethernet, USB, RS232 or the like, preferably controlled by an absolute position measuring system, and can, for example, be controlled by Teaching be set. The named gripper is designed in such a way that it can execute one or more work steps necessary for the test. A suitable extension finger may allow better accessibility.

Applicable for the purposes of this invention are all types of robots, especially linear, SCARA and articulated robots. The robot picks up the appropriate tools for performing the release tests with its gripper and performs the release test. The steel platform for the robot is preferably anchored in the ground to absorb the resulting moments and not transmit the vibrations to the release device.

According to an advantageous further development of the release test device according to the invention, at least one water bath, each with a flow heater for heating the test containers of the test stations, is mounted on the frame. Alternatively, the test vessels can be heated by any other suitable method. The water bath can be made of plastic. The heater and the water bath can be connected with suitable couplings and hoses. The temperature of the water bath can be done with the help of a water heater. A water heater can alternatively be used for the heating of several water baths. The heater is preferably connected to the release test device via a serial interface.

Furthermore, it is advantageous if at least one horizontal worktop is provided.

Furthermore, it is advantageous that the stirrers of the individual test stations are sequentially switchable, preferably electrically by means of an electric motor or pneumatically. The stirrers of a release unit can be driven by a common electric motor. Thus, the test vessels can be stirred independently, but still the same speed is guaranteed for all agitators. The stirrers can be connected to each other with toothed discs and timing belt, and it is also advantageous if the switched stirrers are coupled with a clutch to the speed control.

In an advantageous embodiment of the release test device according to the invention, the test stations are arranged in one or more rows with eight test stations each. It is particularly advantageous if the test stations are arranged in two substantially parallel rows, each with eight test stations, and the industrial robot is arranged between the two rows. Of course, in the sense of the release device according to the invention, any number of test stations in any patterns, such as circular, semicircular or in triangles and / or in different planes one above the other, be arranged. All mechanical and electrical drive parts of the agitator are preferably housed below the worktable. The water bath and the drive arms of the agitator, however, are arranged above the work table and provide good accessibility of the industrial robot and / or the operator.

It is also advantageous if the test stations are assigned external temperature sensors for the temperature measurement in the test container. The test containers are preferably made of glass and meet the requirements of USP and EP. The control of the agitators, in particular the speed, preferably takes place via a controlled by a microprocessor board. The date and time can be recorded with a real-time clock on the board.

Within reach of the industrial robot is at least one collecting container for stripping sinkers, which is equipped with a light barrier for checking this step. The medium filling means may in the simplest case be at least one tube. This is preferably connected to a device for medium dosing. The medium filling of the test container is preferably carried out gravimetrically. For this purpose, the device for medium metering may consist of at least one pump and one balance. For example, a single-channel be provided hose pump, a balance and a reciprocating pump. The test medium itself can be made manually and stored in a, preferably acid-resistant, storage container.

In the course of a further development of the device according to the invention, an automatic production of the test medium from individual components, degassing, temperature control and / or metering can also be integrated into the device. Optionally, the test medium can also be preheated. Likewise, a pH measurement with pH meters can be carried out in the storage container. The degassing of the medium can be achieved by vacuum and / or by heating and stirring of the medium. The dosage of the test medium is achieved by means of a single-channel peristaltic pump, a balance and a reciprocating pump. The medium is pumped by the hose pump from the storage tank into an intermediate tank on the balance. From this, the reciprocating pump extracts and delivers the predetermined amount into the test vessel, introducing the medium to the glass wall to minimize air pockets. The amount withdrawn is checked by means of the balance. The peristaltic pump is used as a reservoir pump for filling the intermediate container on the balance, wherein preferably a single-channel peristaltic pump with analogue minus interface is used. As a filling pump for filling the test glasses, a wobble piston pump with an interface is preferably used. For gravimetric dosing a suitable calibratable balance with an interface can be used. The intermediate container may preferably consist of acid-resistant material and have an inlet and an outlet opening. The steps of preparing the test medium may be performed by equipment that operates independently of, but preferably in the immediate vicinity of, the industrial robot.

