WO2004026460A1

WO2004026460A1 - Method and apparatus for performing chemical experiments

Info

Publication number: WO2004026460A1
Application number: PCT/NL2002/000606
Authority: WO
Inventors: Anton John Nagy
Original assignee: Avantium International B.V.
Priority date: 2002-09-20
Filing date: 2002-09-20
Publication date: 2004-04-01
Also published as: AU2002324369A1

Abstract

Described is an apparatus for conducting chemical experiments on micro scale, comprising a housing in which a channel of a closed loop of at most 50 ml, is formed for backmixing the reaction mixture with starting materials. Also an assembly of a plurality of such apparatuses and a method for performing chemical reactions with the said apparatus are described.

Description

Method and apparatus for performing chemical experiments

Field of the invention

The invention relates to an apparatus for conducting chemical experiments on micro scale involving at least one reactant, to a modular system of such apparatuses, and to a method for using the said apparatus . Prior Art

Apparatuses having small dimensions for conducting experiments at micro scale are generally known and widely used. The term micro scale is herein defined as involving volumes of reactant in the experiment of at most 50 milliliter, preferably 10 milliliter. Document WO 01/68257 relates to a microreactor comprising a reaction unit including a reaction chamber having a volume of less than one milliliter. The chamber includes an inlet connectable to a source of a chemical or biological starting material and an outlet for release of a product of a chemical or biological reaction involving the starting material. A collection chamber having a volume of at least one liter, is connected to the outlet of the reaction chamber. Further, a mixing chamber including a plurality of inlets for a plurality of sources of chemical or biochemical reactants can be connected to the reaction chamber.

Microreactors are often used in the art to simulate large scale reactions, e.g. in order to determine optimal reaction conditions for a certain chemical or biochemical reaction.

One of the problems encountered with known microreactors is the inability to extrapolate results from microreactors to Constantly Stirred Tank Reactors (CSTR) , so that such microreactors are not suitable to simulate reactions in a CSTR, as in the prior art microreactors, reaction products are not contacted with starting materials, as would occur in a CSTR.

In many chemical and biological reactions, the formed reaction product can then itself react with one or more of the original reactants, resulting in the formation of by-products that have impact on numerous reaction parameters, such as the yield of the desired product. Large-scale batch reactors are nearly always well-mixed systems, wherein the said reaction products are contacted with the starting materials. An example of this is the Constantly Stirred Tank Reactor (CSTR) . In a CSTR, one or more reactants are continuously fed into a tank reactor, wherein the reaction then takes place, forming a product that can be continuously removed. Both the reactants and the product remain in the tank for a specific residence time, and are mixed by, for instance, a dynamic mixer such as an impeller. In the case of a CSTR the residence time distribution tends to be particularly broad, and the product concentration is essentially equal throughout the reactor. In the art, it has been tried to attain this characteristic with microreactors, but up to now this has failed. The phenomenon of contact between starting reactants and reaction products does not occur sufficiently in known microreactors, because most microreactors operate as single-pass reactors with flow hydrodynamics in the plug-flow or laminar regime, therewith prohibiting contact between the starting materials and the formed product. Reactant passing through these reactors encounters a very narrow residence time distribution and ideally is a delta function (in the case of plug flow) . These hydrodynamics are very different from the completely mixed flow encountered in stirred tank reactors. Therefore, it is cumbersome to simulate characteristics of a Constantly Stirred Tank Reactor with known microreactors. This implies that reactions, which have been tested in existing microreactors, are often impossible to scale up to full-size production reactors such as a CSTR.

Another problem encountered with known microreactors is that a large concentration gradient exists from the entry point to the reactor and the exit thereof. This concentration gradient makes assessment of the reaction kinetics extremely difficult, because the reaction rate varies over the length of the reactor.

Another problem encountered with known microreactors is the phenomenon of clogging of the reactants in the reactor. This phenomenon is particularly problematic when the flow profile of the reactants through the reactor is very laminar and when the channels are very narrow (on the orders of tens to hundreds of microns) . The laminar flow profile can occur in the entire reactor, but also very locally. Sedimentation or solidification may start, resulting in clogging of the reactor. This may result in a failure of the experiment, and damage to the reactor. This effect seriously limits the types of chemistry, which can be performed in microreactors . Reactions resulting in high viscosities or particle formation are extremely difficult to perform. Examples of these are slurry-phase reactions, polymerization reactions and precipitation reactions .

Another problem of known microreactors is the limited maximum residence time period that can be achieved. For a given volumetric flow rate, the average residence time of the reactants is directly proportional to the reactor volume. The extremely small volumes associated with standard microreactors (on the order of hundreds of microliters) intrinsically imply an extremely short residence time. The maximum average residence time for reaction is, therefore, very limited. Typical residence times for commercially available microreactors lie between 1 and 1000ms. Many reactions, however, require a relatively long time for completion. It is impossible to perform experiments with these reactions in known microreactors .

Another problem of known microreactors is the limited residence time and residence time distributions that can be achieved. Due to the plug flow, the reactants entering the reactor will pass through the reactor in predominantly the same time period. Variations in the distribution of the residence time of the reactants are difficult to attain.

