HUP0100657A2 - Method and arrangement for examination of parallel processes and material properties in profiled block reactor with thermal gradient provided with mixer module and usage thereof - Google Patents

Abstract

An installation enables investigation of simultaneous processes and material characteristics, using a well heat lagged reactor block constructed of an efficient heat conductor (preferably aluminum). Sample holding blocks are separated by insulation (a reactor block clasped by an elastic mechanical coupling, due to the expedient use of 0.1 mm TEFLON (RTM: PTFE)]. The block has preferably 96 sample holding borings, distributed into an 8 x 12 configuration. Peltier batteries are fitted to the lateral sides of the two sample holding end blocks. The temperature of these blocks may be varied independently. When identical temperatures are set by the control unit on both ends, then an identical temperature distribution is reached in all blocks (isothermal mode). When the ends are set to different temperature, then the temperature in the block-reactor changes in a linear fashion to form a temperature gradient (gradient mode). In this case the temperature is the same in the bore of a particular column, but changes in a linear fashion from one column to another.

Description

R01 00657

PUBLICATION ^U %

Method and apparatus for the investigation of processes and material properties carried out in a sectioned block gradient temperature block reactor with an integrated mixing module and their applications

During the work with the device assembly containing a homogeneous block with good thermal conductivity described in claims 1-7 of Hungarian patent No. .......... entitled "Method and apparatus for the examination of parallel processes and material properties in a gradient block reactor and their applications", we experienced the following unfavorable operating characteristics:

1, Temperature range that is difficult to adjust and can only be adjusted indirectly

2. Large gradient difference on the side parallel to the gradient of the sample holes

3. Temperature overshoot

4. Temperature swing

5. Blending the gradient block with a matrix blender was not effective

These operating characteristics make the device layout difficult to use, especially with regard to automatic application.

A thorough examination of the device and the parallel thermal modeling revealed that when using a homogeneous material block with a flow-through cooling system, most of the phenomena and unfavorable properties listed in points 1-4 above cannot be eliminated. Therefore, we set the goal of designing a block with a sectioned block perpendicular to the gradient direction, in which the sample holder blocks with good thermal conductivity and materials with different thermal insulation properties are alternately arranged perpendicular to the direction of the reactor heat flow with good thermal contact. In order to ensure good thermal conductivity, the sections were joined together with a flexible mechanical connection. We noticed that in the case of suitably selected structural elements (aluminum and Teflon), we obtain a sectioned block with favorable thermal properties. By changing the thickness of the Teflon insulating layer, the temperature fluctuations in the longitudinal direction of the block are equalized and the greater part of the gradient falls on the insulating layer, while the temperature difference measured in the two extreme positions of the sample holder hole parallel to the gradient decreases. The homogeneity of the temperature measured at the points of the hole in the sample holder improves with the thickness of the insulating layer. At the same time, by increasing the thickness of the insulating layer, the gradient development only .....the ooignövckcdcu code'ciilaikisa;;k megfciciocn - csaa lassaoban cs larger fíUo/nűLö bados:Inlény aíkaíívno'án'vai okdsíihoió ki. /kikcíisias v-/otó (sóz U.

By using a metal (e.g. silver) or an insulator (Teflon, steel, etc.), the thermokinetic properties of the sectioned reactor block (time required to develop a temperature profile, power requirement) can be further improved at the same gradient.

To eliminate the disadvantageous operating properties listed in points 1-3, it seems advisable to use a cooling-heating element that can perform the cooling and heating functions in a well-controlled manner on its own. Based on our tests, we found a Peltier element that can work at high operating temperatures to be the most suitable for this task. Since the Peltier element operates symmetrically, we were able to control the direction of the heat flow with the polarity of the drive voltage, and the heat transfer performance with the magnitude of the current. In contrast to the flow-through cooling temperature control, the Peltier element can correct the temperature difference in a very short time by applying a reverse voltage in the event of a possible temperature overshoot (active control). The cold side required for the operation of the Peltier elements in the cooling cycle is provided by a thermally coupled block with continuous water cooling.

Due to the insufficiency of the matrix magnetic stirring (disadvantageous operating properties, point 5), the magnetic stirring of the reactor vessels is provided by a permanent magnet rotor placed under the block.

