EP2076782A2

EP2076782A2 - Method and installation for determining at least one parameter of a physical and/or chemical conversion, and corresponding screening method

Info

Publication number: EP2076782A2
Application number: EP07858447A
Authority: EP
Inventors: Pascal Panizza; Galder Cristobal; 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: 2009-07-08
Also published as: WO2008043922A3; US20100129917A1; US8318871B2; US20100152395A1; FR2907227A1; JP5329416B2; WO2008043922A2; JP2010506187A; WO2008043860A1; EP2126591A1; FR2907227B1

Abstract

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

Description

METHOD AND INSTALLATION FOR DETERMINING AU

LESS A PARAMETER OF A PHYSICAL TRANSFORMATION AND / OR

CHEMICAL, AND CORRESPONDING SCREENING METHOD

The present invention relates to a method and an installation for determining at least one parameter of a physical and / or chemical transformation, as well as a corresponding screening method.

By transformation is meant any type of interaction likely to occur in a mixture of at least two components. In a nonlimiting manner, this transformation can be a reaction of chemical and / or physical type, such as for example any type of conventional chemical reaction, in particular polymerization reactions, as well as crystallization or precipitation, gelling, or else among others a modification of a liquid / vapor equilibrium. In a general sense, within the meaning of the invention, such a transformation is capable of implementing chemical phenomena, by exchange or sharing of electrons, physical interactions or repulsions, such as hydrogen bonds, electrostatic interactions, steric attractions or repulsions, affinities for different hydrophilic and / or hydrophobic media, formulation stabilities, flocculations or even phase transfers, for example of the liquid / liquid, solid / liquid or gas / liquid type.

Within the meaning of the invention, the parameters of such a transformation are, in a nonlimiting manner, the kinetics of chemical reaction in a homogeneous or heterogeneous medium, the conditions making it possible to obtain an optimum of yield for chemical reactions, enthalpies of reactions, temporal processes of reactions chemical and physical, as well as solubility or phase diagrams.

The determination of the parameters of a transformation is already implemented, thanks to the microfluidic type flow technique.

These microfluidic flows are for example described in M. Madou "Fundamentals of Microfabrication: The Science of Miniaturization", CRC Press. (1997) . They take advantage of mechanical systems whose micrometric and / or nanometric sizes allow the manipulation of very small volumes of the fluid. This miniaturization, coupled with the use of appropriate analysis techniques, opens the way to many applications in fields as diverse as biology, analytical chemistry, chemical engineering or physics.

Thus, this technique makes it possible to envisage, for example, a set of chemical processes on a chip, so as to recreate a laboratory on a particularly restricted surface, of the order of a few cm ² , that is to say the "lab". -on-Chip ": see in particular J Knight, Nature, 418, 474 (2002). Such miniaturization thus offers important prospects in the field of chemical engineering, with a view to increasing the selectivity and the efficiency of the reactions implemented.

The use of plugs, in particular drops, in the microfluidic field proves very promising. Indeed, these drops whose volume is extremely low, typically between the picolitre and the nanolitre, allow to achieve within them chemical reactions. This is for example described in B. Zheng, LS Roach, R. Ismagilov, J. Am. Chem. Soc. 125, 11170, (2003). Moreover, microfluidic production techniques allow the formation of monodisperse drops with a constant production frequency.

As a result, the drops, which thus form nano-reactors, flow at a constant speed, so that there is an equivalence between the distance traveled and the reaction time. In other words, a drop located at a given point in the fluid flow network is representative of the reaction studied at a given instant. By combining classical analysis techniques, Raman, infra-red, visible or fluorescent, it is then possible to follow the kinetics of a reaction and to adjust the composition of the drops, in order to target the optimal conditions very quickly. chemical reaction, while using only very small volumes of reagents. Even if the microfluidic type techniques have many advantages, such as those mentioned above, they nevertheless involve certain disadvantages. Indeed, they are accompanied by a relatively high realization cost, particularly related to the use of the soft lithography technique. Moreover, the microfluidic flow devices are not easily adjustable. Finally, the microfluidic technique does not allow a satisfactory study of certain types of reaction. Furthermore, in general, there is a continuing need for the industry to develop new products with new properties, for example new chemical compounds or new compositions including new chemicals and / or new product combinations. chemical. The physical and / or chemical transformations of the products are important properties for many applications, which it is very often necessary to test in Research and development. There is a need for processes and facilities to accelerate R & D processes, for example to test a larger number of products and / or to implement testing on smaller quantities of products, and / or to implement perform the tests more quickly, and / or implement tests relating to transformations too slow to be studied in the devices of the prior art mentioned above. That being said, the object of the invention is to propose a method for determining a parameter of a transformation which, while generally allowing the same possibilities as the microfluidic technique, appreciably overcomes the disadvantages associated with the latter. For this purpose, it relates to a determination method according to the appended claim 1.