Another problem with known microreactors is that most require a volumetric reactant feed flowrate on the order of milliliters per minute. This flow rate necessarily results in the production of milliliters per minute of product. This is a relatively large amount of product, which complicates implementation of these systems in a research and development laboratory, where large amounts of waste production are undesired. This problem is aggravated when numerous microreactors are employed in parallel for performing parallel, high- throughput experimentation (also known as combinatorial chemistry) . The presented reactor avoids this problem, by using feed pumps with extremely low volumetric flow rates (microliters/minute) . Yet another problem with known microreactors is that, when operated in parallel, different predetermined conditions are difficult to accomplish. Reaction parameters, such as the starting time, the end time, temperature and pressure all have to be controlled. When this controlling needs to be performed for each reactor separately, the required effort can be quite large. Summary of the invention

Therefore, an object of the present invention is to provide an apparatus for conducting chemical experiments on micro scale involving at least one reactant, enabling to conduct chemical experiments at small scale (i.e. micro scale) with a high degree of backmixing, enabling simulation of a CSTR at microscale.

A further object of the present invention is to provide a microreactor, which exhibits hydrodynamics equal to or approximating a CSTR, thereby creating the possibility of convenient up-scaling from laboratory volumes to production volumes. Another object of the present invention is to provide a continuously operated microreactor, which is ideally suited for performing kinetic studies. This results from the lack of concentration gradients within the reactor when a high recycle ratio is used. Another object of the present invention is to provide a microreactor, which enables one to conduct chemical experiments at small scale, without the risk of clogging.

Another object of the present invention is to provide a microreactor that can operate with long residence time periods (e.g. several minutes to hours) without requiring the addition of residence time modules or other additional components.

Another objective of the present invention is to provide a microreactor that can exhibit widely varying residence time distributions ranging from very broad (CSTR) to relatively narrow (Plug Flow Reactor) . Another object of the present invention is to provide a continuously operated miniature laboratory reactor, which can operate with very low volumetric flow rates (in the order of microliters per minute) .

A further object of the present invention is to provide a system in which many chemical experiments can be carried out in parallel, with predetermined different conditions in every single microreactor. At least one of the above objects is attained with an apparatus for conducting chemical experiments on micro scale, involving a reaction mixture comprising at least one reactant, the apparatus comprising a housing in which a channel for fluid transfer is formed, wherein said at least one reactant can form a product, said channel having the form of a closed loop of at most 50 ml, wherein said housing comprises at least one first inlet channel, connected to said loop channel, for feeding the at least one reactant into said loop channel, and at least one first outlet channel, connected to said loop channel, for discharging said product from said loop channel, and wherein said apparatus further comprises a circulation device for circulating the reaction mixture through said loop channel.

With the apparatus according to the present invention, chemical or biochemical reactions requiring long reaction times can be performed on a small scale.

Circulating the reactants in the loop channel enables mixing of the reaction mixture, that may comprise one or more reactants and a reaction product, with the starting materials fed through the first inlet. Further, circulation improves heat transfer and prevents substantial clogging of the microreactor.

The word micro and the word miniature, although not meant to be limiting, refer to a volume of at most 50 milliliter. The wording loop channel indicates an endless continued channel wherein the fluid can flow. Closed loop reactors having large scale dimensions exist, but are used in production environments, and have entirely different characteristics regarding mixing and heat transfer than the microreactor disclosed in the present invention. In addition, these reactors have large dimensions, and can therefore not be used for combinatorial chemistry. These large reactors cannot operate without major temperature gradients and concentration gradients of the reactants in the reactor when highly exothermic reactions are performed, whereas the present invention achieves excellent mixing and high heat transfer characteristics, resulting in a virtually gradient- free reaction environment.

In a preferred embodiment, the apparatus comprises a housing made up of at least two mating parts, at least one of said parts having a recess forming the loop channel. The parts are preferably plates of a metallic material or another suitable material. In at least one plate, a recess is applied, which forms the channel. Preferably, the recess is applied in both plates, both recesses having a semi-circular form. When the two plates are fixed together, the two recesses then form a circular channel, which conveniently defines the loop. In this way, a sturdy reactor can be made, which is relatively easy to construct.

In a further preferred embodiment, the circulation device is positioned external to the housing, wherein a second outlet is formed in the housing, connecting the loop channel to said circulation device, and wherein a second inlet channel is formed in the housing, connecting the circulation device with the loop channel. According to this embodiment, the circulation device can be positioned within the loop channel, the loop channel leaving the housing through the second outlet, passing through the circulation device and re-entering the housing through the second inlet. It is however also possible to divert the fluid from the loop channel in the housing through the circulation device and from the circulation device back into the loop channel in the housing. This has the advantage of providing easy access to the circulation device, thereby enabling convenient maintenance. However, the circulation device may also be incorporated within the housing.

In a preferred embodiment, the apparatus has a cross-sectional area of said loop channel of at most 100 mm², preferably at most 20 mm². These dimensions make the reactor suitable for operating in laboratory conditions, with a cross-sectional area and a volume which is large enough to prevent clogging for most reactions, and small enough to operate with the small volumes required for laboratory chemistry.

Advantageously, the small size of the reactor makes it intrinsically safe. The result of the product (Volume * Pressure) of the reactor is small even when high pressures are used. This added safety significantly simplifies use in laboratories requiring stringent safety precautions.

The loop channel preferably has a high Area to Volume (A/V) ratio. This provides sufficient heat transfer to avoid local heating effects. The loop channel preferably has a certain minimum cross- sectional area to minimize the likelihood of reactor fouling and to provide the ability to operate the reactor at longer residence times . A larger minimal cross-sectional area of the loop channel also reduces the cost to produce hard-to-make miniature parts. A person who is skilled in the art can determine the required minimal dimensions of the channel . In a preferred embodiment, the cross-sectional area of the loop channel is circular. The circular cross-sectional area improves flow conditions and facilitates cleaning of the reactor.

A further advantage of the apparatus is the fact that it is closed and does not need to be opened to the atmosphere for the feeding of reactants. In this way, problems with reaction contamination by impurities like air and water to which an opened reactor is exposed to are eliminated.