In an advantageous embodiment of the release test device according to the invention, the means for storing the release samples to be tested is a tablet magazine for storing tablets and / or granules. Especially for release tests according to USP method 2 (with paddle) For example, a magazine with a plurality of, for example 60, storage containers per release device can be provided, the tablets or granules being stored therein and being filled by the robot one after the other into the test stations. Optionally, the release samples may also be stored in sinkers. Against moisture, the specimens are protected with a lid. These lids must be stripped before being dropped into the test containers and collected in a container.

Furthermore, it is advantageous if the means for storing the tools are one or more magazines for the storage of just unused paddles and / or baskets. Furthermore, it is advantageous if strong magnets for holding and centering the paddles or Baskets are attached to the stirring rods of the agitator. The paddles or baskets can be removed from the robot and inserted into the stir bar. Stirring tools are held in position and centered by strong magnets in the stir bar and paddle or basket. The exchanged stirrers are returned to the magazine by the robot.

The sampling devices associated with the test stations for simultaneous sampling and temperature measurement are preferably combined jets. This results in the removal position and removal height from the specifications of USP or EP. The temperature is measured during sampling in the test glass with a probe. The necessary filtration is carried out optionally with a suitable filter, preferably a Poroplast filter, or with a frit, preferably a glass frit. The sampling tube is preferably made of stainless steel. The filters preferably have a porosity of 5 to 10 microns. A filter magazine can accommodate a variety of filters, for example, more than 100, new filters and in a collection container, the spent filter can be collected. Alternatively, glass frits can be used for filtration, preferably with a porosity of about 10 μm, whereby the frits can be cleaned for reuse in an ultrasonic bath. In an advantageous further development, the filter change takes place by a separate filter changer automatically, so that this step does not have to be performed by the industrial robot.

Particular advantages result in a variant in which the release test device contains a fraction collector and / or an analytical device. In this case, the analysis device may preferably be a UV / VIS spectrometer, an IR spectrometer, an HPLC, an NMR, a GC-MS and / or a diode array spectrometer. Particularly preferably, the analysis is carried out in the flow-through method and / or directly in the test container. Flow measurements can be made, for example, in a flow cell. The direct measurement in the test container, preferably with fiber-optic spectroscopy, via optical fibers. The latter possibility has the advantage that no sample must be taken and no time delays in the measurement occur. Each test vessel can be assigned a suitable spectrometer or several test vessels can be analyzed simultaneously with a multichannel spectrometer.

The samples can be transferred to the analytics devices with a start signal and the results can be received with a return signal. In the online or offline system, the samples can be measured online in the HPLC or UVA / IS with optical fiber or flow cell or collected in the fraction collector and later measured. The withdrawal and return hoses are filled with medium or demineralized water from the corresponding templates.

Using valves and a syringe, a sample or solution of calibration and control standards can be drawn. The valves can now be used for online or offline tests. The test medium or a calibration standard is conveyed and measured or collected by means of the valves through a UVA / IS cuvette or alternatively via a Rheodyne valve in the HPLC apparatus or in a fraction collector. For the purpose of a medium back supplement, medium can be drawn up with a syringe and the withdrawn amount can be supplemented back again via the valves. An optional evaporation compensation can be achieved by eliminating possible evaporation of the medium with the help of a syringe and a valve. will become. In this case, deionized water is filled in the required amount in the test container.

For an advantageous further development of the release test device according to the invention, the latter has an emptying pump, which is connected to suction and cleaning nozzles for emptying and cleaning the test containers. For the purpose of sucking and cleaning after the end of the test, the old medium with the aid of a suction and cleaning nozzle and the robot is sucked or cleaned. For this purpose, the nozzle is shut down to the glass bottom and sucked with a peristaltic pump. At the same time, the glasses and paddle can be cleaned with hot water. As a drain pump for emptying the test glass, for example, a Einkanalschlauchpumpe with interface, a plastic hose, such as Norprene hose can be used. With the help of a water heater, the test station can also be cleaned with hot water if necessary. With a valve in the outflow, the extracted residual media can be collected separately from the cleaning fluid.