Advantageous features of the invention are the subject of the appended claims 2 to 22.

The invention also relates to a determination device according to claim 23 attached.

Advantageous features of the invention are the subject of the appended claims 24 to 32.

The invention finally relates to a screening method according to the appended claim 33. The invention will be described below, with reference to the accompanying drawings, given solely by way of non-limiting examples, in which:

FIG. 1 is a front view, illustrating an installation for determining a parameter of a transformation, which is in accordance with the invention; FIGS. 2A and 2B are front views, illustrating a plug generation module belonging to the installation of FIG. 1, in which the different components are respectively disassembled and mounted relative to one another;

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

- Figure 4 is a front view, similar to Figure 1, illustrating a further embodiment of the invention; FIGS. 5A and 5B are diagrammatic and front views respectively, illustrating holding means at a given temperature equipping the installation of the preceding figures; and Figures 6 to 8 are front views, similar to Figure 1, illustrating two further embodiments of the invention.

It will be noted that, according to one embodiment, the analysis may be carried out at a point in the downstream tubular flow member, for example by spectroscopic type techniques (UV spectroscopy,

Infra-Red, light scattering, ray scattering

X, Raman spectroscopy, fluorescence, etc.) or optical (microscopy, image analysis, etc.) that can, for example, give information on the progress of a reaction.

(by assays of the formed products or residual reagents, for example, in the case of a polymer, by assaying residual amounts of monomers). The appropriate analysis means are for this mode located near the tubular flow member, at one or more given point (s) along the organ. It is not excluded to move the analysis means to obtain information by measurements at various points of the flow and thus at various stages of advancement of the transformation. It is also possible to place several analysis means, identical or different, along the tube. Nor can it be excluded that a single means of analysis can give information on several points of the tube, for example an optical analysis by photography with possibly an image processing. According to another embodiment, which does not exclude the first mode (it can be cumulated), the analysis can be performed directly at the outlet of the tubular flow member, preferably without recovering / isolating the plugs leaving said organ, for example by chromatographic techniques, in particular steric exclusion chromatography suitable for the analysis of polymers, which may for example give information on the exact composition of the transformation product, for example on the characteristics of a polymer, such as its average molecular weight, the distribution of macromolecular chains, the polydispersity index.

The installation according to the invention of Figure 1 comprises firstly a plug generation module, shown schematically in this figure but which is illustrated more precisely in Figures 2A and 2B. This module, designated as a whole by the reference 1, firstly comprises a coupling member 2 approximately cylindrical, made of any suitable material, in particular metal or plastic. This connecting member 2 comprises an internal volume V, placed in communication with the outside by three different ways. For this purpose, this member 2 is first provided with an upper channel 4 and a lower chamber 6, with reference to Figures 2A and 2B. This channel 4 and this chamber 6, which are co-axial, have a cross section respectively lower and greater than that of the internal volume V. Furthermore, the connecting member 2 is hollowed out of a channel 8, said lateral, provided right of Figures 2A and 2B. A tip 10, made for example of PEEK, PTFE, silicone or metal, is fixed by any appropriate means on the walls of the outlet of this lateral channel 8.

The connecting member 2 is associated with different tubular flow members, which will be described in the following. For the purposes of the invention, a tubular flow member is an elongated flow member of closed section, the transverse profile may have any type of shape, in particular oval or square. In the sense of the invention such a member is not formed in a solid body, such as a microchannel which is etched in a wafer. This body is thus bordered by a thin peripheral wall. Unlike microfluidic embodiments, using an assembly, in particular by gluing, two wafer parts together, this tubular flow member can be made in one piece, advantageously.

The various tubular flow members to which the invention refers may be made of a rigid material, such as for example steel. However, as an alternative, it can be provided to make them a semi-rigid material, or flexible, such as for example PTFE, silicone, PVC, polyethylene or PEEK. Alternatively, one can also use a fluorinated product, including PFA type. The flow members may also be made of a fused silica, covered with polyimide, which can be removed locally in a known manner, in particular by means of sulfuric acid, in order to visualize the interior of the flow.