In a preferred embodiment of the apparatus, the loop channel has a volume of at most 10 milliliter. For some reactions, it is possible and desirable to operate with volumes of at most 10 milliliters.

In a preferred embodiment of the apparatus, the loop channel has a volume of at most 5 milliliter. For some reactions, it is possible and desirable to operate with volumes of at most 5 milliliters.

In a preferred embodiment, the apparatus comprises heat-transfer means for adding or removing heat from the loop channel. This heat- transfer means assists in cooling or heating the reactants to a predetermined temperature. In such an apparatus, highly exothermic or endothermic chemical or biological reactions conveniently can be conducted. Conduits may be included, which run through a housing in which the loop channel is provided, the conduits containing a liquid, which may either cool or heat the reactor and the reactants. If a relatively large area/volume ratio and optionally a temperature- regulating device is used in the housing, large quantities of heat may be supplied or removed. The reactor walls are preferably heat conducting, resulting in an excellent temperature control. Electrical, induction or infrared heating may also be used.

In a preferred embodiment, the apparatus comprises a first mixer, positioned upstream of the loop channel, having an inlet for said reactant and an outlet for a reactant mixture, wherein said outlet is connected to the inlet of the loop channel, wherein said first mixer is preferably selected from the group, consisting of a diffusion mixer, a static mixer, a dynamic mixer, and a combination thereof. Preferably this is a static mixer, most preferably a diffusion mixer. The channel dimensions of the mixer should be of approximately the same size as the mean free path of molecules in the liquid phase (1-50 microns) . The diffusion mixer provides, therefore, highly efficient mixing by molecular interdiffusion even for extremely low flows where laminar flow conditions prevail. Implementation of such a mixer allows for the use of fluidic feed pumps exhibiting exceptionally low flow rates, which conveniently results in the production of only miniscule amounts of products, which significantly simplifies implementation in the laboratory. The first mixer can be positioned outside the housing, e.g. connected to the first inlet, but may also be incorporated within the said housing.

Preferably , the reactants are only mixed in the diffusion mixer prior to entry into the loop channel for those instances where it is possible to attain a mixing time, which is substantially faster than the reaction time. This is necessary to avoid excess heat being produced in the micromixer or fouling occurring due to a viscosity increase or particle formation resulting from reaction.

For cases where the reaction rate is faster than the mixing rate the most reactive component is preferably added into the loop channel directly. This option can be provided with an extra inlet to the loop channel. In this way a possible reaction in the mixer is avoided. In the loop channel, adequate heat removal may be provided to avoid local heating effects. For instances where fouling is not a concern, the mixer upstream of the loop channel may be replaced by a dispersion nozzle or other device, adequately suited to providing the necessary mixing for the apparatus under question.

Preferably, the volume of the loop channel is large compared to the volume of the mixer, upstream of the loop channel. This enables maintaining a low volumetric flow rate entering the apparatus, while at the same time enabling relatively large residence times of the reactant in the loop channel .

In order to keep the average residence time in the mixer small compared to the average residence time in the loop channel, the volume of the mixer is preferably substantially smaller than the volume of the loop channel. In a preferred embodiment, the loop channel has a volume which is at least 10 times the volume of the first mixer.

In a preferred embodiment, the apparatus comprises a second mixer, which is positioned inside said loop channel, wherein said second mixer is preferably selected from the group, consisting of a static mixer, a dynamic mixer, and a combination thereof. A further mixing process in the loop channel results in homogenization of the reaction mixture. The circulation of the reactants and the mixing prevent major temperature and concentration gradients from forming inside the reactor. Circulation also results in continuous dilution of fresh feed by reactant, which results in a lowering of the reaction rate with a respective decrease in the amount of heat produced or consumed by the reaction. This enables the reaction to be carried out much more isothermally than would otherwise be possible. In a preferred embodiment said second mixer is a static mixer. This provides excellent mixing and a high gas/liquid mass transfer coefficient. This mixer should preferably result in the formation of small gas bubbles for instances where gas/liquid combinations are being investigated. The mixer may also provide excellent mixing for at least two fluids exhibiting largely different dynamic viscosities. This mixer preferably directs flow in such a way as to enhance the heat transfer from the fluid to the wall, hence providing optimum temperature control over the reaction.

It is also possible for the second mixer to be a dynamic mixer such as an impeller or homogenizer, incorporated into the loop channel to realize adequate gas dispersion, solids suspension or other mixing.

The term "second mixer" is used herein to discriminate from the first mixer described above; however, the apparatus according to the present invention may very well comprise a second mixer without a first mixer being present, or vice versa.

In a preferred embodiment, the circulation device is a pump. The pump used for the loop channel preferably provides a sufficiently high volumetric flow rate to allow for a high recycle ratio, excellent mixing and high heat-transfer coefficients. The pump chosen is preferably inert for the media and reactants that are pumped. In particular, pumps capable of coping with solids suspensions are preferred. Micro gear pumps or micro-membrane pumps are ideally suited for this purpose.

In another preferred embodiment, the apparatus further comprises measurement means connected with the loop channel, selected from the group consisting of pressure measurement means, temperature measurement means, spectroscopic measurement means, volumetric flow sensors, and a combination thereof. The measurements provide information on the degree of completion of the reaction and the selectivity of reaction to particular products. In a preferred embodiment, the measurement means are connected to a control means, which effects a variation in the process conditions based on a pre-determined response to variations in the measured parameter. With this information, the process can be ended or prolonged according to the objectives of the experiment.

