US20100129917A1

US20100129917A1 - Method and installation for determining at least one parameter of a physical and/or chemical conversion

Info

Publication number: US20100129917A1
Application number: US12/445,224
Authority: US
Inventors: Pascal Panizza; Cristobal Galder; Bertrand Pavageau; Annie Colin
Original assignee: Universite des Sciences et Tech (Bordeaux 1); Rhodia Operations SAS
Current assignee: Universite des Sciences et Tech (Bordeaux 1); Rhodia Operations SAS
Priority date: 2006-10-13
Filing date: 2007-10-15
Publication date: 2010-05-27
Also published as: FR2907227A1; US8318871B2; US20100152395A1; JP5329416B2; FR2907227B1; JP2010506187A; WO2008043922A2; EP2076782A2; WO2008043922A3; WO2008043860A1; EP2126591A1

Abstract

A method, in which a succession of plugs (G) made of a physicochemical system capable of conversion in a carrier phase (P) is made to flow, in a tubular flow member (12), and at least one analysis of at least one plug is carried out and the or each parameter is deduced therefrom.

Description

The present invention relates to a method and an installation for determining at least one parameter of a physical and/or chemical conversion, and to a corresponding screening method.
The term “conversion” is understood to mean any type of interaction that can occur in a mixture of at least two components. Without being limiting, this conversion may be a reaction of the chemical and/or physical type, such as, for example, any type of conventional chemical reaction, especially polymerization reactions, and also a crystallization or a precipitation or a gelling, or else inter alia a modification of a liquid/vapor equilibrium. In general, within the context of the invention, such a conversion can involve chemical phenomena, by exchange or sharing of electrons, physical interactions or repulsions, such as hydrogen bonds, electrostatic interactions, steric repulsions or attractions, affinities for various hydrophilic and/or hydrophobic media, formulation stabilities, flocculations or phase transfers, for example of the liquid/liquid, solid/liquid or gas/liquid type.
Within the context of the invention, the parameters of such a conversion are, without being limiting, the chemical reaction rates in a homogeneous or heterogeneous medium, the conditions for obtaining an optimum chemical reaction yield, reaction enthalpies, time-varying chemical and physical reaction processes, and solubility diagrams or phase diagrams.
The parameters of a conversion have already been determined using the technique of microfluidic flows.
Such microfluidic flows have for example been described by M. Madou in “Fundamentals of Microfabrication: The Science of Miniaturization”, CRC Press, (1997). They make use of mechanical systems of micron-scale and/or nanoscale size that enable very small fluid volumes to be handled. Such miniaturization, coupled with the use of appropriate analytical techniques, opens the way to very many applications in fields as diverse as biology, analytical chemistry, chemical engineering and physics.
This technique thus makes it possible to envision for example a number of chemical processes on a chip so as to recreate a laboratory on a particularly small surface, with an area of a few cm², i.e. a “lab-on-chip”: see in particular J. Knight, Nature, 418, 474, (2002). Such miniaturization thus offers great potential in the field of chemical engineering, with a view to increasing selectivity and yield of the reactions involved.
The use of plugs, particularly droplets, in the microfluidic field proves to be very promising. This is because such droplets, of extremely small volume, typically between 1 picoliter and 1 nanoliter, enable chemical reactions to be carried out within them. This has for example been described by B. Zheng, L. S. Roach, and R. Ismagilov in J. Am. Chem. Soc. 125, 11170, (2003). Moreover, microfluidic production techniques allow monodisperse droplets to be formed with a constant production rate.
As a consequence, the droplets, which thus form nanoreactors, flow at a constant rate so that an equivalence exists between the distance travelled and the reaction time. In other words, a droplet located at a given point in the fluidic flow system is representative of the investigated reaction at a given instant. By combining conventional analytical techniques, of the Raman, infrared, visible or fluorescent type, it is then possible to monitor the reaction kinetics and adjust the composition of the droplets, in order for the optimum chemical reaction conditions to be very rapidly screened, while using only very small volumes of reactants.
Although the microfluidic technique has many advantages, such as those mentioned above, it does have, however, certain drawbacks. Firstly, it is accompanied by a relatively high implementation cost, owing in particular to the use of the soft lithography technique. Secondly, microfluidic flow devices cannot be easily modulated. Finally, the microfluidic technique does not allow certain types of reaction to be studied satisfactorily.
Moreover, in general, there is a constant requirement in the industry to develop new products, having new properties, for example new chemical compounds or new compositions comprising new chemicals and/or new combinations of chemicals. The physical and/or chemical conversions of the products are important properties for many applications, which very often have to be tested in research and development processes. There is a need for methods and installations that accelerate the research and development process, for example so as to test a larger number of products and/or carry out tests on smaller quantities of products and/or to carry out the tests more rapidly and/or to carry out tests relating to conversions that are too slow to be studied in the abovementioned devices of the prior art.
In this regard, the aim of the invention is to provide a method of determining a parameter of a conversion which, whilst still offering the same possibilities as the microfluidic technique overall, substantially remedies the drawbacks associated with the latter.
For this purpose, one subject of the invention is a determination method according to the appended claim 1.
Advantageous features of the invention form the subject matter of the appended claims 2 to 22.
Another subject of the invention is a determination device according to the appended claim 23.
Advantageous features of the invention form the subject matter of the appended claims 24 to 32.
A final subject of the invention. is a screening method according to the appended claim 33.

