HU221665B1 - Process and apparatus for examination procedures and material features-made the process parallel-in a gradient block-reactor and uses for thereof - Google Patents

Abstract

The application relates to a device whose core is a reactor block (1) made of thermally insulated material with good thermal conductivity (preferably aluminum), in which there are 96 sample-holding holes (2) of arbitrary geometry, preferably located in an 8×l2 geometry, and its two end plates are its temperature can be separately regulated with cooling/heating blocks (3) placed on both sides. If the temperature of the two end plates is set to the same value as the regulator (11), then the same temperature distribution is obtained in the reactor block (isothermal operation). If it is set to different temperature values, a linear temperature gradient is formed in the reactor block (gradient operation). The gradient operation results in the same temperature in the holes in a column, which varies linearly between the columns. By using the block reactor, the time of temperature and other parameter-dependent chemical, physical and biochemical processes, as well as the examination of material properties, can be significantly reduced. ŕ

Description

Many instrument manufacturers and combinatorial chemical companies are developing block-based matrix reactors for parallel synthesis. (Stem Corporation, England; H + P, Germany; Beckmann, Ontogen, USA, etc.) The principle of these blocks is to place the reactor vessel, usually made of glass, into the blocks without the use of a fluid to heat the vessel holding the vessel, or by cooling it. Thus, a fixed geometry run / cooled parallel synthesis reactor can be constructed with any geometry that is capable of performing solution or solid phase chemical reactions by means of adaptive fluid handling systems. The commercially available models have isothermal behavior, i.e. the reactor vessels in the block have the same temperature throughout the block, so that the chemical reactions that can be performed therein can only have the same temperature.

The present invention relates to a gradient block reactor, a matrix reactor in which the temperature of two end faces of a thermally insulated reactor block can be separately controlled. In the reactor, when the temperature of the two end-plates of a well-conductive (preferably aluminum) block is adjusted to a different value, the reactor geometry is unstable due to a stationary heat flux, non-homogeneous block temperature, along the preferred direction of the matrix. Thus, the temperature measured at positions evenly spaced between them can be refined according to the raster scale or continuously. Of course, the two-sided temperature control allows the homogeneous block temperature (isothermal operation) to be achieved with the same temperature set on the end plates. The apparatus also allows combinatorial examination of the chemical and physical properties and temperature parameters of the transformations. Applying the combinatorial principle to a temperature parameter, of course, multiplies the information obtained in experiments without the need for a large number of complex individual temperature controls.

The development of such a system is justified by the fact that it is capable of examining, in appropriate time (t) time, the temperature (T) dependence of physical, chemical or biochemical processes or properties, also with other relevant analytical or observing equipment of appropriate geometry.

U.S. Patent No. 5,270,183 to Beckman Research Institute of the City of Hope discloses an apparatus and method for producing DNA sequences. The reaction mixtures are injected into a so-called "Flow" stream and the medium is passed through various temperature zones. In this respect it is similar to the subject matter of the application, as the disclosed solution relates to multi-temperature processes, but while the above patent relates to a fluid process, our invention relates simultaneously to a series of reaction blocks and processes for performing different temperature processes. . Another important difference is that in the above description, zones of different temperatures are created by unique thermostation, while in the present invention, the forced heat flow created in arbitrary geometry creates locations of varying individual temperatures by temperature control of the two ends of the block.

US 5770157 (Ontogen Corporation) discloses a method for creating chemical libraries. In the document, the embodiment discloses a reaction block comprising interchangeable reaction vessels. In the reaction block, parallel reactions at an isothermal temperature of 8 * 12 matrix can be performed under the same conditions. The object of the present invention is that the temperature of the columns perpendicular to the heat flux in the well-conducting (preferably aluminum) block of the desired matrix arrangement allows for different reactions to be investigated.

Among the embodiments, the gradient block reactor made of good thermally conductive material (preferably aluminum) with a temperature-controlled inhomogeneous block temperature, allows one to use the module as an isothermal and gradient block block, more stable heat flow control, and enables optimization of sequential processes also, especially with regard to the kinetic study of "one additional" multi-step chemical reactions or special multicomponent reactions (Ugi reaction).

The patent details a specific area: an inhomogeneous bulk temperature gradient block reactor platform for chemical process research and development, where we explored the possibility of applying this new principle.

The following describes the non-homogeneous block temperature gradient block reactor and the procedures and processes that can be performed in it.