In a preferred embodiment, the apparatus further comprises a support for a solid reactant positioned within said loop channel. Some reactions need catalyzing in order to start or to continue reaction. In one instance this is accomplished by adding a solid catalyst into the loop channel. If the catalyst is a solid, it may be restricted to the loop channel via the incorporation of a separation means in the feed and outlet lines to and from the loop channel. Preferably, a sintered frit, membrane or other separation means is employed, when a gas/liquid/solid or liquid/solid slurry solution is investigated. The separation means prevents solid catalyst from coming into contact with valves, which may be damaged by abrasive solids. In a preferred embodiment, the support is removable from the loop channel. This enables rapid replacement of the catalyst in an easy manner.

In a preferred embodiment, the apparatus further comprises a sample outlet connected with the loop channel, for discharging a sample from the loop channel. If a sufficiently high internal recycle rate is used, no major concentration gradients will exist within the reactor. The location for sampling will no longer be critical because the concentration of reactants and products is the same at every point within the loop channel. Sampling of the reactants provides information into the degree of completion of the reaction and the selectivity of the reaction. With this information, the process can be ended or prolonged according to the objectives of the experiment. In a preferred embodiment, the sample outlet comprises a frit for separating any solid catalyst suspended in said loop channel from said at least one reactant and product. The frit prevents any solids to exit the loop channel . The apparatus according to the invention preferably comprises a fluid conduit in the housing, for providing heating and/or cooling fluid to the said housing. The housing can thus be kept at a predetermined temperature, therewith controlling the temperature of the reaction mixture in the loop channel. In another embodiment, the housing of the apparatus according to the invention comprises recesses for receiving heating or cooling cartridges. Preferably, these recesses are located in close vicinity of the loop channel to provide optimal temperature transfer between the cartridge and the reaction mixture within the loop channel . The invention also relates to an assembly for conducting at least two chemical experiments in parallel, comprising a first and at least one second apparatus according to the invention, wherein the first inlets of the first and the at least one second apparatus are connected to a common inlet. Advantageously, in such an apparatus a plurality of reactions can take place in parallel.

Preferably, the first outlets of the said first and the said at least one second apparatus are connected to a common outlet. Preferably, any measurements are performed upstream of the common outlet, as within the outlet a mixture of different reaction mixtures is collected.

In a further preferred embodiment of the present invention, said first and said at least one second apparatus are designed as modules. The reactors are implemented as a module, comprising e.g. the loop channel, circulation device, the second static mixer, and, if present, any catalyst holder, valves and measurement means. This facilitates the ease of operation. The word module indicates that these components are fixed together in a sturdy way and can be handled as a single object. The modules can be similarly arranged and operated in large numbers .

Such a modular system may be completely automated and a plurality of chemical or biochemical reactions can be conducted simultaneously and in a very easy manner. In a further preferred embodiment of the present invention, the assembly comprises a common fluid transfer manifold, the manifold comprising at least one inlet for entry of at least one reactant into said manifold, the inlet being connected to the first inlets of the first and the at least one second apparatus . This enables a convenient arrangement of the modules and good supply of the at least one reactant to the modules .

In a further preferred embodiment of the present invention, the assembly comprises a common fluid transfer manifold, the manifold comprising, at least one outlet for discharging at least one reactant from said manifold, the outlet being connected to the first outlets of the first and the at least one second apparatus. This enables a convenient arrangement of the modules and good discharge of product from the modules . In a preferred embodiment, the loop channels of the apparatuses have identical volumes. This has the advantage of providing similar conditions for the reactions. The loop channels may however have different volumes. This enables performing experiments in which different dimensions of the reactor are to be simulated or where different residence times are studied while using the same feed flows for all reactors.

In a further preferred embodiment of the present invention, the assembly comprises a common mixer, positioned upstream of the loop channels of the first and at least one second apparatus, said mixer being selected from the group, consisting of a diffusion mixer, a static mixer, a dynamic mixer, and a combination thereof. This has the particular advantage that all reactants are well mixed, with using a single mixer.

In a further preferred embodiment of the present invention, the assembly comprises the loop channels of the first and at least second apparatus each being connected to a separate mixer upstream of the respective loop channel for mixing of the at least one reactant prior to entry in respective loop channel, wherein each said mixer is selected from the group, consisting of a diffusion mixer, a static mixer, a dynamic mixer, and a combination thereof. The mixer can be incorporated in the module. When the mixing is executed directly before the entry of the reactants into their respective loop channels, there advantageously is no time lag between the mixing and the entry into the loop channel. This minimizes the extent of reaction prior to the introduction of the reactants into the recycle loop channel, resulting in well-controlled, reproducible experimental conditions . In a further preferred embodiment of the present invention, the apparatuses are arranged in parallel. This enables an orderly operation of the experiments.

In a further preferred embodiment of the present invention, the circulation devices of the modules of the modular system are driven from a single drive mechanism. This has the advantage of limiting the number of mechanical parts necessary for the system.

In a further preferred embodiment of the present invention, the apparatus has a module connection device with which the modules can be coupled to and decoupled from the common fluid transfer manifold in one single operation. This has the advantage of simplifying the coupling operation and reducing the risk of damaging one or more of the connectors.

A further aspect of the present invention relates to a method for simulating operating conditions of a Constantly Stirred Tank Reactor (CSTR) at micro level, involving at least one reactant, the method comprising the steps of:

- feeding said at least one reactant into a loop channel, having a volume of at most 50 milliliter, for forming a product from said at least one reactant; - circulating said at least one reactant in said loop channel, for a predetermined residence time period, thereby mixing said formed product with said at least one reactant; and

- removing said product from said loop channel .

A Constantly Stirred Tank Reactor is difficult to scale down to micro proportions, e.g. because the stirring with a dynamic mixer becomes problematic. As outlined above, micro reactors comprising a loop channel enable the required backmixing for optimal simulation of reactions performed in a CSTR. The advantage of the present method is that a very good simulation of reaction conditions of a CSTR can be obtained at micro scale.