The invention will be described below with reference to the appended drawings given solely by way of nonlimiting examples, in which:

FIG. 1 is a front view illustrating an installation for determining a parameter of a conversion, in accordance with the invention;

FIGS. 2A and 2B are front views illustrating a plug generation module forming part of the installation of FIG. 1, in which the various components are shown disassembled and assembled relative to one another, respectively;

FIG. 3 is a front view, similar to FIG. 1, illustrating an alternative embodiment of the invention;

FIG. 4 is a front view, similar to FIG. 1, illustrating an additional alternative embodiment of the invention;

FIGS. 5A and 5B are schematic and front views respectively, illustrating means for maintaining a given temperature, with which the installation of the above figures is equipped; and

FIGS. 6 to 8 are front views, similar to FIG. 1, illustrating two additional alternative embodiments.

It should be noted that, according to one method of implementation, the analysis may be carried out at a point downstream of the tubular flow member, for example by spectroscopic techniques (UV spectroscopy, infrared spectroscopy, light scattering, X-ray scattering, Raman spectroscopy, fluorescence, etc.) or optical techniques (microscopy, image analysis, etc.) which may for example give information about the progress of a reaction (by assaying the products formed or the residual reactants, for example, in the case of a polymer, by assaying the residual amounts of monomers). The suitable analytical means are, for this method of implementation, located close to the tubular flow member, at one or more given points along the member. It is not excluded to move the analytical means so as to obtain the information by measurements at various points along the flow and therefore at various stages in the progress of the conversion. Nor is it excluded to place several analytical means, whether identical or different, along the tube. Nor is it excluded for a single analytical means to be able to provide information at several points along the tube, for example optical analysis by photography possibly with image processing. According to another method of implementation, which does not exclude the first one (it may be combined therewith), the analysis may be carried out directly at the outlet of the tubular flow member, preferably without recovering/isolating the plugs exiting said member, for example by chromatographic techniques, especially steric exclusion chromatography suitable for analyzing polymers, which may for example provide information about the precise composition of the conversion product, for example about the characteristics of a polymer, such as its average molecular weight, the distribution of the macromolecular chains and the polydispersity index.
The installation according to the invention shown in FIG. 1 firstly comprises a plug generation module shown schematically in this figure, but illustrated more precisely in FIGS. 2A and 2B. This module, denoted. in its entirety by the reference 1, firstly comprises an approximately cylindrical coupler 2, made of any suitable material, especially a metal or plastic. This coupler 2 has an internal volume V that communicates with the outside via three different pathways.
For this purpose, said member 2 is firstly provided with an upper channel 4 and a lower chamber 6, with reference to FIGS. 2A and 2B. Said channel 4 and this chamber 6, which are coaxial, have respectively a smaller cross section and a larger cross section than that of the internal volume V. Moreover, a lateral channel 8, provided on the right in FIGS. 2A and 2B, is drilled into the coupler 2. A nozzle 10, for example made of PEEK, PTFE, silicone or metal, is fastened by any suitable means to the walls of the outlet of this lateral channel 8.
Various tubular flow members, which will be described below, are joined to the coupler 2. Within the context of the invention, a tubular flow member is an elongate flow member of closed cross section, the transverse profile of which may be of any shape, particularly oval or square. Within the context of the invention, such a member is not provided in a solid body, such as for example a microchannel etched in a wafer.
This member is thus bordered by a thin peripheral wall. Unlike the microfluidic constructions in which two wafer parts are joined together, especially by bonding, this tubular flow member can advantageously be made as a single part.
The various tubular flow members according to the invention may be made of a rigid material, such as, for example, steel. However, as an alternative, they may be made of a semi-rigid, or even flexible, material such as, for example, PTFE, a silicone, PVC, polyethylene or PEEK.
As a variant, a fluorinated product, especially of the PFA type, may also be used. The flow members may also be made of a fused silica. coated with a. polyimide, which it is possible to remove locally in a known manner, especially by means of sulfuric acid, so as to see the inside of the flow member.
Firstly, a first tubular flow member is provided, namely a capillary tube 12 made for example of PTFE or silicone, having an equivalent internal diameter of typically between 10 microns and 50 mm. Furthermore, there are two other tubular flow members, namely two other capillary tubes 13 and 14 made for example of PEEK.
The capillary tube 13 has a smaller equivalent diameter than the capillary tube 14, given that, as will be explained in detail hereinafter, this capillary tube 13 in service passes through the internal volume of the capillary tube 14. In this regard, the typical values of the equivalent diameters are 50 microns in respect of the inner capillary tube 13 and 250 microns in respect of the outer capillary tube 14, respectively. Moreover, this outer capillary tube 14 has an equivalent diameter smaller than that of the capillary tube 12. Finally, given that the capillary tube 13 passes through the tube 14, its outside diameter is smaller than the internal diameter of the peripheral capillary tube 14.
Within the present text, the term “equivalent diameter” of the various flow members is understood to mean the diameter that the internal walls of these members would have, for a given area, if they were of circular cross section. In the case in which they are circular, this equivalent diameter obviously corresponds to the inside diameter of these members.