The phenomenon of non-homogeneous block temperature induced by forced heat flow was discovered in the investigation of a disrupted homogeneous block temperature (isothermal) reactor. The insulation of the reactor block on one side of the reactor body was damaged, and the heat exchange with the environment at the site of the injury had become significant as the temperature increased. This resulted in a stationary heat flow in the well-conductive (aluminum) block, which created locations (temperature gradient) that were decreasing in parallel with the direction of the heat flow. I assumed that by repairing the insulation, the heat flow inside the block would stop and the block temperature would be homogeneous again. My hypothesis was confirmed that by correcting the thermal insulation the homogeneous temperature distribution in the isothermal block was restored.

By consciously applying the phenomenon of inhomogeneous block temperature induced by said forced heat flow, I carried out experiments as to whether such a block could be created with proper design.

The essence of an inhomogeneous block temperature gradient block is that a well-conducting block (preferably made of aluminum) can be formed at one temperature by cooling at one end and by heating at the other end by heating at a different temperature.

HU 221 665 Bl

Thus, the solution according to the invention is an apparatus for the simultaneous physical, chemical and biochemical processes and syntheses in an inhomogeneous block temperature block reactor. The apparatus consists of a metal (aluminum) reactor block, a cooling / heating block (s), a sealing enclosure, a sheath, optionally a sample opening, optionally a reaction vessel bore and other means for adjusting the reaction parameters.

In a preferred embodiment of the present invention, the apparatus comprises a thermometer (s), cooling manifolds, cable system and a separate control unit for adjusting any temperature range.

In another case, the apparatus comprises a magnetic (matrix) mixing unit.

To achieve lower temperatures, the unit may be connected to a thermostat suitable for freezing through the refrigerant piping (s) and valves and taps to exclude refrigerant circulation and drain the refrigerant.

The apparatus may include a cover (inert) to exclude air humidity and oxygen.

The unit includes a (multi-channel) liquid handling machine.

The device may include a PC connector for computer control.

To facilitate automation of measurements, the apparatus includes an analytical unit for processing, measuring, evaluating the sample, such as an analytical sample handling unit for processing the sample and an automated HPLC apparatus with an injector for an analytical or visual monitoring device for measuring, evaluating the samples.

The process according to the invention is suitable for parallel physical, chemical and biochemical processes and syntheses in an inhomogeneous block temperature reactor. According to the method, the test of a mixture of X of different compositions is carried out at different temperatures of Y, between T and T ₂ , using the apparatus described above.

Temperatures can also be set such that, during the process, the temperatures between T _t and T ₂ vary according to a predetermined empirical formula Τ _χη = Τ ₁ + ΔΤ _η , and Tj is the heated side temperature.

In the process, the temperature between T ₁ and T ₂ is preferably: T _{X 1} , Τχ 2 .., ΤχΝ varies according to the linear equation T _xn = T, + A *, where "X" is the distance from the initial temperature and "a" is the slope coefficient of change in temperature in ° C / unit length, and Tj is the heated side temperature.

The apparatus described above is used to investigate physical, chemical and biochemical phenomena in batch, combinatorial, and parallel fashion, possibly at different or variable temperature (s).

The apparatus described above is used for the visual or instrumental examination of a material property, such as melting point, refractive index, electrical conductivity, fluorescence, photoelectric effects, catalytic effect.

The apparatus is a gradient block reactor in a matrix format, optionally equipped with stirred batch glass reactors, in which the reactor vessels are preferably made of glass in holes perpendicular to the heat flow.

The apparatus comprises tubular reactor assemblies of any geometry and arrangement, which are perpendicular to or parallel to the formed heat flow, and feed pumps suitable for feeding into the tubular sections and a storage vessel for the outlet section.

If the metal (aluminum) block, together with the cooling / heating system, is sufficiently thermally isolated from the environment, the temperature of the columns of the matrix in the blocks can be linearly adjusted in a virtually arbitrary range by temperature control at both ends.

When active temperature control is provided on both sides of the reactor, such as an electric heating and liquid heat exchanger, the reactor is capable of operating as a forced-flow heat gradient or isothermal reactor. This provides the following technical advantages over this version:

- Provides control of any temperature range setting.

