阅读说明：本技术 色谱法 (Chromatography method ) 是由 弗朗索瓦·帕门蒂尔 于 2017-10-12 设计创作，主要内容包括：本发明提出了一种物质交换方法,其中包含待分离成分的气态、液态或超临界流动相通过包含固定相的填料进行循环,所述方法的特征在于：-所述填料包含多个毛细导管,所述毛细导管由至少一种第一材料制成,导管在所谓的上游面和所谓的下游面之间经过填料,其中流动相经过上游面进入填料,经过下游面流出填料,-每个导管至少在其一部分内壁上包含至少一种第二材料,所述第二材料由有机或无机多孔凝胶构成,-所述第二材料的厚度使得导管内部形成至少一个没有固体物质的管状通道,并且通向流动相通路,所述通道在所述毛细导管的上游面和下游面之间连续延伸,-第二多孔材料的厚度为通道直径的0.05-0.5倍,-该方法是在流动相速度为流动相最佳速度的5.0-50倍时完成的,所述流动相最佳速度是在工艺条件下,根据占比较大的待分离化合物的范德姆特(Van Deemter)曲线的最小值确定的,-毛细导管的总体积占填料总体积的15％以上。(The invention proposes a method for exchanging substances, in which a gaseous, liquid or supercritical mobile phase containing the components to be separated is circulated through a packing comprising a stationary phase, said method being characterized in that: -the packing comprises a plurality of capillary ducts made of at least one first material, which ducts pass through the packing between a so-called upstream face through which the mobile phase enters the packing and a so-called downstream face through which the packing exits, -each duct comprises at least one second material on at least a portion of its inner wall, the second material consisting of an organic or inorganic porous gel, -the thickness of the second material being such that at least one tubular channel free of solid matter is formed inside the duct and opens into a passage for the mobile phase, the channel extending continuously between the upstream and downstream faces of the capillary duct, -the thickness of the second porous material being between 0.05 and 0.5 times the diameter of the channel, -the process being carried out at a mobile phase velocity of between 5.0 and 50 times the optimal velocity of the mobile phase, the optimum speed of the mobile phase is determined under the process conditions according to the minimum of the Van Deemter curve of the larger compound to be separated, the total volume of the capillary ducts representing more than 15% of the total volume of the packing.)

1. A mass exchange process in which a gaseous, liquid or supercritical mobile phase containing components to be separated is circulated through a packing comprising a stationary phase, the process being characterized in that:

the packing comprises a plurality of capillary conduits made of at least one first material, which conduits pass through the packing between a so-called upstream face, through which the mobile phase enters the packing, and a so-called downstream face, through which the mobile phase exits the packing,

each of said conduits comprising at least one second material on at least a portion of its inner wall, said second material being constituted by an organic or inorganic porous gel,

the thickness of the second material being such that the conduit is internally formed with at least one tubular passage free of solid matter and open to a mobile phase passage, the passage extending continuously between the upstream and downstream faces of the capillary conduit,

the thickness of the second material is 0.05-0.5 times the diameter of the channel,

said method being carried out at a mobile phase velocity of 5.0 to 50 times the mobile phase optimum velocity determined under the process conditions according to the minimum of the Van der Waals curve of the compounds to be separated which are relatively large,

the total volume of the capillary duct accounts for more than 15% of the total volume of the filler.

2. The method according to claim 1, characterized in that a material exchange is carried out to achieve the chromatographic separation.

3. The method of claim 2, wherein the material separation is accomplished by multiple cycles.

4. A method according to any of claims 2 or 3, characterized in that the method is performed in a cycle time of less than 600 seconds, more advantageously less than 180 seconds, even more advantageously less than 30 seconds.

5. The method of any one of the preceding claims, wherein the thickness of the second porous material is 0.05-0.25 times the channel diameter.

6. Method according to any of the preceding claims, characterized in that the method is performed on a chromatography column, wherein the conduit of the chromatography column comprises a porous material with a thickness of 0.01-0.15 times the diameter of the channel, eluting at a rate of 5-25 times the optimal rate of the mobile phase determined under process conditions according to the minimum of the van der waals curve of the compounds to be separated, which is relatively large.

7. The method of any of the preceding claims, wherein the thickness of the second material is supported by a non-porous capillary wall.

8. A method according to any of the preceding claims, wherein the diameter of the channel is less than 150 microns, preferably less than 50 microns, more preferably less than 15 microns.

9. A method according to any of the preceding claims, wherein the second material is silica gel.

10. The method according to any of the preceding claims 1 to 7, characterized in that the second material is a polymeric gel.