It is first provided a first tubular flow member, namely a capillary 12 made for example of PTFE or silicone, which has an equivalent internal diameter typically between 10 micrometers and 50 mm. In addition, there are two other tubular flow members, namely two other capillaries 13 and 14 made for example of PEEK. The capillary 13 has an equivalent diameter smaller than that of the capillary 14 since, as will be detailed hereinafter, this capillary 13 enters into service in the interior volume of the capillary 14. In this respect, the typical values of the equivalent diameters are respectively 50 micrometers for the inner capillary 13 and 250 micrometers for the outer capillary 14. Moreover, this outer capillary 14 has an equivalent diameter which is smaller than that of the capillary 12. Finally, since the capillary 13 enters the 14, its outer diameter is smaller than the inner diameter of the peripheral capillary 14.

In the present text, the term "equivalent diameter" of the various flow members, the diameter that would present the inner walls of these organs, for the same surface, if they were circular section. In the case where they are circular, this equivalent diameter obviously corresponds to the internal diameter of these organs.

In order to constitute the actual module 1, it is first of all to drive the outer capillary 14 into the channel 4, while arranging the inner capillary 13 in the volume of this outer capillary 14. In addition, the capillary 12 in the chamber 6, until its end comes into abutment against the shoulder 6 'separating the chamber 6 from the internal volume V. The outer capillary 14, which is centered and guided in the channel 4, is recessed until protruding beyond the shoulder 6 '. In other words, the facing walls of the capillaries 12 and 14 form a covering zone, denoted R, which extends immediately downstream, namely at the bottom of the shoulder 6 'in FIG. 2B. Moreover, the downstream end 13 'of the inner capillary 13 is flush with the downstream end 14' of the outer capillary 14. In other words, these two downstream ends occupy the same axial position, - with reference to the main axes of the different capillaries 12, 13 and 14.

Furthermore, the upstream capillaries 13 and 14 receive means for injecting two fluids, of a type known per se. The injection means of each fluid comprise a not shown tube, of flexible type, which is associated with a syringe and a syringe pump, also not shown. Similarly, the tip 10 cooperates with means for injecting a third fluid, which comprise for example an additional tube, also flexible, which is associated with a syringe and a syringe not shown.

Again with reference to Figure 1, the downstream capillary 12 opens into a tray 16, provided with refrigeration means of conventional type. This tray is therefore adapted to quench, or quench, the transformation involved in the capillary 12, as will be seen in what follows. Finally, downstream of the quenching tank 16, the capillary 12 is placed in communication with an analysis apparatus 18, of the chromotograph type, itself connected to a processing computer 20.

The implementation of a determination method, achieved through the installation described above, will now be explained in the following. It is a question of injecting, into the two downstream capillaries 13 and 14, two fluids A and B capable of forming a mixture, itself capable of undergoing a transformation within the meaning of the invention. By way of purely nonlimiting example, these two fluids can generate a chemical reaction of conventional type, in particular acid-base, or a radical polymerization of acrylic acid or of diallyl dimethyl ammonium chloride (DiAllylDiMethylAmmonium Chloride) DADMAC, a reaction oxidation, or a reaction of hydroxylation of phenol with H ₂ O ₂ by acid catalysis.

Moreover, the tip 10 injects an auxiliary fluid P, which is immiscible with the mixture of the first two fluids mentioned above. The injection rate typical of these different fluids is for example between 500 .mu.l / h and 50 ml / h. The ratio between, on the one hand, the flow of auxiliary fluid P and, 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 auxiliary fluid P is greater than the sum of those of A and B, with for example a ratio close to 2.

The auxiliary fluid then flows into the interior volume V, more precisely into the annular space formed by the walls facing the two capillaries 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 a so-called mixing zone, noted M. Thus, the two reactive fluids, which flow into the respective capillaries 13 and 14, are found only at this mixing zone, and not before the latter.

Furthermore, immediately downstream of the overlap zone R, these two fluids A and B are brought into contact, in a so-called contact zone denoted by C, with the immiscible carrier fluid P. The presence of this zone R makes it possible to visualize the formation of the drops, which allows the user to control the manipulation. Indeed, in the absence of such a covering area, the drops would be formed in the connecting member 2, which is not necessarily transparent.

Since the carrier fluid P is immiscible with the fluids A and B, drops G, each consisting of the mixture of A and B, are formed at the contacting zone C. note that these drops G form plugs, forming themselves a physico-chemical system within the meaning of the invention.

Consequently, by independently imposing the respective flow rate, on the one hand, of the two fluids A and B and, on the other hand, of the carrier fluid P, it is possible to form droplets 13 and 14 immediately downstream of the capillaries 13 and 14. Monodisperse G of dispersed phases. Since these drops are emitted at a constant frequency denoted _f_, their volume v is given by the formula v = cj / f_, where q is equal to the sum of the flow rates of A and B. In other words, the measure frequency f, for example using a simple laser pointer illuminating a photodiode, allows to access the volume v of the drops G, without resorting to heavier techniques of image processing. Thus, for a given geometry, namely fixed diameters of capillaries 12, 13 and 14, it is possible to vary in a simple manner the size of the drops formed by changing only the flow rate of the different immiscible fluids.

