U.S. patent application number 12/445224 was filed with the patent office on 2010-05-27 for method and installation for determining at least one parameter of a physical and/or chemical conversion.
Invention is credited to Annie Colin, Cristobal Galder, Pascal Panizza, Bertrand Pavageau.
Application Number | 20100129917 12/445224 |
Document ID | / |
Family ID | 37885828 |
Filed Date | 2010-05-27 |
United States Patent
Application |
20100129917 |
Kind Code |
A1 |
Panizza; Pascal ; et
al. |
May 27, 2010 |
METHOD AND INSTALLATION FOR DETERMINING AT LEAST ONE PARAMETER OF A
PHYSICAL AND/OR CHEMICAL CONVERSION
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.
Inventors: |
Panizza; Pascal;
(Noyal-Sur-Vilaine, FR) ; Galder; Cristobal;
(Shanghai, CN) ; Pavageau; Bertrand; (Villenave
D'Ornon, FR) ; Colin; Annie; (Bordeaux, FR) |
Correspondence
Address: |
BUCHANAN, INGERSOLL & ROONEY PC
POST OFFICE BOX 1404
ALEXANDRIA
VA
22313-1404
US
|
Family ID: |
37885828 |
Appl. No.: |
12/445224 |
Filed: |
October 15, 2007 |
PCT Filed: |
October 15, 2007 |
PCT NO: |
PCT/FR07/01685 |
371 Date: |
January 28, 2010 |
Current U.S.
Class: |
436/52 ;
422/68.1 |
Current CPC
Class: |
B01F 5/0647 20130101;
B01F 5/0085 20130101; B01F 5/0646 20130101; G01N 35/08 20130101;
Y10T 436/117497 20150115; B01F 13/0071 20130101; B01F 3/0807
20130101; G01N 2035/00386 20130101 |
Class at
Publication: |
436/52 ;
422/68.1 |
International
Class: |
G01N 35/08 20060101
G01N035/08 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 13, 2006 |
FR |
0608991 |
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
(G.sub.0), 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.
Description
[0001] 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.
[0002] 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.
[0003] 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.
[0004] The parameters of a conversion have already been determined
using the technique of microfluidic flows.
[0005] 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.
[0006] 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
cm.sup.2, 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.
[0007] 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.
[0008] 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.
[0009] 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.
[0010] 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.
[0011] 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.
[0012] For this purpose, one subject of the invention is a
determination method according to the appended claim 1.
[0013] Advantageous features of the invention form the subject
matter of the appended claims 2 to 22.
[0014] Another subject of the invention is a determination device
according to the appended claim 23.
[0015] Advantageous features of the invention form the subject
matter of the appended claims 24 to 32.
[0016] A final subject of the invention. is a screening method
according to the appended claim 33.
[0017] The invention will be described below with reference to the
appended drawings given solely by way of nonlimiting examples, in
which:
[0018] FIG. 1 is a front view illustrating an installation for
determining a parameter of a conversion, in accordance with the
invention;
[0019] 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;
[0020] FIG. 3 is a front view, similar to FIG. 1, illustrating an
alternative embodiment of the invention;
[0021] FIG. 4 is a front view, similar to FIG. 1, illustrating an
additional alternative embodiment of the invention;
[0022] 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
[0023] FIGS. 6 to 8 are front views, similar to FIG. 1,
illustrating two additional alternative embodiments.
[0024] 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.
[0025] 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.
[0026] 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.
[0027] 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.
[0028] 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.
[0029] 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.
[0030] 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.
[0031] 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.
[0032] 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.
[0033] 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.
[0034] 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.
[0035] 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.
[0036] 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.
[0037] 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.
[0038] The implementation of a determination method by the
installation described above will now be explained below.
[0039] 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 H.sub.2O.sub.2.
[0040] 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 .mu./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.
[0041] 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.
[0042] 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.
[0043] 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.
[0044] 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.
[0045] 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.
[0046] 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.
[0047] 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.
[0048] 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.
[0049] 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.
[0050] 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.
[0051] 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 G.sub.1 flowing downstream of
this sack 16 are of the same nature and correspond to a reaction
time t.sub.1 which is itself associated with the abscissa X.sub.1
(see FIG. 1) corresponding to the entry of the capillary tube 12
into the sack 16.
[0052] 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.
[0053] Moreover, if the flow rates of the components A and B are
modified, the time t.sub.1, associated with the abscissa X.sub.1 of
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.
[0054] 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.
[0055] 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.sub.1, 100.sub.2, and 100.sub.3 and one outlet
100.sub.4. Two capillary tubes 113 and 114 pass through the hollow
body, starting from the first two inlets 100.sub.1 and
100.sub.2.
[0056] 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.sub.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.sub.3
communicates with a nozzle 110', the function of which will be
explained below.
[0057] Finally, the outlet 100.sub.4 of 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.sub.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.
[0058] 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.
[0059] 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'.
[0060] 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.
[0061] 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.
[0062] 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.
[0063] 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.
[0064] 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.
[0065] 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.
[0066] 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.
[0067] 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.
[0068] 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.
[0069] FIG. 4 illustrates an additional embodiment of the
invention. In this embodiment, there is again a capillary tube 12
in which first droplets G.sub.0 are formed, in a manner similar to
that described above. At least one other component intended to be
introduced into each primary droplet G.sub.0 is 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.
[0070] The embodiment shown in FIG. 4 lends itself particularly to
polymerization reactions. Thus, each primary droplet G.sub.0 may 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.
[0071] 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.
[0072] 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.
[0073] 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.
[0074] 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).
[0075] 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.
[0076] 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.
[0077] 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.
[0078] 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.degree. 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.
[0079] 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.
[0080] 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.
[0081] 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.
[0082] 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.
[0083] 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.
[0084] 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.
[0085] 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.
[0086] 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.
[0087] The invention achieves the objectives mentioned above.
[0088] 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.
[0089] 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.
[0090] Moreover, a microfluidic chip cannot be modulated given
that, to modify part of its hydraulic circuit, it has to be
fabricated anew.
[0091] 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.
[0092] 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.
[0093] 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.
[0094] 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.
[0095] 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.
[0096] This is advantageous, particularly for the purpose of
studying slow chemical reactions.
[0097] 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.
[0098] 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.
[0099] 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.
[0100] 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.
* * * * *