It is also advantageous if the test stations are assigned one or more cameras for monitoring. The video cameras may, for example, be arranged on the worktop in spatial proximity to the individual test stations.

Further, it is advantageous if all mechanical and electrical drive parts are arranged below the work table and the water bath with the test stations, the industrial robot and the drive arms of the agitator substantially above the work table.

Furthermore, it is advantageous if a plurality of components of the release device are integrated in the system via an interface.

An advantageous further development of the device according to the invention enables a particularly rapid performance of the release test. For this purpose, above the test vessels, a suitable stage is movable or stationary positive. oniert. Such a platform can preferably accommodate a plurality of sampling means, so that a simultaneous sampling can take place from several or all test vessels. Such a stage may alternatively or additionally accommodate any further means, for example probes for surveying. The stage can preferably be brought by the industrial robot in the desired position over the test vessels. It is particularly advantageous if the stage can be locked above the test vessels, since the industrial robot is then available for further independent steps. Optionally, several such platforms may also be present for replacement. The advantage of one or more such stages arises from the possibility to process several test vessels at the same time. In the course of a further advantageous embodiment variant, a tablet magazine can be arranged above an above-mentioned stage, which is equipped by the industrial robot. The release samples can then pass from the tablet magazine, preferably through appropriate passages in the stage, in the test vessels. When using the said stages, the cleaning and filling and / or emptying of the test vessels and the movement of the stages can be carried out by the industrial robot. For the purposes of this invention, any work steps that can take place in parallel in several test vessels can be carried out with the aid of appropriate stages.

It is also advantageous if one or more or all components of the release test device are arranged in at least one frame. Such a frame may consist of one or more, in particular two, interconnected frame and a separate switching PC cabinet. The computer device for storing measurement data and predetermined parameters can be accommodated in the switch PC cabinet or alternatively also in the frame of the release test device itself. Thus, the entire frame may for example consist of three components: a first frame, a second frame and a switching PC cabinet. Furthermore, adjustable feet can be provided for adjusting the frame and for absorbing the vibrations. To secure the work area can Plastic folding doors and a positive opening safety switch must be provided.

The two frames may preferably be coupled together to the one frame and provided with shelves to accommodate all peripherals. The work table should be disconnected from the frame so as not to transmit the robot's vibrations to the release device.

For the purposes of the present invention, a method for automatic release testing in temperature-controlled test containers of a release test device, the method comprising at least the following steps:

Dosing a test medium into the test containers,

Inserting release samples into the test containers or inserting the release samples in sinkers into the test containers;

Stirring of the test medium in the test container by means of rotating agitators;

- Sampling and / or analysis and

- emptying and / or cleaning the test containers,

wherein at least one of said steps is carried out with the aid of a program-controlled handling device, preferably an industrial robot with at least three degrees of freedom and with at least one gripper.

It is particularly advantageous if the industrial robot preferably has four to six degrees of freedom. Furthermore, it is advantageous if the gripper is a pneumatic gripper. The industrial robot can preferably be controlled via an absolute path measuring system. A particularly simple change of method can be achieved by holding and centering the paddles or baskets on the stirring rod of the agitator via strong magnets. You can use USP method 2 (paddle) or USP method 1 (basket). Alternatively, the use of sinkers for floating DUTs is possible. All paddles can be stopped in the same position to facilitate handling by the robot. On Switching between methods, such as paddle or basket, is automatically possible.