To produce the actual module 1, the outer capillary tube 14, is firstly inserted into the channel 4 while the inner capillary tube 13 is placed in the volume of this outer capillary tube 14. The capillary tube 12 is also placed in the chamber 6 so that its end butts against the shoulder 6′ that separates this chamber 6 from the internal volume V.
The outer capillary tube 14, which is centered and guided in the channel 4, is inserted up to a point where it projects beyond the shoulder 6′. In other words, the facing walls of the capillary tubes 12 and 14 form an overlap region, denoted by R, which extends immediately downstream, namely below the shoulder 6′ in FIG. 2B. Moreover, the downstream end 13′ of the inner capillary tube 13 is flush with the downstream end 14′ of the outer capillary tube 14. In other words, these two downstream ends occupy the same axial position relative to the principal axes of the various capillary tubes 12, 13 and 14.
Moreover, the upstream capillary tubes 13 and 14 accommodate injection means of the type known per se for injecting two fluids. The injection means for each fluid comprise a flexible tube (not shown) connected to a syringe and a syringe plunger (these not being shown either). Similarly, the nozzle 10 cooperates with injection means, which comprise for example an additional, equally flexible, tube, connected to a syringe and a syringe plunger (not shown), for injecting a third fluid.
Again with reference to FIG. 1, the downstream capillary tube 12 opens into a sack 16 provided with conventional refrigeration means. This sack is consequently designed to quench the conversion taking place in the capillary tube 12, as will be seen below. Finally, downstream of the quenching sack 16, the capillary tube 12 communicates with an analyzer 18, of chromatograph type, which is itself connected to a processing computer 20.
The implementation of a determination method by the installation described above will now be explained below.
Two fluids A and B suitable for forming a mixture, which itself can undergo a conversion within the meaning of the invention, are injected into the two capillary tubes 13 and 14. As a purely nonlimiting example, said two fluids may generate a conventional, especially an acid-base, reaction or even a radical polymerization of acrylic acid or of DADMAC (diallyldimethylammonium chloride), an oxidation reaction or the acid-catalyzed hydroxylation of phenol by H₂O₂.
Moreover, an auxiliary fluid P, which is immiscible with the mixture of the aforementioned two first fluids, is injected via the nozzle 10. The flow rate at which these various fluids are typically injected is for example between 500 μ/h and 50 ml/h. The ratio of, on the one hand, the flow rate of the auxiliary fluid P to, on the other hand, the sum of the flow rates of the two fluids A and B is for example between 0.5 and 10.
Advantageously, the flow rate of the auxiliary fluid P is greater than the sum of the flow rates of A and B, with for example a ratio close to 2.
The auxiliary fluid then flows into the internal volume V, more precisely into the annular space formed by the facing walls of the two capillary tubes 12 and 14. In addition, immediately downstream of the downstream ends 13′ and 14′ of the upstream capillaries 13 and 14, the first two fluids are brought into mutual contact in what is called a mixing zone, denoted by M. Thus, the two reactive fluids that flow through the respective capillary tubes 13 and 14 meet only in this mixing zone, and not before it.
Moreover, immediately downstream of the overlap region R, these two fluids A and B are brought into contact, in what is called a contact zone, denoted by C, with the immiscible carrier fluid P. The presence of this region R makes it possible to see the droplet formation, thereby enabling the user to control the manipulation. This is because, when such an overlap region is absent, the droplets would be formed within the coupler 2 which is not necessarily transparent.
Given that the carrier fluid P is immiscible with the fluids A and B, droplets G, each of which is formed by the A and B mixture, are formed in the contacting zone C. It should be noted that these droplets G form plugs, which themselves form a physico-chemical system within the meaning of the invention.
Consequently, by independently setting the respective flow rates of the two fluids A and B on the one hand and that of the carrier fluid P on the other, it is possible to form, immediately downstream of the capillary tubes 13 and 14, monodisperse droplets G of dispersed phases. Given that these droplets are emitted at a constant frequency, denoted by f, the volume v is given by the formula: v=q/f, where q is equal to the sum of the flow rates of A and B. In other words, by measuring the frequency f, for example using a simple laser pointer illuminating a photodiode, it is possible to obtain the volume v of the droplets G without having to use more complicated image processing techniques. Thus, for a given geometry, mainly fixed diameters of the capillary tubes 12, 13 or 14, it is possible to vary the size of the droplets formed simply by modifying just the flow rates of the various immiscible fluids.
The various droplets G thus produced then flow through the downstream capillary tube 12, where the aforementioned conversion takes place. Thus, as the droplets G progress along said capillary tube, this conversion proceeds according to the state of progress of the conversion, that is to say the nature of the mixture formed by the initial fluids A and B is progressively modified. In other words, the most recently formed droplet, namely that located furthest to the left in FIG. 1, comprises the two components A and B, which are not substantially mixed. Next, as the droplets move along toward the downstream, these two components are better and better mixed in the following droplets. Even further downstream, the conversion intended to be studied is then increasingly advanced.
In this regard, it is advantageous for the characteristic time of this conversion to be appreciably longer than the time to mix the two components. This emphasizes the fact that the method according to the invention is particularly applicable for studying slow conversions, such as slow chemical reactions.