Technical Field

The present invention relates to a chromatography column comprising a porous stationary phase.

Background

Chromatography is typically achieved using porous packing consisting of a bed of fine particles of a few microns or tens of microns in diameter. These packings produce large pressure drops in operation, from a few tens of bars to a few hundreds of bars, and yield is low.

These characteristics prevent their widespread industrial use as separation processes.

Belov et al in the example of U.S. patent PCT US2004/032958 propose attempts to solve this problem by using a multi-capillary packing consisting of capillaries running in parallel. However, no mention is made anywhere in this text of the optimum operating conditions of the production process.

The products set forth in the examples were not characterized. Nor is there any description of chromatographic separation.

French patent 1459175 to parameterier proposes a new solution to the problems posed by these fillers, which is characterized by the fact that the channel partition walls are brought into a porous state. This structure makes the passing efficiency very high. However, considering the simplicity of application and the low requirements on efficiency, it can prove more economical to produce solid walls of extremely high mechanical strength.

The invention proposes a composite packing for chromatography, comprising at least one capillary duct made of at least one first vitreous material, each duct passing through the packing between a so-called upstream face, through which the mobile phase enters the packing, and a so-called downstream face, through which the mobile phase exits the packing, wherein:

each conduit comprising at least one second material on at least a portion of its inner wall, said second material being constituted by an organic or inorganic gel and being porous in the desolvated state,

the thickness of the second material is such that the interior of the conduit forms at least one tubular channel free of solid matter and open to the mobile phase passage, the channel extending continuously between the upstream and downstream faces of the capillary conduit.

Disclosure of Invention

The invention proposes a method for exchanging substances, in which a gaseous, liquid or supercritical mobile phase containing the components to be separated is circulated through a packing comprising a stationary phase, said method being characterized in that:

the packing comprises a plurality of capillary conduits made of at least one first material, the conduits passing through the packing between a so-called upstream face, through which the mobile phase enters the packing, and a so-called downstream face, through which the mobile phase exits the packing,

each conduit comprising at least one second material on at least a portion of its inner wall, said second material being constituted by an organic or inorganic porous gel,

the second material having a thickness such that the conduit interior forms at least one tubular passage free of solid matter and open to the mobile phase passage, the passage extending continuously between the upstream and downstream faces of the capillary conduit,

the channels have an average diameter of less than 250 microns,

the thickness of the second porous material is 0.05 to 0.5 times the diameter of the channel,

the method is carried out at a mobile phase velocity which is 5.0 to 50 times the optimum velocity of the mobile phase, said optimum velocity of the mobile phase being determined under process conditions according to the minimum of the Van Deemter curve of the compounds to be separated which is relatively large,

the total volume of the capillary duct accounts for more than 15% of the total volume of the filler.

Advantageously, the method according to the invention is characterized in that a material exchange is carried out to achieve the chromatographic separation.

Advantageously, the method according to the invention is characterized in that the material separation is accomplished by means of a plurality of cycles.

Advantageously, the method according to the invention is characterized in that it is carried out in a cycle time of less than 600 seconds, more advantageously less than 180 seconds, even more advantageously less than 30 seconds.

Advantageously, the method according to the invention is characterized in that the thickness of the second porous material is between 0.05 and 0.25 times the diameter of the channels.

Advantageously, the method according to the invention is characterized in that it is carried out on a chromatography column in which the conduit comprises a porous material having a thickness of 0.01 to 0.15 times the diameter of the channel, and the elution speed is 5 to 25 times the optimum speed of the mobile phase determined, under the process conditions, on the basis of the minimum value of the van der waals curve of the compounds to be separated, which is relatively large.

Advantageously, the method according to the invention is characterized in that the thickness of the second material is supported by the non-porous capillary wall.

Advantageously, the method according to the invention is characterized in that the diameter of the channels is less than 150 microns, preferably less than 50 microns, more preferably less than 15 microns.

Advantageously, the method according to the invention is characterized in that the second material is silica gel.

Advantageously, the method according to the invention is characterized in that the porous material is a polymeric gel.

According to a preferred embodiment of the invention, the second porous material is a copolymer of styrene and divinylbenzene containing sulfo, carboxyl, amino or quaternary ammonium groups.

Advantageously, the second porous material supports a liquid stationary phase.

Advantageously, the chromatography is carried out using a simulated moving bed.

Advantageously, the chromatography is carried out using a continuous annular rotating device.