The sinkers are inserted with the robot into the glasses and brought out again with strong magnets, stripped into a collecting container and checked with a light barrier, whereby the sinkers are made of stainless steel and can be slightly magnetic. The test vessels are covered in the working position of the agitators (shut down) by a lid with silicone gasket to minimize evaporation. An evaporation compensation can be dispensed with if the evaporation from the vessel over 24 h is less than 1%. The device can be checked with USP tablets at any time and complies with the USP specifications. A device inspection using a QA station for Quality Assurance purposes can be performed separately for each station. An automatic device check for paddle height, speed, vibration and centering is possible on an ongoing basis. All product-contacting parts are preferably acid and vapor resistant. The test glass is preferably made of borosilicate glass, the stirring tools and the stirring rod are made of stainless steel, optionally with additional coatings, the housing is preferably powder-coated and all aluminum parts are anodized. All materials can be selected according to the requirements of the tests to be performed.

According to the method of the invention, the samples are measured by spectroscopic and / or chromatographic methods, preferably in HPLC or UVA / IS with optical fiber or flow cell, online or collected in a fraction collector and measured later. If the samples are to be taken for analysis, it is also possible to measure the temperature at the time of removal by means of a combination nozzle. But even with the in situ measurement, a temperature determination or the recording of any other parameters can be carried out simultaneously.

This method can be carried out particularly advantageously if the test stations are monitored by video cameras. Furthermore, it is advantageous if the resolution of the video cameras is recorded in fast motion. that can. Furthermore, it is advantageous if the temperature measurement in the test vessel is carried out with an external sensor.

The switching PC cabinet can house the power supply, the robot controller, a PC, a keyboard and / or a monitor.

All components integrated in the device are integrated in the system via an interface and can be exchanged for an alternative device if required.

The operation of the release test device is preferably carried out via a PC software. For this purpose, it is advantageous if a computer program with program code is provided for carrying out all method steps described herein, when the program is executed completely or partially in a computer. Also of advantage is a computer program with program code which is stored on a machine-readable carrier for performing at least one of the method steps described herein when the program is executed in a computer.

Further advantages and details of the method according to the invention and the device according to the invention are described below with reference to the drawings for some embodiments. Show it:

1 shows a release testing device 1 according to an embodiment variant with an industrial robot 10, a frame 20 and a release unit 30,

2A release test device 1 according to an embodiment of an industrial robot 10, with two frames 20, 21 and two release units 30,

2B shows a switching and PC cabinet 22, 3A, B release unit 30 with eight test stations 32 in front view and in side view,

3C release unit 30 with eight test containers 33 with the industrial robot 10,

4 water bath 50 for heating the test stations 32,

5 shows a dosage arrangement 60 for gravimetric medium filling,

6 is a schematic representation of a tablet magazine 70,

7A tablet insertion with the industrial robot 10,

FIG. 7B shows the procedure of inserting a sinker 35 with the industrial robot 10 into a test container 33, FIG.

8 shows the attachment or removal of a basket 34 by the industrial robot 10 to a stirring bar 39, FIG.

9 shows the temperature measurement and sampling from a test container 33 by the industrial robot 10,

10 a schematic representation of a filter magazine 90 with collecting container 91 for filter 92,

Fig. 11 schematic representation of the sampling for the analysis and

Fig. 12 the suction and the cleaning after the test end with a

Extraction and cleaning nozzle by the industrial robot 10. 1 shows a variant embodiment of the release test device 1 with an industrial robot 10, a release unit 30 with test stations 32, a frame 20 for receiving a tablet magazine 70. The industrial robot is placed on a pedestal anchored in the floor and placed in the center of the frame. The frame 20 may be followed by another frame, not shown in the drawing, with a release unit 30. Thus, a total of sixteen test stations can be operated by the industrial robot 10. On the side hinged doors 3, the accessibility of the equipment is guaranteed from the outside. The industrial robot used in this embodiment variant has a range of approx. 600 mm, a repeat accuracy of +/- 0.02 mm, an interface for Ethernet, USB or RS232 and is controlled with an absolute position measuring system. The rotation angle is approx. 270 ° and the adjustment is done by teaching. The gripper 2 can perform all necessary steps for the test. The industrial robot 10 takes with its gripper 2 the corresponding nozzles, tubes or containers u. Ä. And performs the release test.