As in the case of the microfluidic techniques mentioned in the preamble of the present description, the droplets G thus form small reactors flowing at a constant speed, so that there also exists an equivalence between the distance that they have travelled and the reaction time. In FIG. 1, the origin O on the axis XX corresponds to the zone M, namely the formation of the droplets G. Thus, a droplet G located at a given point along the capillary tube 12, namely a given abscissa in this reference frame, is representative of the conversion at a given instant.
It should also be noted that it is advantageous to mix the two initial fluids A and B in a mixing zone M that is substantially coincident with the contacting zone C where they come into contact with the carrier fluid P. Consequently, there is no contacting between the two initial fluids A and B before the formation of the droplets G, so that the origin O associated with the conversion corresponds to the instant when these two fluids A and B enter the downstream capillary tube 12. In other words, with reference to FIG. 1, the abovementioned origin O of the distances on the axis X-X is particularly clearly identified.
The conversion, carried out in accordance with the invention, is therefore studied with great precision. Moreover, if a chemical reaction is studied that results in the formation of a solid product, this measurement prevents any blockage effect—if the two reactants were to be placed in contact with each other before droplet formation, the aforementioned solid would be liable to obstruct the corresponding flow member.
When the droplets G have entered that zone of the capillary tube 12 which runs into the refrigerated sack 16, the conversion undergone by these droplets is then stopped, due to the effect of the quenching caused by the low temperature in the sack 16. Under these conditions, all the droplets G₁flowing downstream of this sack 16 are of the same nature and correspond to a reaction time t₁which is itself associated with the abscissa X₁(see FIG. 1) corresponding to the entry of the capillary tube 12 into the sack 16.
Under these conditions, downstream of the sack 16, a settling effect takes place owing to the difference in density between the droplets and the carrier phase. The droplets thus separated are then suitable for analysis by means of the chromatograph 18. The computer 20 then processes the data delivered by the chromatograph 18, so as to determine at least one desired parameter of the aforementioned conversion.
Moreover, if the flow rates of the components A and B are modified, the time t₁, associated with the abscissa X₁of the sack 16, which corresponds to the elapsed time from the formation of the droplets, will also be modified. As a result, it is possible to analyze the conversion at different stages without, however, moving the quenching sack 16. Thus, for a given length of capillary tube 12, for example 1 meter, it is possible to vary the residence time between 5 minutes and 1 hour simply by modifying these flow rates.
An alternative embodiment of the invention is illustrated in FIG. 8. Here, the mechanical components similar to those in FIG. 1 have been assigned the same reference numbers increased by 100.
Firstly, there is an upstream member 100, which is intended to bring together several capillary tubes without, however, there being any mixing of the fluids in these capillary tubes. Said member 100, which is hollow, has overall a cross shape having three inlets 100 ₁, 100 ₂, and 100 ₃and one outlet 100 ₄. Two capillary tubes 113 and 114 pass through the hollow body, starting from the first two inlets 100 ₁and 100 ₂.
However, unlike the first embodiment, these two capillary tubes 113 and 114 are not concentric but placed beside one another, so as to extend through the outlet 100 ₄. It should be noted that the capillary tube 114 has a right-angled bend in the hollow body of the member 100. In addition, the third inlet 100 ₃communicates with a nozzle 110′, the function of which will be explained below.
Finally, the outlet 100 ₄of the upstream member 100 runs into a third capillary tube 115, of larger size than the capillary tubes 113 and 114. Thus downstream of said outlet 100 ₄, the capillary tubes 113 and 114 are placed alongside one another, while still being surrounded by the peripheral wall of the capillary tube 115.
These three capillary tubes 113 to 115 then run into a module 101, similar to the module 1 of FIG. 1. The module 101 includes in particular a coupler 102 and a nozzle 110.
Downstream of the module 101 there is a capillary tube 112, similar to the capillary tube 12, which has a greater diameter than the peripheral capillary tube 115. Similarly to the first embodiment, the downstream ends 113′, 114′ and 115′ of the three capillary tubes 113 to 115 are mutually flush, that is to say they occupy the same axial position. In addition, the facing walls of the capillary tubes 112 and 115 form an overlap region denoted by R′.
Droplet formation in the capillary tube 112 takes place as follows. Two fluids A and B suitable for forming a mixture are injected into the capillary tubes 113 and 114. In addition, a fluid C is injected from the nozzle 110′ into the capillary tube 115 via the hollow body of the member 100.
This fluid C may be a third reactant, capable of reacting with the fluids A and B. As a variant, C may be an adjuvant fluid, such as a catalyst or a buffer, which has no effect on the actual nature of the reaction, but only on its parameters, such as its rate.
Finally, as in the embodiment shown in FIG. 1, an auxiliary fluid P, which is immiscible with the first three fluids A, B and C, is injected via 110. Under these conditions, droplets G′ form immediately downstream of the overlap region R′, in a manner similar to that described with reference to FIG. 1.
As a variant, at least one other capillary tube, such as the capillary tube 113 or 114, may be placed inside the peripheral capillary tube 115. Each other capillary tube is used for the flow of an additional fluid, which may be reactive or may be adjuvant to the reaction.
The embodiment shown in FIG. 8 has specific advantages in terms of compactness. Thus at least two capillary tubes of small cross section, such as the capillary tubes 113 and 114, which are placed side by side inside a single capillary tube 115 of larger cross section may be used.