The different drops G thus produced then flow into the downstream capillary 12, being the place of the aforementioned transformation. Thus, as the G drops progress in this capillary, this transformation takes place, namely that the nature of the mixture formed by the initial fluids A and B gradually changes, depending on the state of progress. of transformation. In other words, the most recently formed drop, namely the leftmost one in Figure 1, comprises the two components A and B, which are substantially unmixed. Then, as we move downstream, these two components are better and better mixed in the following drops. Then, even further downstream, the transformation that we want to study is more and more advanced.

In this regard, it is advantageous that the characteristic time of this transformation is significantly greater than the mixing time of the two components. This makes it possible to emphasize that the process according to the invention is particularly applicable to the study of slow transformations, such as slow chemical reactions. As in the case of the microfluidic techniques mentioned in the preamble of the present description, the drops G thus form small-sized reactors flowing at a constant speed, so that there exists also an equivalence between the distance they have traveled and the reaction time. FIG. 1 shows the axis XX whose origin corresponds to the zone M, namely the formation of the drops G. Thus, a drop G located at a given point of the capillary 12, namely a given abscissa of this landmark is representative of the transformation at a given moment.

It will also be noted that it is advantageous to mix the two initial fluids A and B in a mixing zone M which is substantially merged with the contacting zone C with the carrier fluid P. In fact, it does not occur by therefore no contact between the two initial fluids A and B before the formation of the drops G, so that the origin 0 associated with the transformation corresponds to the moment when these two fluids A and B are admitted into the downstream capillary 12. In other words, with reference to FIG. 1, the origin 0 of the axis XX of the distances, mentioned above, is identified in a particularly clear manner. This therefore gives great precision to the study of the transformation, implemented in accordance with the invention. Moreover, in the case where a chemical reaction is studied which leads to the formation of a solid product, this measure makes it possible to avoid any clogging phenomenon. Indeed, if the two reagents were brought into contact before the formation of the drops, the aforementioned solid would be likely to obstruct the corresponding flow member.

Then, when the drops G are admitted in the zone of the capillary 12 extending in the refrigerated tank 16, the transformation undergone by these drops is stopped, under the effect of the tempering induced by the low temperature prevailing in the tank 16. In these circumstances, all Gi droplets flowing downstream of this tray 16 are of the same kind, and correspond to a reaction time ti, itself associated with abscissa Xi (see Figure 1) corresponding to the outlet of the capillary 12 in the tray 16. Under these conditions, downstream of the tray 16, there is a settling phenomenon, because of the difference in density between the drops and the carrier phase. These drops thus separated then lend themselves conveniently to analysis, via the chromatograph 18. The computer 20 then processes the data provided by the chromatograph 18, so as to determine at least one desired parameter of the above-mentioned transformation.

Moreover, if the flow rate of the components A and B is modified, the time ti, associated with the abscissa Xi of the tank 16, which corresponds to the time elapsed since the formation of the drops, will also be modified. In this way, it is possible to analyze the transformation at different stages, without however moving the quench tank 16. Thus, for a given length of capillary 12, for example 1 meter, it is possible to vary the time residence between 5 minutes and 1 hour, with a simple modification of these flows.

An alternative embodiment of the invention is illustrated in Figure 8. On the latter, the mechanical elements similar to those of Figures 1 are assigned the same reference numbers, increased by 100.

First there is an upstream member 100, which is intended to gather several capillaries, but without ensuring a mixing function of the fluids flowing in these capillaries. This member 100, which is hollow, generally defines a cross shape having three inputs 100i, 10O ₂ and 10O ₃ , and an output 10O ₄ . Two capillaries 113 and 114 penetrate into the hollow body, from the first two inputs 10Oi and IOO2.

However, unlike the first embodiment, these two capillaries 113 and 114 are not concentric, but are placed next to each other, so as to extend through the outlet 10O ₄ . Note that the capillary 114 is bent at the hollow body of the member 100. In addition, the third input 10O ₃ is placed in communication with a tip 110 ', whose function will be explained below.

Finally, the outlet 10O ₄ of the upstream member 100 opens into a third capillary 115, of greater dimension than those 113 and 114. Thus, downstream of this outlet 10O ₄ , the capillaries 113 and 114 are arranged one to side of the other, while being surrounded by the peripheral wall of the capillary 115.

These three capillaries 113 to 115 then open into a module 101, similar to that 1 of Figure 1. The module 101 comprises in particular a connecting member 102, and a tip 110.