Preferably, the reactant is continuously fed to the loop channel. Preferably the product is also continuously removed from the loop channel, although batchwise or intermittent feeding or removal is also possible. Advantageously, a continuous process in a CSTR can in this way be simulated. By feeding reactants to a loop channel in which the reactants are circulated and continuously removed, and by independently varying the reactant feed volumetric flow rate relative to the internal recycle rate, a wide range of residence time distributions may be obtained.

The feeding of the reactants to the recycle loop may be conducted at very low volumetric flow rates, e.g. microliters per minute, while the circulation of the reactants through the loop may be conducted at higher flow rates, e.g. milliliters per minute. By feeding reactants at a low flow rate and recycling them at a high flow rate it is possible to obtain a high recycle ratio and an essentially temperature-, pressure- and concentration-gradient-free system. Preferably, the method comprises the further step of heating or cooling said at least one reactant with a heat transfer means to add or remove heat during reaction. In this way, highly endothermic and exothermic reactions can be conducted isothermically.

Preferably, the reactant is mixed in a first mixer, positioned upstream of said loop channel, prior to the entry into said loop channel. Preferably this mixing is performed by means of diffusion mixing. Advantageously, the reactants are completely mixed upon entry into the loop channel .

Preferably, the method comprises the further step of mixing said at least one reactant in said loop channel by a second mixer, positioned inside said loop channel, wherein said second mixer is preferably selected from the group, consisting of a static mixer, a dynamic mixer, and a combination thereof. This has the advantage of providing mixing of the formed product with the reactant. Preferably, said second mixing step inside the loop channel is static mixing. This provides good mixing for most reactions and provides good heat exchange with the reactor wall and circumvents the use of additional mechanical parts in the loop channel.

Preferably, the method comprises the further step of circulating the reactant inside said loop channel by means of a pump. This provides excellent circulation with full control of the discharge, with the possibility of having a discharge in the order of milliliters per minute .

In a preferred embodiment of the method of the present invention, the reactant has a residence time in said loop channel considerably longer than the residence time in said first mixer, positioned upstream of said loop channel . In a further preferred embodiment of the method of the present invention, the reactant has a residence time in said loop channel of at least ten times the residence time in said first mixer, positioned upstream of said loop channel. In a further preferred embodiment of the method of the present invention, the reactant has an average residence time in said mixer, positioned upstream of said loop channel, of at most 1 second.

The reaction may start as soon as the reactants are mixed. It is desirable that the reaction takes place in the reactor and not in the diffusion mixer. Therefore, the residence time in the diffusion mixer needs to be small compared to the residence time in the loop channel.

Preferably, the residence time in the diffusion mixer is kept as short as possible.

In a preferred embodiment of the present invention, the method comprises the further steps of performing at least one measurement, preferably selected from the group, consisting of pressure measurements, temperature measurements, spectroscopic measurements, volumetric flow measurements and a combination thereof.

Advantageously, these measurements can be used to control the experiment. Also, the results of the said measurements can be used to determine the reaction kinetics for the performed reaction.

In a preferred embodiment of the present invention, the method comprises the further step of catalyzing said at least one reactant in said loop channel. Some reactions need catalyzing to start or to continue. Introducing a catalyst inside the loop advantageously enables conducting these reactions .

In a preferred embodiment of the present invention, the method comprises the further step of adding a charge of solid catalyst to said loop channel. Some reactions need a solid catalyst to start or to continue. Introducing a solid catalyst inside the loop channel advantageously enables conducting these reactions. In a preferred embodiment of the present invention, the method comprises the further step of taking at least one sample from said loop channel, during circulation of said at least one reactant in said channel. Sampling of the formed product provides the particular advantage of providing better insight in the state of the reaction. The results of the sampling may be used to control the reaction. The solid catalyst may be separated from the sample by means of a frit.

In a further preferred method of the invention, at least two operating conditions of a Constantly Stirred Tank Reactor (CSTR) at micro level are simulated in parallel, involving at least one reactant, said method comprising the steps of:

- providing a first and at least one second apparatus according to the invention, wherein the inlets of said apparatuses are connected to a common inlet; - feeding said at least one reactant to the loop channel of said first and at least one second apparatus for forming a product from said at least one reactant;

- circulating said at least one reactant in said first and said at least one second loop channel, for a predetermined residence time period, thereby mixing said formed product with said reactant; and

- removing said product from said first and said at least one second loop channel.

This method provides the particular advantage of performing combinatorial chemistry with the characteristics of a CSTR.

In a further preferred embodiment of the present invention, the loop channels are heated or cooled to different temperatures.

Advantageously, this provides the possibility of comparing the results of the same chemical reaction at different temperatures . In a further preferred embodiment of the present invention, the loop channels are pressurized to different pressures. Advantageously, this provides the possibility of comparing the results of the same chemical reaction at different pressures.

In a further preferred embodiment of the present invention, the loop channels contain different catalysts. Advantageously, this provides the possibility of comparing the results of the same chemical reaction with different catalysts. In a further preferred embodiment of the present invention, the loop channels have different residence times. Advantageously, this provides the possibility of comparing the results of the same chemical reaction at different residence times. The claims and advantages will be more readily appreciated as the same becomes better understood by reference to the following detailed description and considered in connection with the accompanying drawings in which like reference symbols designate like parts. Brief description of the drawings Figure 1 is a schematic view of an apparatus according to the invention.

Figure 2 is a view of a front plate of a housing of the apparatus according to the invention.