FIG. 3 illustrates an alternative embodiment of the invention, which does not make use of either a quenching sack 16 or a chromatograph 18. In this embodiment, the analysis is consequently not carried out off-line, as in the embodiment shown in FIG. 1, but on-line via a beam-type analyzer. Here, this is a Raman instrument 118, which is connected to a computer 120, the beam 119 of said instrument being directed onto the downstream capillary tube 12.
Thus, in FIG. 3, the analysis is carried out in a zone where the conversion is taking place whereas, in the first embodiment shown in FIG. 1, the analysis is carried out after this conversion has stopped. The beam 116 is directed onto the same point on the capillary tube 12, and several successive plugs flowing through this point are analyzed. A significant amount of information, relating to the progress of the conversion at this given point, can thereby be obtained.
Alternatively, the beam 119 may be moved axially so as to obtain abscissae of the capillary tube 12 and, consequently, different conversion times. As in the first embodiment, the flow rates of the components A and B forming the droplets G may also be modified so as to modify the conversion time for which the analysis is carried out, without however modifying the position of the beam 119.
After the steps described above have been carried out, it was possible to determine at least one parameter of a conversion of a physico-chemical system. This sequence of steps can then be recommenced with another conversion, involving another physico-chemical system and/or other operating conditions. These steps are carried out iteratively for a whole range of conversions so that, after the screening method thus carried out, it is then possible to identify at least one useful conversion depending on the intended application.
FIG. 4 illustrates an additional embodiment of the invention. In this embodiment, there is again a capillary tube 12 in which first droplets G₀are formed, in a manner similar to that described above. At least one other component intended to be introduced into each primary droplet G₀is then injected via a needle 30 tapped into this capillary tube 12. This procedure results in the formation of the definitive droplets G which can then be processed in a manner in accordance with the embodiment described above.
The embodiment shown in FIG. 4 lends itself particularly to polymerization reactions. Thus, each primary droplet G₀may be formed from a first monomer and a polymerization initiator. A second monomer can then be injected, via the needle 30, thereby enabling copolymer blocks to be formed. It is also possible to add, again via this needle 30, an additional amount of initiator, especially if the latter is no longer active.
It should also be noted that it is possible to tap several needles, such as the needle 30, into the main capillary tube 12 at various successive points. Finally, it should be noted that the or each needle 30 may be replaced with a tubing of small transverse size.
The needle 30, connected into the capillary tube 12, may allow an alternative embodiment of the invention to be implemented. In this embodiment (not shown as such), droplet samples are taken from the capillary tube 12. For this purpose, said needle 30 has a large enough diameter not to damage these droplets.
This needle 30 also contains a product capable of blocking the reaction taking place within the droplets. Under these conditions, it is possible to adjust the residence time of the droplets, at the moment of this sampling, by varying the corresponding flow rates. It is then possible to take various samples, which correspond to different stages of the reaction taking place in the droplets.
FIGS. 5A and 5B illustrate an additional embodiment of the invention in which the capillary tube 12 is made of a flexible material, while being associated with a heater 50 for keeping this flexible tube 12 at a given temperature. This heater 50, which is of cylindrical shape, defines an internal volume V open at its two axial ends (see FIG. 5A in which this heater is shown schematically).
This internal volume is bounded by a wall 52, grooves for accommodating this tube being etched in the outer periphery of said wall. For example, these grooves run helically. It should also be noted that it is possible to etch different grooves suitable for accommodating tubes of different diameters.
An external flange 54 (see FIG. 5B), for example made of aluminum, is placed on top of the wall 52, thereby enabling the heater 50 to be confined so as to optimize the thermal regulation. Moreover, the presence of this flange 54 enables the flexible tube 12 to be kept in position in contact with the cylindrical wall 52.
The open ends of the heater 50 are connected to a cryostat 56 (see FIG. 5B) of type known per se, for the circulation of a heat-transfer fluid in closed circuit. Said heat-transfer fluid therefore keeps the flexible tube 12 at a given temperature so that the conversion that it is desired to study takes place under predetermined temperature conditions. Finally, the external flange 54 defines a central window 58 enabling the flexible tube 12 to be seen. Under these conditions, it is possible to optically characterize the transformation by in-line analysis.
The embodiment shown in FIGS. 5A and 5B can therefore be used for conversions while maintaining the desired temperature, which can vary for example between −20 and 200° C. The in-line analysis that can be carried out is for example Raman spectroscopy, or else infrared thermography. Moreover, it is possible to place a great length of flexible tube 12 around the cylindrical wall 52. Under these conditions, the residence time that can be achieved in that part of the flexible tube wound around this cylinder, may be up to several hours.
FIG. 6 illustrates an additional embodiment of the invention in which the capillary tubes 13 and 14 open laterally into the capillary tube 12. Under these conditions, the mixing zone M′, which is coincident with the contacting zone C′, is located between the facing ends of these two capillary tubes.
FIG. 7 illustrates an additional embodiment of the invention in which the capillary tube 13 is not flush with the downstream of the outer capillary tube 14. In other words, the end 13′ is located upstream of the end 14′, while a mixture M formed from A and B flows near said end 14′. In this way, the reactants intended to form the droplet are brought into contact with each other before the actual formation of said droplet.