- In the case of interdependent sequential processes (especially the so-called "one-replacement" chemical reaction without multicomponent or without isolation), different process phases also have different optimum temperature ranges, which should be kept at the actual step or reaction phase after optimization. The next step is the combinatorial change of phase temperature and reaction conditions (gradient control), repeating the optimization cycle until the final step of the complete sequential sequence.

The above-described inhomogeneous bulk temperature gradient block reactor is capable of combinatorial and parallel investigation of physical, chemical and biochemical phenomena in a variety of geometric arrangements and physical implementations. The system is capable of examining continuous or discrete processes within a set temperature range, depending on the geometric division.

1. Formation of an Inhomogeneous Block Temperature Gradient Block with Matrix Mixed Batch Glass Reactors

If the block is formed by drilling holes perpendicular to the heat flux in the aluminum block, reactor vessels, preferably made of glass, can be placed there for chemical reactions or physical examinations. (Figure 1) Reactor vessels located in the holes in the block

The temperature of the stationary heat flow is taken over and the reactions can be carried out at the desired temperature. A block of this design, in a 5-point arrangement, is an automatic method for creating a development workstation. The resulting block is suitable for testing reactions in both isothermal (Fig. 2) and gradient (Fig. 3) modes.

2. Formation of an inhomogeneous block temperature gradient block in a matrix format with continuous isothermal tube reactors perpendicular to the heat flow

If the block is formed by inserting through holes perpendicular to the formed heat flow, they can be provided with tubular reactor sections of any geometry and arrangement suitable for chemical reactions or physical examinations. Supply pumps suitable for feeding the mixture to be tested are placed in the tube sections and a storage vessel is fitted to the outlet tube section. The tubular reactor elements located in the boreholes of the block take over the temperature of the stationary heat stream and carry out the reactions therein at approximately the desired temperature with a continuous flow of any residence time.

3. Formation of an inhomogeneous block temperature gradient block in a matrix format with continuous tubular reactors arranged in parallel with the heat flow

If the block is formed by inserting through holes in parallel with the generated heat flow, they may be provided with tubular reactor sections of any geometry and arrangement suitable for chemical reactions or physical examinations. Supply pumps suitable for feeding the mixture to be tested are placed in the tube sections and a storage vessel is fitted to the outlet tube section. The tubular reactor elements located in the boreholes of the block take over the temperature of the stationary heat stream and carry out the reactions therein in a continuous stream of approximately the desired temperature profile with any residence time.

4. Formation of an inhomogeneous block temperature gradient block with a gradient temperature surface

Alternatively, the property to be tested for temperature can be investigated on an undivided or split surface directly placed on an inhomogeneous block temperature gradient block reactor. In this case, by conducting a vertical heat flow in accordance with a uniform heat flux, a surface is obtained on which the material properties can be examined directly according to the direction of the heat flow, if it can be transformed into an optical or other testable signal.

5. Design of a process development system with an inhomogeneous block temperature gradient block reactor

Process development is usually a method used to optimize multi-step syntheses. The essence is that the parameters influencing the chemical reaction (temperature, solvent, concentration) are changed until the obtained laboratory kinetic (conversion-time) curves are not optimized. This optimum process is reproduced in larger and larger sets of devices up to the desired size. If results other than laboratory results are obtained during scale-up, new aspects of the process optimization will be performed. Due to the classic unique reaction handling, only a small number of individual reactions are handled, providing little information on reaction behavior in the parameter space.

The conventional system employs a sequential method for individual reaction management.

Parallel synthesis (combinatorial) systems

The process development system based on the combinatorial principle differs fundamentally from the conventional process development systems in that they attempt to collect as much kinetic data on reaction behavior as possible using parallel synthesis methods.

Process development platforms based on combinatorial systems have been commercially available since the end of 1998. Reaction vessels (10 to 12 parallel treated) were placed in isothermal blocks or individual temperature control was applied. The isothermal block only allowed the reaction vessels to be treated at the same temperature. The cost of individual temperature control is very high, and it is inconvenient for more than 12 pots. The limited number of possible measurement points is extended by the application of the so-called factorial principle, which does not necessarily lead to a global optimum when temperature-dependent parameters are examined.

Module based on gradient principle

The essence of our system is to multiply the combinatorial analysis of reaction parameters using the gradient principle. One advantage of such a system is that, due to the broader parametric investigation of each reaction step, it is more likely that the global optimum for the reaction parameter space will be found in the first step, but in any event in a much shorter time than available. Another advantage is that the more widely studied parameter range provides an opportunity to interpret possible differences in size increases and to apply the "contingency" optima quickly and ranked. (Figure 4)

Description of the gradient workstation

A gradient workstation is a system of modular devices that perform the following functions.