Downstream of the module 101, there is a capillary 112, similar to that 12, which has a diameter greater than that of the peripheral capillary 115. In a similar manner to the first embodiment, the downstream ends 113 ', 114' and 115 'of the three capillaries 113 to 115 are mutually flush, ie they occupy the same axial position. In addition, the walls facing the capillaries 112 and 115 form an overlap area denoted R '. The formation of drops in the capillary 112 takes place in the following manner. Two fluids A and B, which are suitable for forming a mixture, are injected into the capillaries 113 and 114. In addition, a fluid C is injected from the nozzle. 110 'to the capillary 115, via the hollow body of the body 100.

This fluid C may be a third reagent, capable of reacting with the fluids A and B. Alternatively, C may be an adjuvant fluid, such as a catalyst or a buffer, which does not interfere with the nature itself of the reaction, but on its parameters, such as its speed.

Finally, as in the embodiment of FIG. 1, an auxiliary fluid P, which is not miscible with the first three fluids A, B and C, is injected by 110. In these conditions, immediately downstream of the covering R ', drops G' are formed in a manner analogous to that described with reference to FIG. 1. Alternatively, at least one other capillary, such as that 113 or 114, may be disposed of Inside the peripheral capillary 115. Each other capillary allows the flow of additional fluid, which may be reactive or additive to the reaction. The embodiment of Figure 8 has specific advantages in terms of space. Thus, it is possible to use at least two capillaries of small section, such as those 113 and 114, which are placed side by side inside a single capillary 115 of larger section.

FIG. 3 illustrates an alternative embodiment of the invention, which does not use a quenching tank 16 or a chromatograph 18. In this variant, the analysis is therefore not performed offline or "off". a "as in the embodiment of Figure 1, but in line or. "On line" via a beam type analyzer. This is a Raman 118, whose beam 119 is directed to the downstream capillary 12, which is associated with a computer 120.

Thus, in FIG. 3, the analysis is carried out in an area where the transformation continues while, in the first embodiment of FIG. 1, the analysis is carried out after stopping this transformation. The beam 116 is directed to the same place of the capillary 12, and an analysis of several successive plugs is carried out, flowing there. This provides access to a significant amount of information regarding the progress of processing at that location.

Alternatively, the beam 119 can be moved axially, so as to access the abscissa of the capillary 12 and, therefore, at different processing times. As in the first embodiment, it is also possible to modify the flow rate of the components A and B forming the drops G, so as to modify the transformation time for which the analysis is implemented, without however modifying the position of the beam. .

At the end of the implementation of the steps described above, it has been possible to determine at least one parameter of a transformation of a physicochemical system. It is then possible to repeat this sequence of steps with another transformation, involving another physicochemical system and / or other operating conditions. Iteratively, these steps are carried out for a whole range of transformations so that, at the end of the screening method thus implemented, one can then identify at least one interesting transformation according to the intended application.

FIG. 4 illustrates a further variant embodiment of the invention. We find, on this last, the capillary 12 in which have been formed first plugs Go, in a manner similar to that described above. A needle 30 is then injected onto this capillary 12 at least one other component which is introduced into each primary drop G ₀ . This leads to the formation of definitive drops G, which can then be treated in accordance with the embodiment described above.

The variant of Figure 4 is particularly suitable for polymerization reactions. Thus, each primary drop GB can be formed of a first monomer, as well as a polymerization initiator. Then, through the needle 30, a second monomer can be injected, which makes it possible to form blocks of copolymers. It is also possible to add again, by this needle 30, an additional amount of initiator, especially in the case where the latter is no longer active.

Note also that it is possible to stitch several needles, such as that 30, in different successive locations of the main capillary 12. Finally, note that the or each needle 30 may be replaced by a pipe of reduced transverse dimension.

The needle 30, associated with the capillary 12, may allow the implementation of an alternative embodiment of the invention. In this variant, not shown as such, drops are taken out of the capillary 12. For this purpose, this needle 30 has a sufficient diameter, so as not to damage these drops.

This needle 30 also contains a product capable of blocking the reaction, occurring within the drops. Under these conditions, it is possible to adjust the residence time of the drops, at the time of this sampling, by varying the corresponding flow rates. We can then take different samples, which correspond to different stages of the reaction involved in the drops.

FIGS. 5A and 5B illustrate a further variant embodiment of the invention, in which the capillary 12 is made of a flexible material, while being associated with a heating body 50, making it possible to maintain this flexible tube 12 at a given temperature. This heating body 50, which has a cylindrical shape, defines an internal volume V open at its two axial ends (see Figure 5A, where this heating body is shown schematically).