A possible advantageous configuration of the device is illustrated in the attached figures. The mechanical parts (Figure 1, 1): the sectioned gradient block, the sensors, the Peltier element and the magnetic rotor, as well as the driving electric motor are contained in the gradient reactor block. The control unit (Figure 1, 2):: we have built in the electrical control unit, the power supply connected to it, the computer, the input/output connections regulating and managing, and the display units. The two units are connected by a multi-core electrical cable connection.

The device operates up to a heating range of 80 °C with continuous flow water cooling connected to the water inlets and outlets, above this temperature the water flow can be stopped and the heating can be continued. In automated mode, the water flow is interrupted by solenoid valves controlled by the block temperature measuring probes.

We were able to create a sectioned reactor block with favorable thermal behavior even when using an aluminum heat conductor and a Teflon insulating layer. In the case of an aluminum-Teflon block with a set-up according to Figures 1 and 2, the achievable temperature range was checked by measuring the internal temperature of the stirred reactor vessels placed in the reactor bores.

One preferred embodiment of our invention is that the device includes thermometer(s), cooling pipe joints, a cable system and a separate control unit, enabling the setting of any desired temperature range.

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

The equipment may include a (inertable/coolable) lid to exclude moisture and oxygen and to retain the boiling solvent.

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

The equipment may include a PC connection port suitable for computer control.

To facilitate the automation of measurements, the equipment includes an analytical unit for sample processing, measurement and evaluation, as follows: an analytical sample handling block for sample processing and an analytical or visual observation device for sample measurement and evaluation - optionally an automatic HPLC device equipped with an injector.

The method according to the invention is suitable for carrying out parallel physical, chemical and biochemical processes and syntheses in an inhomogeneous block temperature reactor. According to the method, the examination of a mixture of different composition X is carried out at different temperatures Y - between Ti and T2 - using the above-described apparatus.

The temperatures can also be set so that during the process the temperatures between Ti and T ₂ change according to the predefined empirical formula T _xn = Ti+DT _n , and Ti is the temperature of the heated side.

During the process, the temperature between Ti and T ₂ preferably varies according to the linear equation: T _Xb T _x2 ....Txn a T _xn = Ti+ a * OX, where “X” is the distance from the initial temperature, “a” is the slope coefficient of the temperature change expressed in °C/unit length and Ti is the temperature of the heated side.

The above-mentioned equipment is used for the intermittent, combinatorial and parallel examination of physical, chemical and biochemical phenomena - possibly at different or varying temperatures.

The device described above is used for the visual or instrumental examination of a material property - in a given case, melting point, refractive index, electrical conductivity, fluorescence, photoelectric effects, catalytic effect.

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

The equipment contains tube reactor fittings of arbitrary geometry and arrangement, which fittings are located perpendicular to the formed heat flow, and feed pumps suitable for feeding into the tube sections and a storage vessel are connected to an outlet tube section.

If the metal (aluminum) block is adequately thermally insulated from the environment together with a cooling/heating system, then the temperature of the matrix columns in the blocks can be adjusted linearly and uniformly in practically any range by means of temperature control set at both ends of the reactor.

If active temperature control is provided on both sides of the reactor, e.g. an electric heater and a fluid-mediated cooling element, the reactor can be operated as a forced-flow thermal gradient or isothermal reactor according to the program. This provides the following technical advantages compared to the above version:

• Provides arbitrary temperature range setting with control.

• In the case of continuous sequential processes (especially multicomponent or “one-pot” chemical reactions without isolation), different process phases have different optimal temperature ranges, which must be maintained for the current step or reaction phase after the optimization step (with isothermal control). Next, the phase temperature and reaction conditions must be combinatorially changed (gradient control), repeating the optimization cycle until the final step of the entire sequential process sequence.

The above-described inhomogeneous block temperature gradient block reactor - in a variety of geometric arrangements and physical implementations - is suitable for combinatorial and parallel investigation of physical, chemical and biochemical phenomena. The system is equally suitable for the investigation of discrete processes in set temperature ranges - depending on the geometric partitioning

1. Design of an inhomogeneous bulk temperature gradient block with stirred batch glass reactors arranged in a matrix format

If a block made of aluminum sections is designed by placing holes perpendicular to the heat flow formed in the aluminum sample holder sections, then holders (reactor vessels) suitable for chemical reactions or physical tests, preferably made of glass, can be placed in them. (Figure 1) The reactor vessels placed in the holes of the block take on the temperature associated with the stationary heat flow and the reactions can be carried out in them at the desired temperature. A block with such a design is suitable for the construction of an automatic process development workstation in a 5-point arrangement. The block designed in this way is suitable for the examination of reactions carried out in isothermal (Figure 2) and gradient (Figure 3) modes.