Drawings

FIG. 1 is a schematic cross-sectional view of a cylindrical polycapillary packing in a direction parallel to its major axis;

FIG. 2 is a schematic cross-sectional view of a cylindrical polycapillary packing in a direction perpendicular to its major axis;

FIG. 3 is a schematic structural view of an example of a filler conduit;

FIGS. 4 and 5 illustrate two practical modifications of chromatography;

FIG. 6 shows Van der Waals curves for a polycapillary packing;

FIG. 7 shows comparative yields of polycapillary filler and particulate filler;

fig. 8 shows the comparative yields of polycapillary and particulate fillers over a larger working range.

Detailed Description

The present invention proposes a method of mass exchange in which a gaseous, liquid or supercritical mobile phase containing a component to be separated is circulated through a packing comprising a stationary phase, said method being characterized in that:

the packing comprises a plurality of capillary conduits made of at least one first material, the conduits passing through the packing between a so-called upstream face, through which the mobile phase enters the packing, and a so-called downstream face, through which the mobile phase exits the packing,

each conduit comprising at least one second material on at least a portion of its inner wall, said second material being constituted by an organic or inorganic porous gel,

the second material having a thickness such that the conduit interior forms at least one tubular passage free of solid matter and open to the mobile phase passage, the passage extending continuously between the upstream and downstream faces of the capillary conduit,

the channels have an average diameter of less than 250 microns,

the thickness of the second porous material is 0.05 to 0.5 times the diameter of the channel,

the method is carried out at a mobile phase velocity of 5.0 to 50 times the mobile phase optimum velocity determined under the process conditions according to the minimum of the van der waals curve of the compounds to be separated which are relatively large.

Advantageously, the total volume of the capillary duct represents more than 15% of the total volume of the filler.

In order to increase the theoretical plate number of the chromatography packing, an attempt is made to reduce the transfer resistance of the substance and thus the diffusion length. Therefore, efforts are made to work with thin layers of porous materials and at low elution rates.

In contrast, according to the prior art, in order to increase the hourly yield or capacity of the chromatography packing in preparative applications, it is sought to increase the amount of stationary phase and to work at high elution speeds.

Optimization of the capillary packing according to the invention shows that by reducing the thickness of the porous stationary phase layer, the transfer resistance gain far exceeds the capacity loss, which allows to maintain high efficiency at very high flow phase flows.

This unexpected result forms the basis of the present invention.

This can be achieved by capillary packing, since the thickness of the stationary phase is controlled for this type of material, regardless of the diameter of the channels, whereas particulate packing does not. The particulate filler is limited to a single void fraction of about 35-40%.

On the other hand, the pressure required to obtain a high flow rate of the mobile phase remains a reasonable cost in the prior art, since capillary packing enables high permeability.

This data is mainly from the study shown in figure 7.

On the other hand, when the velocity exceeds 50 times or more the optimum velocity of the van der waals curve, the pressure drop in the bed becomes extremely high.

Advantageously, the method is characterized in that a material exchange is carried out to achieve the chromatographic separation.

Advantageously, all the ducts are straight, penetrating the packing and open to its upstream and downstream faces.

Advantageously, the second layer of porous material is deposited in a different form to the first layer of material and is supported on the inner periphery of said first material.

In such packings, the capillary conduit comprises a portion that is substantially free of solid matter, forming a continuous channel extending from the upstream face to the downstream face of the packing, considered herein as the conduit portion leading to the fluid passage or channel.

The second material deposited on the conduit wall is porous.

In particular, at least the duct wall is provided with a continuous network of holes, said holes opening into the duct.

The capillary duct is advantageously straight, but it is not excluded that the duct has a bend or an angle.

According to the invention, the thickness of the second porous material is between 0.05 and 0.25 times the diameter of the capillary duct leading to the fluid passage or channel.

Advantageously, the chromatography is carried out on a chromatography column in which the conduit comprises a porous material having a thickness of 0.01 to 0.15 times the diameter of the conduit leading to the fluid passage or channel and an elution rate of 5 to 25 times the optimal rate of the mobile phase, said optimal rate of the mobile phase being determined according to the minimum of the van der waals curve.

Advantageously, the conduit leading to the fluid passage or channel is less than 250 microns in diameter, preferably less than 150 microns, more preferably less than 50 microns, more preferably less than 15 microns.

If there are areas of different thickness of the second porous material, the thickness of the material, and the average of the area over the portion of the surface of the pipe that it covers, should be calculated.

Advantageously, the polycapillary packing according to the invention will be made with a diameter of more than 10mm, preferably more than 25mm, more preferably more than 50 mm.

Advantageously, the polycapillary packing according to the invention will be made with a cross-section greater than 1cm²Preferably greater than 5cm²More preferably greater than 20cm²So as to be able to be used for manufacturing purposes.