Figure 3 is a view of a back plate of a housing of the apparatus according to the invention.

Figure 4 is a schematic view of the arrangement of the housing of Fig. 2 and Fig. 3 on top of a connector.

Figure 5 is a schematic perspective view of a modular system with three housings arranged in an array, connected to a common fluid transfer manifold.

Detailed description of the invention

Figure 1 shows a schematic view of a chemical or biochemical reactor in accordance with one embodiment of the invention. The assembly includes fluid supply channels 1, 2 leading into a micromixer 3. These supply channels can supply liquid, gas or vapor reactants to the micromixer 3. The micromixer 3 has an outlet 4, which is connected to an inlet 5 of a closed loop channel 6. The channel 6 comprises a circulation device 7, which may be a pump. A 3-way valve 8 is located in the channel, the valve 8 having an inlet 9, and two outlets 10, 11. One outlet 10 of the valve 8 may be connected to a main outlet 12, which can be used to drain a product from the channel 6. The other outlet 11 of the valve 8 is connected to the channel 6. Thus, the reactants flowing through the 3-way valve 8 may be directed either into the channel 6 or into a main outlet 12. Note that a 3-way valve may be supplemented with a number of 2- way valves if necessary. A portion of the fluid circulating in loop channel 6 is continuously removed via channel 16. This fluid is then channeled into line 12 where product may be collected and/or analyzed.

The loop channel 6 may comprise a second mixer 13. The second mixer 13 is configured to be in line with the loop channel 6. This mixer is preferably located directly downstream of the fluid inlet 5 into the loop channel 6 in order to provide rapid mixing of any reactant entering with the reactant/product mixer flowing in the loop channel. Preferably, as much of loop channel 6 as possible contains mixing elements in order to effect the best mixing possible.

A removable catalyst holder 14 is located in the loop channel 6. In this device, a catalyst can be placed to enhance the reaction in the loop channel 6.

Optionally, a solid catalyst may be suspended as a slurry in solution in loop channel 6. The solid portion is contained within loop channel 6 via the incorporation of separations means in fluidic inlets and outlets. Such separations means may take the form of a membrane, structured or sintered frit made of an appropriate material.

An analytical device 15, such as a spectroscopic measurement device, can be provided at a location in the loop channel. In addition to the main outlet 12, a sample outlet 16 may be provided to discharge samples from the loop channel 6.

The loop channel 6, inlet 5, second mixer 13, catalyst holder 14, analytical device 15, pump 7 and 3-way valve 8 may be enclosed in a housing 17 which is implemented as a module.

A fluid consumption measuring device may be located in feed lines 1,2, 4 or in the loop channel 6. Preferably, a fluid-consumption measuring device is located in feed line 1 or 2. In a preferred embodiment, this fluid-consumption measuring device comprises a mass flow meter used for measuring the amount of fluid, such as gas, consumed during a reaction. In another embodiment, this fluid- consumption measuring device contains a series of valves and pressure sensors configured to repeatedly add fluid to the loop channel 6 when the pressure in loop channel 6 drops below a certain, predefined value. When the fluid comprises gas, the pressure-sensor in this configuration measures the amount of fluid added to the loop by measuring the pressure drop in a reservoir, in which the fluid to be added is contained.

The reactor may optionally be provided with pressure sensors (not shown) e.g. upstream and downstream of the second mixer 13. The measured pressure drop is a function of the reactant and product viscosity. Measuring the pressure drop over the mixer during reaction provides a way of measuring viscosity changes on-line. The reactor may also be provided with a temperature sensor (not shown) to measure the existing temperatures at points in the loop channel. Liquids, vapors and/or gasses are dosed to the micromixer 3 using dosing means 18, which can be pumps, mass-flow, volumetric-flow controllers or other means . The micromixer can mix liquid/liquid or gas/liquid feeds with a flow in the order of microliters per minute. The micromixer 3 comprises a multitude of channels having diameters of 0.01 to 0.1 mm.

The progress of the reaction may be followed in real-time using a sampling outlet 16 and/or various spectroscopic techniques or other analytical equipment. The sampling outlet is preferably connected to a liquid-sampling robot, which is capable of taking fluid samples at regular intervals.

If spectroscopy is used, data acquisition will preferably occur with a high speed (in the order of milliseconds) . The reaction parameters of interest can be continuously monitored over time and a computer-controlled feedback system may vary reaction parameters . This feedback control may be programmed to effect certain parameter changes upon sensing a particular response. For example, the reactor may be programmed to switch to a higher operating temperature if a decrease in conversion is sensed.

The small volume of the reactor of at most 50 milliliter makes it compact, intrinsically safe and allows far better control of highly exo- and endothermic reactions.

Although not shown, the apparatus may comprise one or more additional inlets, connected to the loop, e.g. for feeding of reactants or katalysts. Figures 2 and 3 show a particular embodiment of a modular apparatus according to the invention. The modular reactor consists of two plates, a front plate 41 and a back plate 54. The two plates form the housing. The front plate 41, shown in Fig. 2, defines part of a channel 42, which is closed when the front and back plate are mounted on to each other. A front plate 41 comprises an inlet 49 for feeding a reactant. A static mixer 43 is located in the channel 42. Upstream and downstream of the static mixer 43, connections 44, 45 for pressure sensors are placed in the channel 42. At the bottom of the channel 42, an outlet 46 is defined, that may be connected to a pump. An inlet 47 is also defined, through which the reactants, which have passed the pump, reenter the channel 42. Between the outlet 46 and the inlet 47, the channel 42 is closed by a closure means 48. A product outlet 50 is defined in the channel 42. A holder 51 for a removable catalyst bed is also present in the channel 42. The housing may be constructed as a two-piece metallic housing of stainless steel or any other suitable material. In the back plate of the reactor 54, two Kalrez O-ring seals 52 and 53 seal the channel 42. Both the front plate 41 and the back plate 54 have holes for mounting screws 55, which fix the two plates 41,54 together. In a preferred embodiment, the screws are replaced by a simple clamping mechanism, which allows for greatly simplified opening and closing of the reactor.