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

If a block of aluminum sections is designed by placing holes perpendicular to the heat flow, tube reactor fittings of any geometry and arrangement suitable for chemical reactions or physical tests can be placed in these holes. Feed pumps suitable for feeding the mixture to be tested are placed in the tube sections and a storage vessel is attached to the outlet tube section. The tube reactor elements placed in the holes of the block take over the temperature corresponding to the stationary heat flow and the reactions can be carried out in them at approximately the desired temperature and in a continuous flow with any residence time.

3. Design of a process development system with an integrated sectioned block gradient reactor

Process development is a method generally used to optimize multi-step syntheses. Its essence is that the parameters influencing the chemical reaction (temperature, solvent, concentration) are changed until an optimal laboratory process is obtained - based on the kinetic (conversion time) curves obtained in this way. This optimal process is reproduced in larger and larger groups of devices during scale-up until the desired size is reached. If results that differ from the laboratory results are observed during scale-up, the process is optimized according to new criteria. Due to the classical individual reaction treatment, only a small number of individual reactions are treated, which provides little information on the behavior of the reaction in the parameter space.

The traditional system works with sequential mode and individual reaction treatment.

Parallel synthesis-based (combinatorial) systems

The combinatorial process development system fundamentally differs from traditional process development systems in that it uses parallel synthesis methods to collect as much on-line kinetic data as possible about the behavior of reactions.

Process development platforms based on combinatorial systems. They started to appear in the commercial market from the end of 1998. The reaction vessels (10-12 treated in parallel) were placed in isothermal blocks or individual temperature control was used. The isothermal block only allowed the treatment of reaction vessels with the same temperature. The price of individual temperature control is very high and the control is inconvenient for more than 12 vessels. The limited number of possible measurement points is expanded by applying the so-called factorial principle, which does not necessarily lead to the global optimum value when examining temperature-dependent parameters.

Gradient principle based module

The essence of the system we are developing is to multiply the combinatorial examination of the reaction parameters on a smaller scale by applying the gradient principle. One advantage of such a system is that, due to the broader parametric examination of each reaction step, the probability is higher that the global optimum belonging to the reaction parameter space will be found in the first step, but in any case within a much shorter time than is possible using the available tools. Another such advantage is that the broader examined parameter range allows for the interpretation of possible differences that occur during scale-ups and for the rapid and prioritized application of the applied “contingency” optima. (Figure 4)

Description of the gradient workstation:

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

A. Storage of reaction mixture

B. Thermostating the reaction mixture

C. Stirring the reaction mixture

D. Reaction mixture from air humidity and oxygen

E. Reagent dosing and sampling

F. Sample processing and analysis

The modular design allows the system to be operated manually even when partially installed. In addition to meeting functional and geometric criteria, the built-in elements can be replaced and the operations can be automated to any level - with further development if necessary.

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

• Gradient Block Reactor • Valves and Taps • Inert/Coolable Lid • Analytical Sample Handling Block • Liquid Handling Automation • Injector • HPLC

Gradient Block Reactor

If the holes in sample-holding aluminum sections - which thermostat glass vessels - are designed so that the resulting matrix has the same geometry as a well-plate (8*12 matrix with a 9 mm raster), then we obtain a block reactor whose liquid handling and mixing can be easily solved using commercial equipment. The typical temperature distribution of a block with such a geometry is shown in one of the attached figures of the patent.

In blocks of this design, reaction kinetic studies can be performed. Reaction kinetic curves of X different compositions can be examined simultaneously at Y different temperatures, as shown in Figure 4:

Accordingly, the performance of the block is equivalent to Y isothermal parallel synthesis reactors or X*Y individual synthesizers.

By designing a platinum thermometer and the electronic measuring circuits connected to them, as well as a mechanical holding comb with appropriate geometry, we create a "multi-channel parallel temperature measuring device" that, with one movement, by placing it in the solutions to be tested and connecting the connector to the serial input of a computer, directly measures the individual temperature of the solutions in the glass reactors "on-line".