A) Storage of the reaction mixture

B) Thermostating the reaction mixture

C) Stirring the reaction mixture

D) Reaction mixture of humidity and oxygen

(E) Reagent Dosage and Sampling

F) Sample Processing and Analysis

The modular design allows the system to be operated manually even in partial deployment. In addition to meeting functional and geometric criteria, the system can replace built-in elements and automate operations to any level with further development if needed.

Accordingly, the gradient workstation contains the following elements (Figure 5):

- Gradient block reactor

- Thermostat

HU 221 665 Bl

- Valves and taps

- Magnetic (matrix) mixing unit

- Inert cover

- Analytical sample handling unit

- Liquid handling machine

- Injector

The HPLC

Gradient block reactor

If the holes in the block - which thermostate the glass jars - are shaped so that the resulting matrix has the same geometry as a well-plate (8 * 12 matrix with 9 mm raster), the lattice is a block reactor that is easy to handle and mix. can be solved using commercial equipment. A typical temperature distribution of a block with such a geometry is shown in one of the attached figures. (Annex: provisional patent, conceptual outline of gradient reactor)

In blocks of this configuration, kinetic reactions of the reaction can be carried out.

Accordingly, the performance of the block is equivalent to Y isothermal parallel synthesis reactor and X * Y unique synthesizer.

Micrometers implanted on an insulated surface at the bottom of the reactor block measure the unique temperature of the glass reactors in the columns of the matrix.

- Thermostat

- Valves and taps

- Magnetic (matrix) mixing unit

- Inert cover

- Analytical sample handling unit

- Liquid handling machine

- Injector

- (HPLC)

Thermostat

The two ends of the inhomogeneous block temperature gradient block can also be cooled / heated as needed and circulated with coolant / heating fluid. If the starting point of the gradient is room temperature or higher, the circulating coolant may also be tap water. Lower temperatures can be achieved by connecting a commercially available thermostat pipeline to the gradient block reactor cooling / heating block.

Valves and taps

When changing from a cooling cycle to a heating cycle, the coolant must be removed from the heat exchangers as it may interfere with the gradient. This can be accomplished by purging the pipe section with nitrogen gas under pressure, using a three-position tap or valve.

In the initial prototype we would like to operate the unit manually and later on by electronic control.

Magnetic (matrix) mixing unit

The stirring of the glass reactor vessels in the reactor block was solved by magnetic stirring. In the case of an 8 * 12 inhomogeneous block temperature gradient block, due to the small size of the stirring magnets, the reactor vessels are agitated by rotating a sufficiently large permanent magnet underneath the reactor block. Thus, satisfactory mixing can be achieved even when the inhomogeneous block temperature gradient block is placed on a conventional laboratory magnetic mixer plate.

At higher speeds, rotation of the magnets with a unique magnetic field is required. There is a commercial solution available for the well-plate geometry of 8 * 12 mixing, the most suitable being the H + P 96 Telesystem. This device allows simultaneous control of 96 glass reactor vessels at the same speed.

Inert cover

In many cases, it may be necessary to close the work port when operating the reactor. When testing more sensitive processes, the inertial lid provides the following functions:

- exclusion of air humidity

- exclusion of oxygen

It is not necessary to keep the gradient reactor open since, according to chemical practice, dosing and sampling make up only a small fraction of the total reaction time. A fully open lid can only partially meet the above double criterion. The easiest way to solve the problem is to transfer the gas, which is heavier than air, from a system loaded with a weight lock under the locking lid. If an air drying agent, P ₂ O ₅ , H ₂ SO ₄ , is placed under the lid, box ”in the environment of the reactions.

Liquid handling machine

The liquid handler has the following functions:

- reagent dosing

- sampling the reaction mixture, transferring it to the analytical sample handling unit

- introducing the processed sample into the injector.

The addition of a solution-phase reagent or solvent is easily accomplished using commercial single or multi-channel pipettors. The use of multichannel pipettors allows time column synchronization of inhomogeneous block temperature gradient blocks, eliminating the need for a separate time scale corresponding to 96 well. The use of the automatic 8-channel dispenser offers several advantages over the manual pipette: 1.