Fig. 2A shows a release test device 1 with a centrally located industrial robot 10, two oppositely disposed release units 30, each housed in a frame 20, 21. The test stations 32 are shown with the respective test vessel 33, a camera 37 for monitoring and the agitator 31. Below a work surface 38 are a heater 51 for the water bath shown in Fig. 4, a media tank 61 and for filling the test vessels 33, a peristaltic pump 62, a balance 63 and a piston pump 64th

According to FIG. 2B, a PC 23, a keyboard 25, a monitor 24, and a power supply and robot control, not shown in the drawing, are accommodated in a switching and PC cabinet 22 arranged directly next to the frame 20 or 21.

The release test device 1 may consist of one or two interconnected frames 20, 21 for receiving all devices and the switching PC Cabinet 22 exist. For this purpose, within the frame or within the frames, in particular magazines, robotic handling parts, analytical accessories, video cameras 37, one or more heaters, one or more release test devices 30 and / or pumps for metering the test medium can be accommodated. The computer device for storing measured data and predetermined parameters can be accommodated in the switching PC cabinet 22. Thus, the entire frame may consist of three components: a first frame 20, a second frame 21 and a switching PC cabinet 22. The two frames are preferably so wide that they pass through a 90 cm wide door and are made of aluminum Profiles produced. For this purpose, for example, aluminum profiles, which are naturally anodized, can be used. Furthermore, adjusting feet 26 may be provided for adjusting the frame 20 and for absorbing the vibrations. To protect the work area folding doors 3 and a positive opening safety switch can be provided. The work table 38 should be decoupled from the frame so as not to transmit the vibrations of the industrial robot 10 to the release devices 30.

According to FIGS. 3A-C, a release unit 30 with eight test stations 32 each is shown on a work surface 38. Below the work surface 38 are a heater 51 for the water bath shown in Fig. 4, a media tank 61 and for filling the test vessels 33, a peristaltic pump 62, a balance 63 and a piston pump 64. In Fig. 3C, a stirrer 31 is engaged, whereas the remaining seven agitators 31 are in the up position and thus disengaged. According to FIG. 3C, the industrial robot 10 is shown within reach of a release unit 30. A second release unit 30, which is not shown in the drawing, can likewise be arranged within reach of the industrial robot 10.

According to FIG. 4, a water bath 50 with flow-through heating 51 and an inlet and a drain for heating the test containers 33 of the test stations 32 are provided. The water bath 50 here consists of acrylic glass and can hold about 30 l of water. The heater 51 and the water bath 50 are equipped with quick Couplings and silicone tubes connected. The heater 51 may be a water heater. The heating time of 20 ⁰ C to 37 ° C for example, can be a maximum of 20 minutes. The water bath should be tempered with an accuracy of +/- 0.1 ⁰ C. The heater 51 is connected to the release tester 30 via a serial interface.

According to FIG. 5, the medium filling of the test containers 33 is carried out gravimetrically. For this purpose, a single-channel hose pump 62, a balance 63 and a filling pump 64, for example a reciprocating piston pump, are arranged on the frame. The dosage of the test medium is realized with the aid of the single-channel hose pump 62, the balance 63 and the reciprocating-piston pump 64. The medium is conveyed by the Einkanalschlauchpumpe 62 from the reservoir 61 into an intermediate container on the balance 63. From this, the reciprocating pump 64 extracts and feeds the predetermined amount into the test vessel 33, the medium being introduced to the glass wall to minimize air pockets. The amount removed is checked by means of the balance 63. The single-channel peristaltic pump 62 may have, for example, a maximum delivery rate of 1300 ml / min and a Norpren tube with ID = 4.8 mm. As a filling pump 64 for filling the test glasses 33 is preferably a wobble piston pump with a ceramic head and a RS232 interface with a flow rate of, for example, 900 ml / min and an accuracy <1% used. For gravimetric metering, for example, a verifiable scale 63 with an RS232 interface, a measuring range of 0 to 600 g and a 0.1 g display is used. The intermediate container is preferably made of acid-resistant material and may, for example, have a capacity of 3000 ml as well as an inlet and an outlet opening.