• Valves and taps • Inert/coolable lid • Analytical sample handling block • Liquid handling automat • Injector • (HPLC)

Valves and taps

When changing from a cooling cycle to a heating cycle, the cooling liquid must be removed from the heat exchangers, as it may interfere with the gradient formation. This can be solved by purging the pipe section with pressurized nitrogen gas, using a three-way tap or valve.

In the initial prototype, we intend to operate the unit manually, and later with electronic control.

Inert/coolable lid

In many cases, it may be necessary to close the working opening during reactor operation. The inertizable lid, which can be used for the examination of more sensitive processes, performs the following functions:

• exclusion of air humidity • ensuring reflux (retention of boiling solvent) • exclusion of oxygen

The integrated sectioned block gradient reactor does not need to be kept open, since, in accordance with chemical practice, dosing and sampling only account for a small part of the total reaction time. A completely open lid can only partially meet the above triple criterion. To cool the boiling solvent vapors, it is most appropriate to use an aluminum attachment that matches the grid of the reactor, in which the neck of the glass reactor vessels is cooled with a cooling liquid flowing in a circular cooling tube at a height of approx. 10 mm. by a flow of cooling water. Thus, boiling solvent vapors condense at the cold point and flow back into the reactor vessels. If a gas-tight lid is placed on the cooled lid, the reactor vessels can be inerted - without the risk of solvent transfer - with a simple gas inlet lid. The simplest way to solve the task technically is to flow an inert gas, preferably denser than air, from a system loaded with a weight lock under the lockable lid. If a desiccant, P ₂ O ₅ , H ₂ SO _{4 ,} is placed under the lid in a container protected against dust, then we can simply create a "dry box" in the reaction environment.

Liquid handling machine

The liquid handling machine performs the following functions:

• reagent dosing • sampling from the reaction mixture transfer to the analytical sample handling block introduction of the processed sample into the injector

Solution phase reagent and solvent addition can be easily achieved using commercial single or multi-channel pipettors. The use of multi-channel pipettors allows for time synchronization of the columns of the inhomogeneous block temperature gradient block, thus eliminating the need to include a separate time scale corresponding to 96 wells.

The use of an automatic 8-channel dispenser offers several advantages over a manual pipette:

• can be performed column by column! dosing, not just weighing • reagent solutions can be dispensed from a closed container • all operations can be automatically registered • suitably homogeneous suspensions can also be weighed

Analytical sample handling block

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

• sample processing • sample dilution storage

If the samples cannot be fed directly to the analyzer, it may be necessary to process the samples. This step usually consists of reacting the aliquot samples - which ensures the shelf life of the samples - diluting them, and possibly extracting them. During processing, mixing and tempering are provided by a simple isothermal block and a Telesystem mixer.

If necessary, additional blocks may need to be used.

The processed sample can be transferred directly to the appropriate measuring device using a suitable device. Sampling can be done using a number of devices, preferably with the liquid handling unit itself.

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

Injector

In the case of automated HPLC or other analytical instruments, the most appropriate way to introduce the sample into the instrument is via an injector (HPLC) • sample measurement evaluation

With a suitable daughter-plate and a developed procedure, measurements can be performed using parallel analytical equipment: plate-reader, thin-layer plate, etc.

In the case of instruments suitable for sequential sample processing, measurements can also be performed offline, since it is assumed that the sample parameters do not change further after processing. Analytical measuring instruments can be the following: HPLC, GC, MS, IR, NMR, etc....

sample measurement evaluation

The measurement can be evaluated using visual methods or appropriate software.

In accordance with the modular system, the system elements can be controlled manually independently of each other. The system elements to be developed are designed from the outset to include a connection point suitable for computer control.

figure

Integrated Sectioned Block Gradient Block Reactor

Figure 1 shows the correct version of the integrated sectioned block gradient reactor 8*12 with 10 mm pitch 8.2 mm 6 sample holder holes in top and front views. The gradient block consists of 12 reactor block sections 5 made of a good thermal conductor metal (preferably aluminum). There are 8 8.2 mm holes each on the reactor sections 5. . The reactor sections 5 are separated from each other by 7 (11) 0.1 mm Teflon insulating sheets. Reflector blocks 9 reinforced with a good thermal conductor connection are attached to the outer sides of the two outer reactor sections 5. The 9 reflector blocks, which homogenize and buffer the heat flow, have Peltier elements (3-3 pcs) mounted on their outer surfaces with good thermal conductivity. A flow-through cooling element 12 is connected to the outer side of the Peltier elements with good thermal conductivity. Tap water or other cooling fluid circulation system can be connected to the outlet 13 of the pipe system formed in the flow-through cooling element 12. The cooling fluid flowing in it cools the Peltier elements up to an operating temperature of 80 °C.