With further reference to FIG. 8, it should be noted, by way of a variant, the capillary tube 113 and/or the capillary tube 114 need not be flush with the downstream end 115′ of the outer capillary tube 115. Under these conditions, a mixture is formed between the fluid C and the fluid A and/or the fluid B, before the formation of the droplets G′. In other words, the mixing zone is then located upstream of the end of the capillary tube 115.
It should also be noted that it is possible to form droplets G from more than two components, in a manner different from that described in FIG. 8. Thus, several concentric capillary tubes each for the flow of one of these components may be used. It is also possible to use only two concentric capillary tubes, as in the example shown in FIG. 1, while making at least two reactants flow in at least one of these tubings.
It should be noted that the length of the capillary tube 12 may be advantageously between 50 cm and 10 meters, preferably between 1 and 4 meters. Under these conditions, the residence time of each droplet is for example between 2 minutes and 10 hours.
However, in the case of particularly slow conversions of the polymerization type, it is possible to stop the injection of reactant, via the capillary tubes 13 and 14, at a given moment. Under these conditions, the droplets present in the capillary tube 12 are then immobilized while this conversion continues to take place. Then, after this immobilization time, which enables the conversion to be progressed, reactants are again injected via the upstream capillary tubes 13 and 14, thereby enabling the droplets again to flow through the capillary tube 12.
At least some of the various operations described above may be controlled by a computing means, of the computer type. Under these conditions, this computer is capable in particular of automatically generating the successive compositions of the plugs flowing along the capillary tube 12, of monitoring the temperature of the heater 50, of acquiring the analytical data and of automating the sample collection.
Finally, it should be noted that, as a variant (not shown), the invention is also applicable to a method and to an installation for producing plugs, which involve all or some of the technically mutually compatible characteristics described above. In this case, the analysis of said plugs and the determination of characteristics of a conversion are optional. This embodiment may particularly be used for preparing specimens of products to be tested, or even to prepare products on an industrial scale, especially polymers, in particular by radical polymerization.
The invention achieves the objectives mentioned above.
The merit of the Applicant in having highlighted certain drawbacks associated with the microfluidic technique presented in the preamble of the present description will firstly be emphasized.
Specifically, the microfluidic devices require, for their fabrication, the use of expensive soft lithography techniques, necessitating substantial financial investment and significant expertise in the field. This is why such techniques are not currently available in most industrial laboratories.
Moreover, a microfluidic chip cannot be modulated given that, to modify part of its hydraulic circuit, it has to be fabricated anew.
In addition, the very small dimensions of microfluidic devices require corresponding miniaturization of the analytical tools. This is not always easy to implement, while again being accompanied by substantial additional costs.
The residence times of a plug on a microfluidic chip of conventional size are relatively short. This therefore prevents the kinetics of slow chemical reactions, the characteristic time of which ranges from a few minutes to several hours, from being studied.
Finally, mechanical members of the valve type are required for moving, stopping and routing plugs in a system. On a microfluidic scale, such use proves to be particularly tricky to implement.
Now, the present invention enables these various drawbacks to be remedied. This is because the invention benefits from a flow taking place on a larger scale, of the “millifluidic” type, thereby making it possible to obtain substantially larger plug volumes and flow rates. Moreover, the flow members used in the invention are not provided in a solid body of the wafer type, this being advantageous in terms of costs.
The use of a scale much larger than the microfluidic scale, combined with the use of modulable flow members, enables the residence time of the plugs to be extended.
This is advantageous, particularly for the purpose of studying slow chemical reactions.
It should also be noted that the “millifluidic” flow according to the invention enables objects such as complex plugs to be produced, these not being able to be obtained simply by means of microfluidic flows. Under these conditions, the invention makes it possible in particular for double emulsions to be generated, it not being possible to create these in a simple manner in microfluidic flow.
It should also be noted that the fluid flow rates used in the invention are typically between 1 and 1000 mL/h, i.e. between a few tens of millimeters and a few tens of liters per day. For comparison, the flow rates permitted by the microfluidic technique are considerably lower, namely less than a few tens of milliliters per day.
The invention may in particular be very advantageously applicable, because of the information provided, in the design of processes for producing chemicals, in the design of new chemicals, especially in the design of new polymers, polymerization products and/or polymerization processes. The invention also provides great simplicity of use, and many options in varying the number and order of the reactants used. It is thus possible to introduce certain reactants after others (for example catalysts or initiators or comonomers, or a reactant used in a second synthesis step), trying out, where appropriate, several points (or moments) of introduction, without having to substantially modify microfluidic reactor design or equipment.
Finally, it should be noted that the invention retains the intrinsic advantages of the microfluidic technique in the sense that it substantially permits the same plug management operations.