- can be done per column! dosing, not just weighing

- reagent solutions may be dispensed from a sealed container

- all operations can be registered automatically

a sufficiently homogeneous suspension can be measured.

Analytical sample handling unit

The analytics unit performs the following functions within the gradient module:

- sample processing

- sample dilution storage.

If samples cannot be fed directly to the analyzer, they may need to be processed. This

Step B1 generally consists of reacting the aliquot samples to ensure dilution or possibly extraction of the samples. During processing, mixing and tempering is provided by a simple isothermal block and a Telesystem mixer.

If necessary, additional blocks may be used.

The processed sample may be transferred directly to the appropriate measuring device by a suitable device. Sampling can be done by many means, preferably the fluid handling unit itself.

If the sampling and processing speed is faster than the analytical measurement speed, the sample handling unit can also perform a storage function.

injector

For automated HPLC or other analytical instruments, injection into the instrument is most conveniently accomplished via an injector.

(HPLC)

- Sample measurement evaluation

With proper daughter-plate and elaborate procedure, measurements can be made with parallel analytical equipment: plate-reader, thin-layer plate, etc.

In the case of sequential sample handling instruments, measurements can be made in the off-line mode as it is assumed that the sample parameters no longer change after processing. The analytical instruments may be: HPLC, GC, MS, IR, NMR, etc.

Evaluation of sample measurement

The measurement may be evaluated by visual methods or by appropriate software. Depending on the modular system, the system components can be independently controlled manually. The components to be developed are pre-made with a computer-controlled interface.

Figure 1

Gradient block reactor

Figure 1 is a top view and front view of a 9 * raster gradient reactor 9mm version with 8mm holes. There are 12 holes (2) in 8 rows of 1 piece of good heat conductive metal (preferably aluminum). Into the holes can be inserted glass tubes of 8 mm NSA reactor vessel. On both sides of the reactor block 1 there are formed cooling / running blocks 3, which can be connected to the piping of the external refrigerant system via pipe connections 4. At the end of the cooling / heating blocks, 5 conductive heaters were fitted with good heat conductivity. The temperature of the cooling / running blocks is measured by 6 thermometers inside the blocks. The forced heat flow is provided by the high-quality insulation 8 surrounding the entire reactor body except for the work port 7. The device is protected from mechanical influences by the outer casing 10. The cable system 9 provides the heating energy as well as the transmission and control of the temperature measurement signals via a separate controller.

Figure 2

Example of isothermal operation of an inhomogeneous block temperature gradient block.

The spatial diagram shows the temperatures measured in each stirred reactor vessel as a function of the reactor matrix positions.

Figure 3

Example of an inhomogeneous block temperature gradient block operation.

The spatial diagram shows the temperatures measured in each stirred reactor vessel as a function of the reactor matrix positions.

Figure 4

Determining the optimum reaction temperature

It depicts a possible representation of the kinetic isotherms (product concentration versus time) of the same chemical reactions in the inhomogeneous block temperature gradient block. The highlighted curve shows the maximum product formation for a given composition.

Figure 5

Development of a process development system with an inhomogeneous block temperature gradient block. The gradient workstation contains the following items

21. Gradient Block Reactor

22. Thermostat

23. Valves and taps

24. Magnetic (matrix) mixing unit

25. Inert cover

26. Analytical sample handling unit

27. Liquid Handling Machine

28. Injector

29. (HPLC)

The gradient block reactor 21, in which the chemical reaction in the glass vessels is analyzed, is provided with an analytical sample handling unit 26 for processing samples, 24 magnetic (matrix) mixing units and 25 inert covers, and 28 injectors for sample and reagent handling and dispensing 27 are located in the automatic work space. The valves 23 and valves 23 connect the gradient block reactor 21 to the thermostat 22 and the pressurized air or nitrogen source via pipelines, which, due to space savings, are installed outside the working area of the fluid handling apparatus 27. The injector 28 is connected to the sample entry point (HPLC) of the analytical measuring apparatus 29.

Examples

Example 1

Combinatorial examination of material properties Melting point determination with gradient sheet:

Place the powder of the mixture to be examined in parallel on a gradient sheet in thin strips parallel to the heat flux. After the heat transfer, the melted strip portion is visually or diffused

EN 221 665 BI can be detected automatically and calculated or calculated based on the location of the temperature.