The test medium itself can, for example, be manufactured manually and stored in an acid-resistant storage container 61 with a capacity of, for example, 200 l. Optionally, an automatic production of the test medium from individual components, a degassing, a temperature and / or dosage can be integrated into the device. The test medium can also be preheated. Also can in the reservoir 61 can be carried out a pH measurement, for example with pH meters with standard connection for pH probes with an interface for reading and calibrating with an accuracy of <0.05 pH units. The degassing of the medium can be achieved for example by vacuum and / or by heating and stirring of the medium.

According to FIG. 6, a tablet magazine 70 for storing tablets and / or granules is equipped with 60 storage containers 71. The magazine may for example be attached to a side inner wall of the frame. In release tests according to USP method 2 (with paddle), the tablets or granules can thus be stored in the magazine 70 and filled by the robot one after the other into the test stations. Against moisture, the specimens are protected with a lid 72. These covers 72 must be stripped by the industrial robot 10 and collected in a container before the throw of the release sample to be tested into the test container 33, as shown in FIG. 7A. Further, one or more magazines not shown in the drawing for the storage of paddles and / or baskets 34 may be arranged on the frame.

Fig. 7B shows the use of sinkers 35 for floating DUTs. The sinkers 35 are thrown to the robot 10 into the test tubes 33 and brought out again with a magnetic arm 36, stripped into a receptacle and checked with a light barrier, the sinker is made of stainless steel and can be slightly magnetic.

According to FIG. 8, the stirring rods 39 of the agitator 31 are equipped with strong magnets 29 for holding and centering the paddles or baskets 34. The paddles or baskets can be removed from the robot and inserted into the stir bar. The stirrers are held in position and centered by strong magnets 29 in the stir bar and in the paddle or basket stud. The exchanged stirrers 34 are stored by the robot 10 again in a magazine. Combined nozzles 80 are used according to FIG. 9 for the sampling and simultaneous temperature measurement from the test containers 33. This results in the removal position and removal height from the specifications of USP or EP. The temperature is measured during the sampling in the test glass 33 with a sensor, such as a PT100 probe of 1/3 DIN class B with 4 conductors, a measuring range of -100 ⁰ C to +100 ⁰ C and an accuracy of +/- 0.1 ° C. The necessary filtration is carried out optionally with a Poroplast filter 92 or with a glass frit 105. The sampling tube is preferably made of stainless steel with an outer diameter of about 3 mm and an inner diameter of about 1, 5 mm. The poroplast filters 92 preferably have a porosity of 10 μm.

For example, a filter cartridge 90 shown in FIG. 10 mounted within reach of the industrial robot 10 may receive 120 new poroplastic filters 92, and the spent poroplast filters 92 may be collected in a receptacle 91. Alternatively, glass frits 105, preferably having a porosity of 10 μm, can be used for the filtration, it being possible to clean the frits for reuse in an ultrasonic bath, not shown in the drawing.