The front and back plates 41,54 typically have a width of around 10 cm and a height of 5 - 10 cm.

Figure 4 illustrates the modular design of the reactor. The reactor 60 has a reactor connector 61, which connects all inlets, outlets and electrical connections of the module to a manifold connector 62, located on a common fluid transfer manifold (which is not shown) . The reactor connector 61 and the manifold connector 62 may be connected to each other by means of a locking pin 63. A lever 64 is provided to connect and disconnect the two connectors 61, 62 to and from each other, respectively. The manifold connector has two inlets

65, 66 through which the reactants can be fed. It also has an outlet 67 through which the product can leave the reactor. A micro pump 68 is connected to the manifold connector 62, and pumps the reactants through the closed loop channel 42 of the reactor 60. The connectors 61 and 62 also comprise electrical connectors 69 and 70. The electrical connectors 69 and 70 transmit control signals to operate the sensors and actuators in the reactor.

Figure 5 illustrates a modular system, having a common fluid transfer manifold 80, comprising central liquid inlets 81 and 82. A central product outlet 83 is positioned alongside the liquid inlets 81 and 82. An electric connector 84 is located near the liquid inlets 81 and 82. Figure 5 shows three modules 90, 91 and 92. The inlets of modules 91 and 92 are in communication with the inlets 81 and 82 of the common fluid transfer manifold 80, whereas the outlets of the said modules are in communication with the outlet 83 of the manifold 80 (not shown) . Module 90 is disconnected from the common fluid transfer manifold 80. Levers 100, 101 and 102 are provided to connect and disconnect each module from the common fluid transfer manifold 80. On the common fluid transfer manifold, a manifold connector 103 is illustrated to which a module can connect. For clarity purposes, the modules are illustrated as spaced relatively far apart. In a true model, the spaces between the modules may be considerably smaller.

While the invention has been described and illustrated in its preferred embodiment (s) , it should be understood that departures may be made therefrom within the scope of the invention, which is not limited to the details disclosed herein.

Claims

C L A I S

1. An apparatus for conducting chemical experiments on micro scale, involving a reaction mixture comprising at least one reactant, the apparatus comprising a housing in which a channel for fluid transfer is formed, wherein said at least one reactant can form a product, said channel having the form of a closed loop of at most 50 ml, wherein said housing comprises at least one first inlet channel, connected to said loop channel, for feeding the at least one reactant into said loop channel, and at least one first outlet channel, connected to said loop channel, for discharging said product from said loop channel, and wherein said apparatus further comprises a circulation device for circulating the reaction mixture through said loop channel.

2. The apparatus according to claim 1, comprising a housing made up of at least two mating parts, at least one of said parts having a recess forming the loop channel.

3. The apparatus according to claim 1 or 2, wherein the circulation device is positioned external to the housing, and wherein a second outlet is formed in the housing, connecting the loop channel to said circulation device, and wherein a second inlet channel is formed in the housing, connecting the circulation device with the loop channel.

4. The apparatus according to any of claims 1 - 3, wherein the cross-sectional area of said loop channel is at most 100 mm², preferably at most 20 mm².

5. The apparatus according to any of claims 1 - 4, wherein said cross-sectional area of said loop channel is circular.

6. The apparatus according to any of the preceding claims, wherein said loop channel has a volume of at most 10 milliliter.

7. The apparatus according to any of the preceding claims, wherein said loop channel has a volume of at most 5 milliliter.

8. The apparatus according to any of the preceding claims, further comprising a heat-transfer means for adding or removing heat from the loop channel .

9. The apparatus according to any of the preceding claims, further comprising a first mixer, positioned upstream of the loop channel, having an inlet for said reactant and an outlet for a reactant mixture, wherein said outlet is connected to the inlet of the loop channel, wherein said first mixer is preferably selected from the group, consisting of a diffusion mixer, a static mixer, a dynamic mixer, and a combination thereof.

10. The apparatus according to claim 9, wherein said first mixer is a diffusion mixer.

11. The apparatus according to any of claims 9 - 10, wherein the loop channel has a volume which is at least 10 times the volume of said first mixer.

12. The apparatus according to any of the preceding claims, further comprising a second mixer, which is positioned inside said loop channel, wherein said second mixer is preferably selected from the group, consisting of a static mixer, a dynamic mixer, and a combination thereof.

13. The apparatus according to claim 12, wherein said second mixer is a static mixer.

14. The apparatus according to any of the preceding claims, wherein said circulation device is a pump.

15. The apparatus according to any of the preceding claims, further comprising measurement means connected with the loop channel, selected from the group consisting of pressure measurement means, temperature measurement means, spectroscopic measurement means, volumetric flow sensors, and a combination thereof.

16. The apparatus according to any of the preceding claims, further comprising a support for a solid reactant positioned within said loop channel .

17. The apparatus according to claim 16 wherein said support is removable from the loop channel .

18. The apparatus according to any of the preceding claims, further comprising a sample outlet connected with the loop channel for discharging a sample from the loop channel.

19. The apparatus according to claim 18, wherein said sample outlet comprises a frit for separating any solid catalyst suspended in said loop channel from said at least one reactant and product.

20. The apparatus according to any of claims 8 - 19, further comprising a fluid conduit in said housing, for providing heating or cooling fluid to the housing.