Claims

1.-33. (canceled)

34. A method for determining at least one characteristic of a physical and/or chemical conversion, in which a succession of plugs (G; G′) formed from a physico-chemical system capable of undergoing such conversion is made to flow in a carrier phase (P) along a downstream tubular flow member (12; 112), comprising carrying out at least one analysis of at least one such plug, and deducing the or each parameter therefrom.

35. The method as defined by claim 34, wherein the physico-chemical system is formed from at least two components (A, B; A, B, C) and these two components are made to flow along at least two upstream tubular flow members (13, 14; 113, 114, 115) that communicate into the downstream tubular flow member (12; 112).

36. The method as defined by claim 35, wherein the physico-chemical system (A, B, C) comprises at least three components, each of which flows through a corresponding upstream member (113, 114, 115).

37. The method as defined by claim 36, wherein the physico-chemical system includes at least one adjuvant (C) for the conversion, optionally as a catalyst or a buffer.

38. The method as defined by claim 36, wherein at least three upstream tubular flow members (113, 114, 115) are provided, at least two first upstream members (113, 114) being placed side by side inside a peripheral upstream tubular flow member (115).

39. The method as defined by claim 34, wherein the or each tubular flow member has an equivalent diameter ranging from 10 microns to 50 mm.

40. The method as defined by claim 35, wherein said at least two components (A, B, C) are mixed in a mixing zone (M) substantially at the same time as these components are contacted with the carrier phase (P), in a contacting zone (C) substantially coincident with the mixing zone (M).

41. The method as defined by claim 35, wherein said at least two upstream flow members (13, 14) and the downstream flow member (12) are concentric.

42. The method as defined by claim 40, wherein the contacting zone (C) is located immediately downstream of an overlap region (R; R′) from the downstream flow member (12; 112) and a peripheral upstream flow member (14; 115).

43. The method as defined by claim 34, wherein the conversion taking place in the plugs (G) is stopped, optionally by means of a quench (16), and at least one analysis is carried out off-line, optionally in a chromatograph (18).