This interior volume is bordered by a wall 52, at the outer periphery of which are grooves 55, for receiving this tube. These grooves extend for example helically. It will also be noted that it is possible to engrave different grooves suitable for receiving tubes of different diameters.

An outer flange 54 (see FIG. 5B), for example made of aluminum, covers the wall 52, which makes it possible to confine the tube 50 in order to optimize the thermal regulation. Furthermore, the presence of this flange 54 keeps the flexible tube 12 in position, in contact with the cylindrical wall 52. The open ends of the body 50 are connected to a cryostat 56 (see Figure 5B), of a type known per se. which ensures the circulation in closed circuit of a coolant. The latter then ensures the maintenance at a given temperature of the flexible tube 12, so that the transformation that is desired to study takes place under predetermined temperature conditions. Finally, the outer flange 54 defines a median window 58, making it possible to visualize the flexible tube 12. Under these conditions, it is it is possible to carry out characterizations of an optical nature of the transformation, by online analysis.

The embodiment of these FIGS. 5A and 5B thus makes it possible to implement transformations while maintaining them at the desired temperature, which is liable to vary for example from -20 to 200 ° C. The online analysis, which can be carried out, is for example of Raman spectroscopy type, or infrared thermography. Moreover, it is possible to have a long length of flexible tube 12 around the cylindrical wall 52. Under these conditions, the residence time that can be achieved in the portion of this flexible tube wound around this cylinder can to reach several hours.

FIG. 6 illustrates a further variant embodiment of the invention, in which the capillaries 13 and 14 open laterally into the capillary 12. Under these conditions, the mixing zone M ', which is merged with the contacting zone C , is located between the ends opposite these two capillaries. FIG. 7 illustrates a further variant embodiment of the invention, in which the capillary 13 does not flush with the downstream end of the outer capillary 14. In other words, the end 13 'is upstream of the end 14 ', while a mixture M formed of A and B flows in the vicinity of the latter. In this way, the reagents intended to form the drop are brought into contact before the actual formation of this drop. This embodiment lends itself to the flow of reagents, the mixture of which is not likely to form a solid capable of clogging the capillary 13.

Referring again to FIG. 8, it will be noted that, as a variant, the capillary 113 and / or the capillary 114 may not be flush with the downstream end. 115 'of the outer capillary 115. Under these conditions, a mixture is formed between the fluid C, as well as the fluid A and / or the fluid B, before the formation of the drops G'. In other words, the mixing zone is then located upstream of the end of the capillary 115.

It will be further noted that it is possible to form drops G from more than two components, in a manner different from that described in FIG. 8. Thus, it is possible to use several concentric capillaries, each of which ensures flow of one of these components. It is also possible to use only two concentric capillaries, as in the example of FIG. 1, while flowing at least two reagents into at least one of these pipes. It will be noted that the length of the capillary 12 may advantageously be between 50 cm and 10 meters, preferably between 1 and 4 meters. Under these conditions, the residence time of each drop is for example between 2 minutes and 10 hours. However, in the case of particularly slow, polymerization-type transformations, it is possible to stop the injection of reagent, via the capillaries 13 and 14, at a given moment. Under these conditions, the drops present in the capillary 12 are then immobilized, while this transformation continues to unfold. Then, at the end of this immobilization time, which allows the advancement of the transformation, reagents are injected again by the upstream capillaries 13 and 14, which makes it possible for the drops to flow again into the capillary 12. .

At least some of the various operations, described above, can be controlled by computer means, computer type. In these circumstances, this The latter is capable in particular of automatically generating the successive compositions of the plugs flowing in the capillary 12, of controlling the temperature of the heating body 50, of acquiring the analysis data and of automating the collection of the samples.

Finally, it should be noted that, by way of a variant not shown, the invention also finds application in a method and a plant for producing plugs, capable of using all or some of the characteristics described above, which are technically compatible with each other. . In this case, the analysis of these plugs, as well as the determination of characteristics of a transformation, are optional. This variant can in particular be implemented in order to prepare samples of products to be tested, or even in order to prepare products on an industrial scale, in particular polymers, in particular by radical polymerization.

The invention achieves the previously mentioned objectives. First of all, we will highlight the merit of the Applicant for having brought to light certain disadvantages related to the microfluidic technique presented in the preamble of the present description.

Indeed, microfluidic devices require, for their manufacture, the use of expensive soft lithography techniques, which require a significant financial investment and significant expertise in the field. This is why these techniques are not currently available in most industrial laboratories.

Moreover, a microfluidic chip is not scalable since, to modify a part of its hydraulic circuit, it is necessary to manufacture it again.

In addition, the very small dimensions of the microfluidic devices require corresponding miniaturization of the analysis tools. This is not always easy to implement, while accompanying significant additional costs.