There are 8 platinum thermometers in the two outer reactor sections 5. The temperature control is carried out based on the measured values of the built-in thermometers by the control unit 2 built into a separate box. 96 glass tubes serving as reactor vessels with a diameter of 8.2 mm can be inserted into the sample holes 6. The forced heat flow is ensured by the high-quality reactor external insulation 11 surrounding the entire reactor body except for the working openings 4. The jointing of the sectioned blocks is ensured by a flexible fixing nut placed on a 15-thread spindle. Under the reactor blocks, a large and high-capacity magnetic rotor 19 rotates on a 17-bearing shaft with an electric motor 20 through a V-belt drive 21 in the arrangement according to Figure 1. The equipment is protected from mechanical effects by 3 reactor block covers.

Between the 2 control units and the 1 reactor block, 37 electrical cable bundles provide heating energy, transmit temperature measurement signals, and control temperature and speed.

The switch-on is done with the on/off button 31. The speed of the magnetic rotor 19 is controlled with the speed control button 24. With the data input rocker switch 26, the temperature controller on the corresponding side of the device is set to “SET MODE”, with the temperature control potentiometer 25 we set the desired value, which can be checked on the digital display 29, then by pressing the data input rocker switch 26 again we set the device to “WORK MODE”. The desired temperature value is provided by the device with regulation. The temperature value on the other side is set according to the above steps.

Figure 2

Example of isothermal operation of a sectioned array gradient block.

The figure shows a representative temperature distribution measured in the stirred glass reactor vessels of the sectioned block gradient block reactor. In isothermal settings The minimum temperature achievable by using Peltier elements is reduced compared to the typical values of a flow-through homogeneous block. The maximum temperature is limited by the load capacity of the Peltier elements. The temperature values can be directly controlled.

Figure 3

Example of gradient operation of a sectioned block gradient block reactor.

The figure shows the representative temperature distribution measured in the glass stirred reactor vessels of the gradient block reactor with a sectioned block during gradient operation. The design of the sectioned block and the use of Peltier elements allowed us to create a larger maximum temperature gradient (> 80 °C) between the outer sample holder sections of the reactor (for temperatures above 100 oC), and it became possible to examine the temperature range of -15 - +25 °C in one measurement (for the minimum available temperature setting).

Figure 4

Determining optimal reaction temperature

The integrated block-shaped gradient plot represents a possible picture of the kinetic isotherms (product concentration versus time) of identical chemical reactions in the matrix rows. The highlighted curve shows the maximum product formation corresponding to the given composition.

Figure 5

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

The gradient workstation includes the following items:

38. PC

39. Gradient Block Reactor

40. Valves and taps

41. Inert/coolable lid

42. Analytical sample handling block

43. Liquid handling machine

44. Injector

45. HPLC

The gradient block reactor 39, in whose glass vessels the chemical reaction is investigated, together with the analytical sample handling block 42 for processing the samples, are provided with an inert/coolable lid 41 and are placed together with the injector 44 in the workspace of the liquid handling automation 43, which performs the sample and reagent movement and dosing. The valves and taps 40 connect the gradient block reactor 39 to the cooling medium and to a source of pressurized air or nitrogen through pipelines; these elements are installed outside the workspace of the liquid handling automation 43 to save space. The injector 44 is connected to the sample input point (HPLC) of the analytical measuring device 45.

Examples

Example 1

Combinatorial investigation of material properties

Insert the 8 mm glass reactor vessels and magnetic stirrers into the 6 holes. Set the desired block temperature at both ends of the reactor. Prepare stock solutions of the starting material(s) and reagent(s) and pipette them into the reactor vessels. Measure the solid from a suspension in a suitable solvent using a pipette or calibrated cannula.

From the reaction vessels, aliquot samples are taken from the appropriate solutions at specified intervals with a pipette and processed to determine the composition of the mixture by appropriate analysis. The amounts of the components are recorded in a table.

If necessary, the experiment is repeated in a different temperature range.