44. The method as defined by claim 43, wherein the conversion is stopped in the downstream tubular flow member (12).

45. The method as defined by claim 43, wherein sample plugs are taken from the downstream tubular flow member and the conversion is then stopped.

46. The method as defined by claim 34, wherein a beam (119) of an analyzer (118), optionally of Raman type, is directed onto a zone of the downstream tubular flow member (12) in which the conversion continues to take place.

47. The method as defined by claim 46, wherein the beam (119) is directed onto one same point of the downstream tubular flow member (12) and several plugs flowing in succession through said point are analyzed.

48. The method as defined by claim 34, wherein at least one part of the downstream flow member (12) is placed in a device (50) for maintaining a defined temperature.

49. The method as defined by claim 34, wherein at least certain plugs are immobilized in the downstream flow member (12), thereby enabling the conversion to continue without these plugs moving, and then these plugs are again made to flow through this downstream tubular member (12) after observation of this latency time.

50. The method as defined by claim 34, wherein primary plugs (G₀), comprising a first monomer and a polymerization initiator, are made to flow through the tubular flow member, and at least one other component, optionally another monomer and/or an additional amount of an initiator, is added to each primary plug to form definitive plugs (G).

51. The method as defined by claim 34, wherein the plugs (G) are made to flow through the downstream tubular flow member (12) at a rate ranging from 1 mL/h to 1,000 mL/h.

52. The method as defined by claim 34, wherein the length of the downstream tubular flow member (12) ranges from 50 cm to 10 m.

53. The method as defined by claim 34, wherein the parameter deduced is a degree of progress of the conversion, optionally a rate of disappearance of reactive products, a rate of appearance of products resulting from a principal reaction, or else a rate of production of by-products resulting from this main reaction.

54. The method as defined by claim 53, wherein the composition of several plugs and/or the temperature of the temperature-maintaining device is controlled by a computing means and/or the results of the various analyses are acquired by said computing means.

55. The method as defined by claim 34, wherein at least one of said tubular flow members is flexible.

56. A device for determining at least one parameter of a physical and/or chemical conversion, comprising:

a downstream tubular flow member (12; 112), the equivalent diameter of which ranges from 10 microns to 50 mm;

means (10, 13, 14; 110, 113, 114, 115) for generating a sequence of plugs (G; G′) separated by a carrier phase (P) in this downstream tubular flow member (12; 112);

analytical means (18; 118) for analyzing these plugs; and

means (20; 120) for determining the or each parameter.

57. The device as defined by claim 56, wherein the downstream tubular flow member (12) is placed in communication with means (16) which make it possible to stop said conversion, optionally by means of a quench, and this downstream tubular flow member (12) then communicates into an external analyzer (18), optionally of chromatograph type.

58. The device as defined by claim 56, wherein the analytical means comprise an analyzer (118), optionally of Raman type, having a beam (119) suitable for being directed onto the downstream tubular flow member (12).

59. The device as defined by claim 56, optionally the means for generating the plugs (G) comprises at least one upstream tubular flow member (13, 14; 113, 114, 115), each of which is suitable for supplying a component of said physico-chemical system, the or each upstream tubular flow member communicating into the downstream tubular flow member (12; 112), the generating means further including a means (10; 110) for supplying the carrier phase (P), said supply means also communicating into the downstream tubular flow member (12).

60. The device as defined by claim 59, wherein at least two upstream tubular flow members (13, 14) are provided that have downstream ends (13′, 14′) defining a mixing zone (M) in which the components of the plugs are mixed, these downstream ends (13′, 14′) communicating into the downstream tubular flow member (12) in a contacting zone (C) approximately coincident with the mixing zone (M).

61. The device as defined by claim 56, wherein the length of the downstream tubular flow member (12) ranges from 50 cm to 10 m.

62. The device as defined by claim 56, further comprising a member (50) for maintaining a given temperature, near which at least part of the downstream tubular flow member (12) is situated.

63. The device as defined by claim 62, wherein the member for maintaining a given temperature comprises a hollow body (50) defining an internal volume (V) for accommodating a heat-transfer fluid, this internal volume being bounded by a wall (52) around the periphery of which said part of the downstream tubular flow member (12) is situated.

64. The device as defined by claim 63, wherein at least one series of peripheral grooves (53) is cut into the wall (52), each series of grooves enabling a downstream tubular flow member (12) of corresponding transverse size to be accommodated.

65. The device as defined by claim 63, wherein the part of the downstream tubular flow member placed around the wall (52) is surmounted by a peripheral flange (54), in which a window (58) is provided for being viewed by an analyzer.

66. A method of screening several conversions of a physico-chemical system, in which several different conversions are carried out, by modifying said physico-chemical system and/or the operating conditions, at least one parameter of each conversion is determined according to the method as defined by claim 34, and at least one preferred conversion having at least one preferred parameter is identified.