The residence times of a plug on a microfluidic chip of conventional size are relatively low. This does not therefore allow to study the kinetics of slow chemical reactions, whose typical time is a few minutes to several hours.

Finally, the movement, stopping and referral of plugs in a network require the use of mechanical members of the valve type. At the microfluidic scale, such use is particularly difficult to implement.

However, the present invention overcomes these various disadvantages.

Indeed, the invention takes advantage of a flow operating on a larger scale, of the "millifluidic" type, which allows to obtain much higher flow rates and cap volumes. Furthermore, the flow members used in the invention are not formed in a solid body, wafer type, which is advantageous in terms of costs.

The use of a scale much higher than microfluidics, combined with the use of modulatable flow members, makes it possible to increase the residence time of the plugs. This is advantageous, particularly for the purpose of studying slow chemical reactions. In addition, it will be noted that the millifluidic flow in accordance with the invention makes it possible to produce objects, such as complex plugs, which can not be obtained simply by means of microfluidic flows. Under these conditions, the invention makes it possible in particular to generate double emulsions that it is not possible to create in a simple microfluidic manner.

It should also be noted that the fluid flow rates used in the invention are typically between 1 and 1000 mL / h, or between a few tens of milliliters and a few tens of liters per day. By comparison, the flow rates allowed by the microfluidic are significantly lower, namely less than a few tens of milliliters per day. The invention can notably find very advantageous applications, by the information provided, in the design of chemical preparation processes, in the design of new chemicals, especially in the design of new polymers, polymerization products, and / or or polymerization methods. The invention also offers a great simplicity of use, and many possibilities of variations in the number and order of the reagents used: it is thus possible to introduce certain reagents after others (for example catalysts or catalysts). initiators or comonomers or a reagent used in a second synthesis step), if necessary by trying several points (or moments) of introduction, without having to significantly modify a microfluidic reactor equipment or design.

Finally, it should be noted that the invention makes it possible to preserve the inherent advantages of microfluidics, in this sense that it appreciably allows the same cap management operations.

Claims

1. A method of determining at least one characteristic of a physical and / or chemical, in which is made to flow in ^a tubular flow member (12; 112), said downstream a succession of plugs (G; G ') formed of a physicochemical system capable of undergoing said transformation in a carrier phase (P), at least one analysis of at least one plug is carried out and the or each parameter is deduced therefrom.

2. Method according to claim 1, characterized in that the physicochemical system is formed of at least two components (A, B; A, B, C) and these two components are circulated in at least two parts of the body. upstream tubular flows (13,14; 113,114,115) which open into the downstream tubular flow member (12; 112).

3. Method according to claim 2, characterized in that the physicochemical system (A, B, C) comprises at least three components, each of which flows into a corresponding upstream member (113, 114, 115).

4. Method according to claim 3, characterized in that the physico-chemical system comprises at least one adjuvant (C) of the transformation, such as a catalyst or a buffer.

5. Method according to claim 3 or 4, characterized in that there is provided at least three upstream tubular flow members (113, 114, 115), at least two first (113, 114) upstream members being placed side by side. rib within a peripheral upstream tubular flow member (115).

6. Method according to one of the preceding claims, characterized in that the or each tubular flow member has an equivalent diameter. between 10 micrometers and 50 mm, preferably between 50 microns and 5 mm, more preferably between 100 micrometers and 1 mm.

7. Method according to one of claims 2 to 6, characterized in that said at least two components (A, B, C) are mixed in a mixing zone (M), substantially at the same time as contacting these components with the carrier phase (P), in a contact zone (C) substantially coincident with the mixing zone (M).

8. Method according to one of claims 2 to 7, characterized in that said at least two upstream flow members (13, 14) and the downstream flow member (12) are concentric.

9. A method according to claim 7 or 8, characterized in that the contacting zone (C) is located immediately downstream of a covering zone (R; R ') between the downstream flow member (12). 112) and a peripheral upstream flow member (14; 115).

10. Method according to any one of the preceding claims, characterized in that stops the transformation involved in the plugs (G), in particular by means of a quench (16), and carries out at least one offline analysis, especially in a chromatograph (18).

11. The method of claim 10, characterized in that stops the transformation in the downstream tubular flow member (12).

12. Process according to claim 10, characterized in that the plugs are taken out of the downstream tubular flow member, and then the transformation is stopped.

13. Method according to one of claims 1 to 9, characterized in that directs a beam (119) of an analysis apparatus (118), for example RAMAN type, to an area of the downstream tubular flow member (12) in which the transformation continues to unfold.