Referring to FIG. 11, an arrangement 100 for analysis according to an embodiment is shown schematically. For the analysis, the samples taken can preferably be measured online by means of HPLC or UVA / IS with optical fiber or flow cell 104 or collected in a fraction collector and later measured. For the purpose of the analysis, additionally or alternatively, any methods, such as, for example, IR spectroscopy, HPLC, NMR, GC-MS and / or diode array spectroscopy, may be used, the analysis devices 106 necessary and shown schematically also being incorporated into the frame of the release test device 1 integrated or can be arranged outside. The samples are transferred to the analytics devices with a start signal and the results are received with a return signal. In the online or offline system, the samples can be measured online in the HPLC or UVA / IS with optical fiber or flow cell 104 or in the fraction Collect collectors and later be measured. The withdrawal and return hoses are filled with medium or deionized water from the corresponding templates 61, 107 in accordance with FIG. 11. With the aid of the valves V3, V2, V1 and a syringe 101, for example 20 ml syringe, the solution of KaMb- rier and control standards or a sample from a test vessel 33 by means of a frit 105, a filter 92 or a cannula 108 in pulled the storage hose 103. With the help of valves V1 and V2, online or offline tests can now be carried out. The test medium or the calibration standard located in the storage tube 103 is conveyed and measured or collected by means of the valves V1 and V2 through a UVA / IS cuvette 104 or alternatively via a Rheodyne valve, for example into the HPLC apparatus or into a fraction collector. For the purpose of medium back supplement is drawn with the syringe 101 medium into the syringe 101 and the valves removed V1, V2 and V3 the amount removed back into the corresponding test vessel 33 added. An optional evaporation compensation is achieved by drawing, with the aid of the syringe 102, for example a 25 ml syringe, and the valve V4, demineralized water from a deionised water reservoir 107 into the syringe 102 and filling the required quantity into the test container 33. As syringe pumps 101, 102 glass syringes are preferably used. Acid-resistant 3/2 way solenoid valves can be used as valves.

Fig. 12 shows a suction and cleaning nozzle 120 for emptying and cleaning the test container 33 after the test end. For this purpose, the medium is suctioned with the aid of the suction and cleaning nozzle 120 and the robot or the test vessel 33 is cleaned. For this purpose, the nozzle 120 is shut down to the glass bottom and the medium sucked off with a hose pump, not shown in the drawing. At the same time, the test glasses 33 and paddle 34 can be cleaned with hot water. For example, a single-channel peristaltic pump can be used as the emptying pump for emptying the test glass 33. With the help of a water heater, the test station 32 can also be cleaned with hot water if necessary. Thus, with the release test device according to any one of the described embodiments, a release test can be automatically performed. In this case, the industrial robot 10 in particular the steps

Dosing a test medium into the test containers 33, injecting release samples into the test containers 33 or inserting the release samples in sinkers 35 into the test containers 33,

- Sampling and simultaneous temperature measurement with a combi nozzle 80 and

- Aspirate the medium and clean the test container 33, perform.

The test vessels are covered in the working position of the agitators (shut down) by a lid with silicone gasket to minimize evaporation. An evaporation compensation can be dispensed with if the evaporation from the vessel over 24 h is less than 1%. The device can be checked with USP tablets at any time and complies with the USP specifications. A manual equipment check with a QA station can be carried out separately for each station. An automatic device check for paddle height, speed, vibration and centering is possible on an ongoing basis. All product-contacting parts are preferably acid and vapor resistant. The test glass is preferably made of borosilicate glass, the stirring tools and the stir bar made of stainless steel and the housing is preferably powder-coated and all aluminum parts are anodised.

The connections used are preferably a serial interface RS232 and RS485, a mains connection 110-240 V, PT100 temperature sensor, mains connection for heating and an interface for heating. Operation is preferably via the PC software.

All components integrated in the device are integrated in the system via an interface and can be exchanged for an alternative device if required. LIST OF REFERENCE NUMBERS

I release test device, dissolution test device, dissolution test device 2 grippers