In Example 1, the following properties were tested with the device that is the subject of the patent according to temperature:

Solubility of solids and liquids in solvents

Determining distribution coefficients

Based on the above data, the following physical chemical processes were modeled. Crystallization Extraction

Example 2

Chemical process research and development with an inhomogeneous bulk temperature gradient block reactor using a semi-manual method.

Chemical reaction carried out in the arrangement according to Figure 1. Insert the 8 mm glass reactor vessels and the magnetic stirrers into the 6 holes. Set the desired block temperature at both ends of the reactor. Prepare stock solutions of the starting material(s) and reagent(s) and pipette them into the reactor vessels. Measure the solid from a suspension in a suitable solvent using a pipette or calibrated cannula.

At specified intervals, an aliquot sample is taken from the reaction vessels with a pipette and processed to determine the composition of the mixture by appropriate analysis. The changes in the components are recorded in a table.

If necessary, the experiment is repeated in a different temperature range.

In the experimental setup, Example 2 was successfully applied to the following chemical reactions:

Claisen condensation

Hydrolysis of sensitive substances (1,3-dioxobutanoic acid esters)

Heck reaction (coupling of aromatic bromoaldehydes with trimethylsilylacetylene) Condensations (condensation of dioxo compounds with hydrazines)

Ullmann reaction (reaction of aromatic halogen compounds with (poly)amines) Fischer indole reaction of hydrazones

Schiff base reactions

Example 3

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

The inhomogeneous block temperature gradient block is placed on a multichannel magnetic stirrer. The 8 mm glass reactor vessels and magnetic stirrers are inserted into the 6 holes. The desired block temperature and the thermostat temperature are set at both ends of the reactor. Stock solutions are prepared from the starting material(s) and reagent(s) and the diluent liquid used for sample dilution and processing. The diluent solution is pipetted into the analytical isothermal block, the starting material(s) and reagent(s) solutions into the inhomogeneous block temperature gradient block reactor vessels using the automated liquid handling robot. The solid material is measured from a suitable solvent suspension using a liquid handling robot or a calibrated cannula. The reaction space is inertized by completely closing the inertization lid.

An aliquot sample is taken from the reaction vessels at specified intervals using a liquid handling robot and added to the appropriately prepared dilution solution. After processing, the composition of the mixture is determined by appropriate analysis. The changes in the components are recorded in a table.

If necessary, the experiment is repeated in a different temperature range.

Example 4

Optimization of multi-component or “one-replacement” reactions

The common element of multi-component and “one-stop” reactions is that the joint optimum of several sequential processes must be found by breaking them down into phases based on the different kinetic curves belonging to each sub-process. The optimization is performed using the procedure according to Example 4, with the difference that the individual non-isolated phases are performed in successive elementary steps. In the first elementary step, the corresponding 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 (Ij ₀ , ti ₀ , ci ₀ ...) obtained in the examination of the previous phase are applied homogeneously to the entire block. Accordingly - the temperature of the gradient block is set to isothermal with the bilateral control (Figure 2) and after the optimal (tio) reaction time determined in the first step, the combinatorial (temperature gradient (Figure 3) and other parameters (c)) examination of the next phase is applied. The optimal values obtained in this way (Τχ ₀ , tio, Ci...; T _2o , t ₂ o,c _2o ...) are applied to the next phase in two consecutive isothermal Ti ₀ or T _2o cycles for the given ti ₀ or t _2o time and then 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

Testing the heat tolerance of enzymes

The activity of enzymes increases with increasing temperature according to the Arrhenius equation. However, the structure of the enzyme changes unfavorably as a result of increasing temperature (e.g. denaturation). The result of the two opposing processes usually leads to an optimum. In the arrangement shown in Figure 1, the biochemical reaction can be carried out in the temperature range appropriately designed in the block. In the rows of the gradient block with inhomogeneous block temperature, identical enzyme reactions are examined as a function of temperature. The enzyme kinetic curves can be determined by standard biochemical or analytical methods. Knowing the kinetic curves, the optimal temperature (range) for the given enzyme reaction can be specified. In the rows of the reactor block, the temperature dependence of other parameters affecting the enzyme reaction or other enzyme reactions (different enzymes or substrates) can be examined. In the arrangement shown in Figure 5, the optimization can be performed automatically.

Example 6

Temperature optimization of microbiological processes

The heat tolerance of mutant strains can be examined in an inhomogeneous block temperature gradient block using the method of Example 4, with the difference that culture medium and an aliquot of the mutant strains formed by irradiation are pipetted into the reactor vessels and after the appropriate incubation period, the growth of the bacteria is examined under a microscope.