14. A method according to claim 13, characterized in that directs the beam (119) to the same location of the downstream tubular flow member (12), and an analysis is made of several plugs s successively flowing audit. in law.

15. Method according to any one of the preceding claims, characterized in that there is at least a portion of the downstream flow member (12) in a holding member (50) at a predetermined temperature.

16. Method according to any one of the preceding claims, characterized in that immobilizes, in the downstream flow member (12), at least some plugs, which allows the transformation to continue without displacement of these plugs, then it is again flow these plugs in this downstream tubular member (12), after observing this latency time.

17. Process according to any one of the preceding claims, characterized in that primary plugs (GB), comprising in particular a first monomer and a polymerization initiator, flow in the tubular flow member, and at least one other component is added to each primary plug, in particular another monomer and / or a further quantity of an initiator, so as to form definitive plugs (G).

18. Process according to any one of the preceding claims, characterized in that the plugs (G) are flowed into the downstream tubular flow member (12) at a flow rate of between 1 ml / h. and 1000 mL / h, preferably between 5 and 100 mL / h.

19. Process according to any one of the preceding claims, characterized in that the length of the organ downstream tubular flow (12) is between 50 cm and 10 m, in particular between 1 and 4 m.

20. Method according to any one of the preceding claims, characterized in that the parameter which is deduced is a rate of progress of the transformation, for example kinetics of disappearance of reactive products, kinetics of appearance of resulting products. a main reaction, or a kinetics of production of byproducts to this main reaction.

21. Method according to the preceding claim, characterized in that it controls, by a computer means, the composition of several plugs and / or the temperature of the holding member and / or is acquired by said computer means, the results different analyzes.

22. Method according to any one of the preceding claims, characterized in that at least one of said tubular flow members is flexible.

Apparatus for determining at least one parameter of a physical and / or chemical transformation, comprising:

- A tubular flow member (12; 112), said downstream, whose equivalent diameter is between 10 micrometers and 50 mm, preferably between 50 micrometers and 5 mm, more preferably between 100 micrometers and 1 mm

means (10, 13, 14, 110, 113, 114, 115) for generating a series of plugs (G; G ') separated by a carrier phase (P) in this downstream tubular flow member (12); 112) means (18; 118) for analyzing these plugs; and

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

24. Device according to claim 23, characterized in that the downstream tubular flow member (12) is placed in communication with means (16) for stopping said transformation, in particular by means of quenching, and this downstream tubular flow member (12) then opens into an external analyzer (18), in particular of the chromatograph type.

25. Device according to claim 23, characterized in that the analysis means comprise an analysis apparatus (118), for example RAMAN type, having a beam (119) adapted to be directed towards the flow member. downstream tubular (12).

26. Device according to one of claims 23 to 25, characterized in that the plug generating means (G) comprise at least one upstream tubular flow member (13, 14; 113, 114, 115), each of which is adapted to feed a component of said physicochemical system, the or each upstream tubular flow member opening into the downstream tubular flow member (12; 112), the generating means further comprising feed means (10; 110) of the carrier phase (P), also opening into the downstream tubular flow member (12).

Device according to claim 26, characterized in that at least two upstream tubular flow members (13, 14) are provided which have downstream ends (13 ', 14') defining a mixing zone (M). components of the plugs, these downstream ends (13 ', 14') opening into the downstream tubular flow member (12) in a contacting zone (C) substantially coincident with the mixing zone (M).

28. Device according to one of claims 23 to 24, characterized in that the length of the organ downstream tubular flow (12) is between 50 cm and 10 m, in particular between 1 and 4 m.

29. Device according to one of claims 23 to 28, characterized in that the device further comprises a holding member (50) at a given temperature, in the vicinity of which extends at least a portion of the flow member. downstream tubular (12).

30. Device according to claim 29, characterized in that the holding member at a given temperature comprises a hollow body (50), defining an interior volume (V) for receiving a heat transfer fluid, this interior volume being bordered by a wall (52) at the periphery of which extends said portion of the downstream tubular flow member (12).

31. Device according to claim 30, characterized in that the wall (52) is hollowed out by at least one series of peripheral grooves (53), each series of grooves allowing the reception of a downstream tubular flow member (12). ) of corresponding transverse dimension.

32. Device according to one of claims 30 or 31, characterized in that the portion of the downstream tubular flow member disposed around the wall (52) is capped by a peripheral flange (54), in which is provided a window (58) for viewing by an analysis apparatus.

33. A method for screening several transformations of a physico-chemical system, in which several different transformations are implemented, by modifying said physico-chemical system and / or operating conditions, determining at least one parameter of each transformation according to the process according to any one of claims 1 to 16 and at least one preferred transformation having at least one preferred parameter.