Example 2

Chemical Process Research and Development with Inhomogeneous Block Temperature Gradient Block Reactor Semi-Manual

Chemical reaction in the arrangement of Figure 1.

The inhomogeneous block temperature gradient block is placed on a laboratory magnetic stirrer. Insert the 8 mm glass reactor vessels and magnetic stirrers into the holes 2. Set the coolant flow rate at the lower temperature block and the desired block temperature at both ends of the reactor. Stock solutions of starting material (s) and reagent (s) are prepared and pipetted into reactor vessels. The solid is measured from a suspension of the appropriate solvent by pipette or calibrated cannula.

An aliquot sample is removed from the reaction vessels at intervals determined by pipette and processed to determine the composition of the mixture by appropriate analysis. The changes in the components are recorded in a table. (The table is not part of the scope of protection.)

If necessary, the experiment is repeated at different temperature ranges.

Example 3

Chemical process research and development in the layout shown in Figure 5 automatically

The inhomogeneous block temperature gradient block is placed on a multi-channel magnetic stirrer. Insert the 8 mm glass reactor vessels and magnetic stirrers into the holes 2. Set the desired block temperature and thermostat temperature at both ends of the reactor. Stock solutions are prepared from starting material (s) and reagent (s) and from dilution liquid used for sample dilution and processing. The diluent solution is pipetted into analytical isothermal block, starting material (s), and reagent (s) into an inhomogeneous block temperature gradient block reactor vessel using an automated fluid handling robot. The solid is inoculated from a suitable solvent suspension with a fluid handling robot or calibrated cannula. The reaction space is inert by completely closing the inert lid.

An aliquot sample from the reaction vessels is determined at intervals using a liquid handling robot and added to a properly prepared diluent. Worked up by appropriate analysis to determine the composition of the mixture. The changes in the components are recorded in a table. (The table is not part of the scope of protection.)

If necessary, the experiment is repeated at different temperature ranges.

Example 4

Optimization of multi-component or one-way reactions

A common element of multicomponent and one-to-one reactions is the search for the optimum of several sequential processes in phases, based on the different kinetic curves for each subprocess. The optimization is carried out according to the procedure of Example 4, except that each of the non-isolated phases is carried out in successive elementary steps. In the first elementary step, the appropriate kinetic curves are obtained by combinatorial examination of the first phase (gradient operation: inhomogeneous block temperature, e.g., Figure 3). In the second elementary step, the optimal temperature, reaction time, and other reaction parameter values (Tj ₀ , t ₁₀ , c ₁₀ ...) obtained in the previous phase are already applied homogeneously to the whole block. Accordingly, the temperature of the gradient block is set to isotherm by the two-way control (Fig. 2), and after the optimal reaction time (t _{] 0} determined in the first step, the following phase combinatorial (temperature gradient (Fig. 3) and other parameters (c) ). The optimum values thus obtained (T ₁₀ , t _w , C j ...; T ₂₀ , t ₂₀ , c ₂₀ ...) are then applied for two consecutive isothermal cycles T ₁₀ and T ₂₀ respectively for the given t ₁₀ , and t is applied to the next phase for t ₂₀ , and thereafter the combinatorial optimization of the third phase is performed. The above elementary steps are performed according to the same algorithm until all phases are optimized.

Example 5

Temperature optimization of biochemical processes

Investigation of heat resistance of enzymes

The activity of enzymes increases with increasing temperature according to the Arrhenius equation. However, the increase in temperature results in an unfavorable change in the structure of the enzyme (e.g. denaturation). The result of the two opposing processes usually leads to optimum. In the arrangement of Figure 1, the biochemical reaction can be carried out at a temperature range suitably formed in the block. In the rows of the inhomogeneous block temperature gradient block, the same enzyme reactions are tested as a function of temperature. Enzyme kinetic curves can be determined by conventional biochemical or analytical methods. Knowing the kinetic curves, the optimal temperature (range) for a given enzyme reaction can be determined. In the rows of the reactor block, temperature dependence of other parameters affecting the enzyme reaction or other enzyme reaction (different enzyme or substrate) can be investigated. In the arrangement of Figure 5, the optimization can be performed automatically.

Example 6

Temperature optimization of microbiological processes

The heat tolerance of mutant strains in an inhomogeneous block temperature gradient block can be assayed by the procedure of Example 4, except that the medium and aliquots of the mutant strains formed by irradiation are pipetted and the bacteria are assayed at the end of the appropriate incubation period.