Claims (17)

Requirements: 1.) Equipment for implementing parallel physical, chemical and biochemical processes and syntheses in an integrated sectioned block reactor, characterized in that the equipment consists of a sectioned reactor block made of a combination of elements with good thermal conductivity and insulating properties - optionally made of aluminum section (5) and Teflon (7), cooling/heating elements - optionally Peltier element (10), the insulation surrounding them (11), a cover (3), - optionally a working opening for inserting samples (4), - optionally reaction vessel holding holes (6) and other reaction parameter adjustment units (2, 38). 2.) The device according to claim 1, characterized in that it includes thermometer(s) (8) enabling the setting of any desired temperature range, cooling pipe joints (13), cable system (37) and a separate control unit (2). 3.) The device according to claims 1 or 2, characterized in that the device comprises a - optionally built-in - magnetic - optionally matrix - mixing unit (motor (20), V-belt (21), V-belt pulley (18), shaft bearing (17), magnetic rotor (19)). 4.) The device according to any one of claims 1-3, characterized in that it comprises cooling pipeline(s) suitable for circulating the coolant and valves and taps (40) for excluding the circulation of the coolant and for draining the coolant. 5.) The device according to any one of claims 1-4, characterized in that the device comprises a reactor cover (41) - optionally inertable/coolable - in order to exclude air humidity and oxygen. 6.) The device according to any one of claims 1-5, characterized in that the device comprises a - optionally multi-channel - liquid handling machine (43). 7.) The device according to any one of claims 1-6, characterized in that the device comprises a PC connection suitable for computer control (36). 8.) The device according to any one of claims 1-7, characterized in that the device comprises an analytical sample handling block (42) for sample processing. 9.) The device according to any one of claims 1-8, characterized in that it is connected to an automated HPLC (45) device, optionally equipped with an injector (44), for the analytical or visual observation device for measuring and evaluating the samples. 10.) Method for implementing the investigation of parallel physical, chemical and biochemical processes, syntheses and material properties using a gradient block reactor (39), characterized in that the investigation of a mixture of different composition X is carried out at different temperatures Y, optionally between Ij and T ₂ , using the apparatus according to any one of claims 1-9. 11.) Method for the examination of sequential physical, chemical and biochemical processes, syntheses and material properties carried out in parallel without isolation, characterized in that in the first step, the optimal temperature, time and other set parameters for the process phase are determined by operating the apparatus according to claims 1-9 in inhomogeneous (gradient) mode, then in the second step, the conditions of the first step are uniformly applied to the entire block and, operating the apparatus in homogeneous (isothermal) mode, the apparatus is first performed under optimal conditions for the first process phase, then the operating mode of the apparatus is again set to inhomogeneous (gradient) mode to determine the optimal values for the second process phase, and so on until the entire process phase sequence is fully optimized. 12.) The method according to claim 10, characterized in that during the method the temperature between Ti and T ₂ : Τχι, Τχ2 ....Txn varies according to a linear equation: T _xn ⁼ Tj+ a * DX, where “X” is the distance from the initial temperature, “a” is the slope coefficient of the temperature change expressed in °C/unit of length and Ti is the temperature of the heated side. 13.) The method according to claim 10, characterized in that during the method the temperatures between Ti and T ₂ : T _X1 , T _X2 ....Txn can be individually set to a predetermined value and the : T _xn =T!+DT _n , varies according to a predefined empirical formula and Ti is the temperature of the heated side. 14.) Use of a device comprising an inhomogeneous block temperature reactor according to any one of claims 1-9 for the intermittent, combinatorial and parallel investigation of physical, chemical and biochemical phenomena - optionally at different or varying temperatures. 15.) Use of a device comprising an inhomogeneous block temperature reactor according to claims 1-2 or 4-9 for the examination of processes taking place in a continuous tube reactor, where the fluid to be examined flows in a tube reactor placed perpendicular to or parallel to a suitably designed heat flow. 16.) Use of an apparatus comprising an inhomogeneous block temperature reactor according to any one of claims 1-10 for the implementation of process development, research and development tasks, where the multi-step influencing parameters - temperature, solvent, concentration, catalyst and others - are optimized in one or more steps. 17.) Use of the apparatus according to claims 1-9 for optimizing multicomponent or multistep (“one pot”) reactions.