21. The apparatus according to any of claims 8 - 20, wherein the housing comprises recesses, for receiving heating or cooling cartridges.

22. An assembly for conducting at least two chemical experiments in parallel, comprising a first and at least one second apparatus according to any of the previous claims, wherein the first inlets of the first and the at least one second apparatus are connected to a common inlet .

23. The assembly according to claim 22, wherein the first outlets of the said first and the said at least one second apparatus are connected to a common outlet.

24. The assembly according to claim 22 or 23, wherein said first and said at least one second apparatus are modules.

25. An assembly according to any of claims 22 to 24, comprising a common fluid transfer manifold, the manifold comprising at least one inlet for entry of at least one reactant into said manifold, the inlet being connected to the first inlets of the first and the at least one second apparatus .

26. An assembly according to any of claims 22 to 25, comprising a common fluid transfer manifold, the manifold comprising, at least one outlet for discharging at least one reactant from said manifold, the outlet being connected to the first outlets of the first and the at least one second apparatus.

27. The assembly according to any of claims 22 - 26 wherein the loop channels of the apparatuses have identical volumes .

28. The assembly according to any of claims 22 - 27, further comprising a common mixer, positioned upstream of the loop channels of the first and at least one second apparatus, said mixer being selected from the group, consisting of a diffusion mixer, a static mixer, a dynamic mixer, and a combination thereof.

29. The assembly according to any of claims 22 - 27, the loop of the first and at least second apparatus each being connected to a separate mixer upstream of the respective loop channel for mixing of the at least one reactant prior to entry in respective loop channel, wherein each said mixer is selected from the group, consisting of a diffusion mixer, a static mixer, a dynamic mixer, and a combination thereof.

30. The assembly according to any of claims 22 - 29, wherein said apparatuses are arranged in parallel.

31. The assembly according to any of claims 22 - 30 wherein said circulation devices in the different apparatuses are driven from a single drive mechanism.

32. The assembly according to any of claims 25 - 31, wherein each apparatus has a connection device with which said at least one apparatus inlet and said at least one apparatus outlet can be coupled to and decoupled from said common fluid transfer manifold in one single operation.

33. A method for simulating operating conditions of a Constantly Stirred Tank Reactor (CSTR) at micro level, involving at least one reactant, said method comprising the steps of:

- feeding said at least one reactant into a loop channel, having a volume of at most 50 milliliter, for forming a product from said at least one reactant;

- circulating said at least one reactant in said loop channel, for a predetermined residence time period, thereby mixing said formed product with said at least one reactant; and

- removing said product from said loop channel.

34. The method according to claim 33, wherein the said reactant is continuously fed to the loop channel.

35. The method according to claim 33 or 34, wherein the said product is continuously removed from the loop channel.

36. The method according to any of claims 33 - 35, comprising the further step of heating or cooling said at least one reactant with a heat-transfer means to add or remove heat during reaction;

37. The method according to any of claims 33 - 36, comprising the further step of mixing said at least one reactant in a first mixer, positioned upstream of said loop channel, prior to the entry into said loop channel .

38. The method according to claims 33 - 37, wherein said mixing, prior to entry in said loop channel, is diffusion mixing.

39. The method according to any of claims 33 - 38, comprising a second mixing step of said at least one reactant by a second mixer, positioned inside said loop channel, wherein said second mixer is selected from the group, consisting of a static mixer, a dynamic mixer, and a combination thereof.

40. The method according to any of claims 33 - 39, wherein said second mixing step, inside said loop channel, is static mixing.

41. The method according to any of claims 33 - 40, wherein said at least one reactant is circulated inside loop channel by means of a pump.

42. The method according to any of claims 33 - 41, wherein said at least one reactant has a residence time in said loop channel considerably longer than the residence time in said first mixer, positioned upstream of said loop channel.

43. The method according to any of claims 32 - 41, wherein said at least one reactant has a residence time in said loop channel of at least ten times the residence time in said first mixer, positioned upstream of said loop channel .

44. The method according to any of claims 32 - 42, wherein said at least one reactant has an average residence time in said first mixer, positioned upstream of said loop channel, of at most 1 second.

45. The method according to any of claims 32 - 43, comprising the further steps of performing at least one measurement, preferably selected from the group, consisting of pressure measurements, temperature measurements, spectroscopic measurements, volumetric flow measurements and a combination thereof.

46. The method according to any of claims 32 - 44, comprising the further step of catalyzing said at least one reactant in said loop channel .

47. The method according to any of claims 32 - 45, comprising the further step of adding a charge of solid catalyst to said loop channel .

48. The method according to any of claims 32 - 46, comprising the further step of taking at least one sample from said loop channel, during circulation of said at least one reactant in said loop channel.

49. A method for simulating at least two operating conditions of a Constantly Stirred Tank Reactor (CSTR) at micro level in parallel, involving at least one reactant, said method comprising the steps of:

- providing a first and at least one second apparatus according to claims 1 - 21, wherein the inlets of said apparatuses are connected to a common inlet;

- feeding said at least one reactant to the loop channels of said first and at least one second apparatus for forming a product from said at least one reactant; - circulating said at least one reactant in said first and said at least one second loop channels, for a predetermined residence time period, thereby mixing said formed product with said reactant; and

- removing said product from said first and said at least one second loop channels.

50. The method according to claim 48 wherein the loop channels are heated or cooled to different temperatures.

51. The method according to claim 48 or 49 wherein the loop channels are pressurized to different pressures.

52. The method according to any of claims 48 - 50 wherein the loop channels contain different catalysts.

53. The method according to any of claims 48 - 51 wherein the loop channels have different residence times.