Claims (18)

Apparatus for performing parallel physical, chemical and biochemical processes, syntheses in a homogeneous / inhomogeneous block temperature reactor, characterized in that the apparatus is made of a well-conducted reactor block (1), optionally made of aluminum (3), cooling / heating block (s). ), the surrounding insulation (8), the enclosure (10) - optionally a sample opening (7) - optionally a reaction vessel bore (2) and other reaction parameter adjusting units. Apparatus according to claim 1, characterized in that it comprises a thermometer (s) (6) for adjusting any temperature range, a heat sink (4), a cable system (9) and a separate control unit (11). Apparatus according to claim 1 or 2, characterized in that the apparatus comprises a magnetic mixing unit (24), optionally a matrix. 4. Apparatus according to any one of claims 1 to 3, characterized in that it comprises a thermostat (22) suitable for freezing, cooling conduit (s) for recirculating refrigerant, and valves and taps (23) for preventing recirculation of refrigerant. 5. Apparatus according to any one of claims 1 to 4, characterized in that the apparatus comprises a reactor cover (25), optionally inert, to exclude air moisture and oxygen. 6. Apparatus according to any one of claims 1 to 3, characterized in that the apparatus comprises an optional multichannel liquid handling apparatus (27). 7. Device according to any one of claims 1 to 3, characterized in that the device comprises a PC connection (12) for computer control. 8. Apparatus according to any one of claims 1 to 3, characterized in that the apparatus comprises an analytical sample processing unit (26) for processing the sample. 9. Apparatus according to any one of claims 1 to 3, characterized in that it is connected to an analytical or visual monitoring device for measuring, evaluating the samples, optionally an automatic HPLC (29) device with an injector (28). 10. A process for performing parallel physical, chemical, and biochemical processes, syntheses, and material properties in an inhomogeneous block temperature gradient block reactor (21), characterized in that X is tested at different temperatures of Y at different temperatures from T _t to T ₂ . perform steps 1-9. Apparatus according to any one of claims 1 to 4. 11. A process for examining sequential physical, chemical, and biochemical processes, syntheses, and material properties without isolation, characterized in that, in the first step, steps 1-9. The apparatus of claims 1 to 4 is operated in an inhomogeneous (gradient) mode to determine the optimal temperature, time, and other parameters for the process phase, and in the second step apply the conditions of the first step uniformly throughout the block and operate the apparatus in homogeneous (isotherm) mode. the first process phase is first performed under optimum conditions, and then the apparatus operation mode is again set to an inhomogeneous (gradient) mode to determine the optimum values for the second process phase, and so on, until the entire process phase sequence is fully optimized. The method of claim 10, wherein the temperature between T ₁ and T ₂ : T _Xb TX 2 - TXN varies according to a linear equation: T _xn = T ₁ + a * AX where "X" is the distance from the initial temperature and "a" is the slope coefficient of change in temperature in ° C / unit of measurement and Tj is the heated side temperature. The method of claim 10, wherein the temperatures between T ₁ and T ₂ : T _{X 1} , T _{X 2} ... T _{X N are} individually adjustable to a predetermined value and: ^Τ χη ^{= Τ} 1 ^{+ ΔΤ} η »varies according to a predetermined empirical formula, and Tj is the heated side temperature. 14. Use of an apparatus comprising an inhomogeneous block temperature reactor according to any one of claims 1 to 6 for the investigation of physical, chemical and biochemical phenomena in batch, combinatorial and parallel fashion, possibly at different or variable temperature (s). 15. Use of a device comprising an inhomogeneous block temperature reactor according to any one of claims 1 to 7, for visual inspection or instrumentation of a material property, optionally melting point, refractive index, electrical conductivity, fluorescence, photovoltaic effects, catalytic effect. 16. or 4-9. Use of an apparatus comprising an inhomogeneous block temperature reactor according to claim 1 to investigate a process in a continuous tubular reactor, wherein the fluid to be tested is flowing in a tubular reactor arranged perpendicularly or parallel to the designed heat flow. 17. Use of a device comprising an inhomogeneous block temperature reactor according to any one of claims 1 to 7 for carrying out process development, research and development tasks, wherein the multi-step influencer - temperature, solvent, concentration, catalyst and other - is optimized in one or more steps. 18. Use of the apparatus according to claims 1 to 6 for optimizing multi-component or multi-step reactions.