3 folding doors

10 handling equipment, industrial robots, robots

I 1 pedestal 20 frame 1 21 frame 2

22 switching and PC cabinet

23 computers

24 monitor

25 Keyboard 26 adjustable feet

29 magnet

30 release unit

31 agitator

32 test station 33 test container, test container

34 paddles or basket

35 sinkers

36 magnetic arm

37 Video camera 38 Worktop

39 stir bar

50 water bath

51 Heating, water bath

60 Arrangement for gravimetric medium filling 61 Medium container, medium storage container, medium tank

62 peristaltic pump, medium filling

63 balance, medium filling

64 filling pump, reciprocating pump, medium filling 70 tablet magazine

71 sample tubes, sample container

72 lids

80 Combi nozzle 81 Temperature sensor

82 sampling tube

90 filter magazine

91 collection container

92 filters, Poroplast filter 100 Analytical arrangement

101 syringe pump, syringe for sampling and medium replenishment

102 syringe pump, syringe for evaporation compensation

103 storage hose

104 UV-VIS cuvette 105 Frit, glass frit

106 analysis device

107 VE water mask

108 cannula

120 Suction and cleaning nozzle 125 Peristaltic pump, draining

Claims

claims:

1. Release test device for automatic release and measurement of drugs from a drug preparation consisting of

- One or more release units, each comprising one or more test stations with test containers for receiving release samples, stirrers associated with the test stations for stirring the release samples and one or more means for heating the test containers, and

- A computer device, characterized in that the release test device further comprises at least one program-controlled industrial robot, wherein the indoor robot has at least three degrees of freedom and at least one gripper, and within reach of the industrial robot

- the release unit (s) and

- means for storing the release samples to be tested, preferably one or more tablet magazine / s, and / or means for storing tools of the industrial robot, preferably one or more magazine / s for receiving unused paddles and / or baskets are arranged.

2. Release test device according to claim 1, characterized in that continue within range of the industrial robot

one or more sampling devices for taking samples from the test containers, preferably combination nozzles for sampling and simultaneous temperature measurement, at least one medium for filling the medium of the test containers and / or

- One or more, preferably connected to an emptying pump, suction and / or cleaning nozzle / s for emptying and / or cleaning the test container are arranged.

3. Release test device according to claim 1 or 2, characterized in that the gripper is a pneumatic gripper and the Industrierobo- ter is preferably mounted on an anchored in the ground pedestal.

4. Release test device according to claim 3, characterized in that the agitators of the individual test stations are sequentially switchable and the agitators of a release unit are preferably driven by a common electric motor.

5. release testing device according to claim 4, characterized in that the test stations are arranged in one or more rows with eight test stations, the test stations are preferably arranged in two substantially parallel rows with eight test stations and the industrial robot between the two rows is arranged

6. Release test device according to claim 5, characterized in that the test stations are each assigned external temperature sensors for the temperature measurement in the test container.

7. release testing device according to claim 6, characterized in that at least one receptacle for stripping of sinkers with a light barrier for review is located within reach of the industrial robot.

8. release testing device according to claim 7, characterized in that the / the means for medium filling is connected to a device for medium dosing / are, wherein the device for medium dosing preferably consists of at least one pump and a balance.

9. release testing device according to claim 8, characterized in that the removal device with a fraction collector and / or a Analyzer is preferably connected, wherein the analysis device is preferably a UV / VIS spectrometer, an IR spectrometer, an HPLC device, an NMR device, a GC-MS device and / or a diode array spectrometer.

10. Release test device according to claim 9, characterized in that the test stations are associated with one or more cameras for monitoring.

11. A method for automatic dissolution testing of release samples in temperature-controlled test containers of a release test device according to one of claims 1 to 10, comprising at least the following steps:

Dosing a test medium into the test containers,

Stirring of the test medium in the test container by rotating stirring tools,

- Sampling and / or analysis and

- emptying and / or cleaning the test containers,

wherein at least one of said steps is performed by means of a program controlled industrial robot having at least three degrees of freedom and at least one gripper.

12. The method according to claim 11, characterized in that the industrial robot is controlled by an absolute displacement measuring system and preferably adjusted by teaching.

13. The method according to claim 12, characterized in that the sample removal and a temperature measurement are carried out simultaneously with a combination nozzle.

14. The method according to claim 13, characterized in that for the analysis, preferably with the aid of spectroscopic and / or chromatographic techniques, samples taken or measured directly in the test vessel.

15. Computer program with program code for carrying out method steps according to one of claims 11 to 14, when the program is executed completely or partially in a computer.