Advantageously, the length of the conduit is greater than 10 microns, preferably greater than 50 microns, more preferably greater than 200 microns.

In fact, it is simple to manufacture and can be extended to any desired diameter, decimeters or meters.

This emphasis constitutes one aspect of the present invention.

In fact, up to now, fillers for mass exchange cannot be made on a large scale with channels having a diameter of less than 250 microns.

The diameter of a capillary conduit leading to a fluid passage or channel, refers to the diameter of the conduit or hydraulic diameter without matter, in which a fluid composed of a mobile phase is free to flow in a convective manner.

Since the thickness of the second porous material layer is thin, a high-speed diffusion phenomenon occurs therein. This makes the packing very efficient and allows for much higher flow rates of the mobile phase. Both factors combine significantly to improve the yield per unit volume.

On the other hand, the pressure drop of the polycapillary packing in operation is ten times smaller than the pressure drop of the particulate packing. This allows for a significant reduction in packing volume for a given separation operation.

Finally, the cycle time of such a packing is extremely short, and it is preferable to separate one of the materials sequentially from the plurality of materials to be treated.

The combination of these factors constitutes the present invention.

These characteristics allow the filler of the invention to be used for preparative chromatography when it is desired to separate large amounts of material free of impurities.

The amount of these substances will advantageously be greater than 10 mg per hour, preferably greater than 1 g per hour, more preferably greater than 100 g per hour.

Advantageously, these quantities are divided into a plurality of very rapid injections in a discontinuous process.

Indeed, as can be seen from the following table (see fig. 7), the cycle time of chromatography according to the invention is extremely short (see elution timeline for capillary/particle bed) compared to the particle packing. This constitutes an aspect of the invention.

Advantageously, the material to be purified will be separated out by means of a number of cycles.

According to the first embodiment, the loop will last less than 3600 seconds. Especially in the case of ion exchange devices.

Advantageously, in chromatography, each cycle will last less than 600 seconds, preferably less than 150 seconds, more preferably less than 30 seconds.

Advantageously, each cycle will last for more than 3 seconds, preferably more than 10 seconds. This may extend the service life of the control member.

Under the condition of adopting a circulation method, the circulation time is the interval time of two material sample injections.

In the case of continuous loop chromatography, the cycle time is expressed as the time taken for the packing to circulate once.

In the case of a simulated moving bed, the circulation time will be the residence time of the mobile phase in all the basic packings constituting the process.

The volume of these fillers will advantageously be greater than 1cm³Preferably greater than 100cm³And more preferably greater than 1 liter.

In the present invention, the van der waals curve will be measured at high dilution to be as linear as possible in the chromatographic range.

Advantageously, the dilution concentration of the substance for which the van der waals curve is to be measured in the sample to be separated will be less than 5% (molar), more advantageously less than 5% o (molar), even more advantageously less than 500 parts per million (molar).

Advantageously, the van der waals curve should be determined using the larger mole fraction of the species to be separated.

The process conditions mean that the same stationary phase, the same temperature and the same elution solvent, and possibly the same mobile phase elution gradient, and the same temperature gradient of the column, the length of which is the same as the length of the column in the process, are used for measuring the van der waals curve.

Advantageously, the Van der walls curve can be measured on a standard chromatographic column with a diameter of 4.6 mm.

It is known in the prior art that, in terms of the number of chromatographic theoretical plates, the performance varies only slightly with the diameter of the column.

Thus, the performance of a column with a larger diameter can be inferred as the performance obtained from a column of the diameter used for analysis, and is easier to fabricate and operate.

Advantageously, the second porous material has a pore volume of between 0.15 and 0.95 (cm) of the material³/cm³)。

Advantageously, the second porous material has a pore volume of between 0.3 and 0.80 (cm) of the material³/cm³)。

Advantageously, the chromatography is performed on a chromatography column comprising a second porous material having a thickness of 0.01-0.25 times the diameter of the capillary conduit leading to the fluid passage or channel, eluting at a rate of 2-25 times the optimal rate of the mobile phase, said optimal rate of the mobile phase being determined according to the minimum of the van der waals curve.

Preferably, the chromatography is performed on a chromatography column comprising a second porous material having a thickness of 0.01-0.15 times the diameter of the capillary conduit leading to the fluid pathway or channel, eluting at a rate of 5-25 times the optimal rate for the mobile phase, as determined by the minimum of the van der waals curve.

More preferably, the chromatography is performed on a chromatography column comprising a second porous material having a thickness of 0.01-0.10 times the diameter of the capillary conduit leading to the fluid pathway or channel, eluting at a rate of 5-50 times the optimal rate for the mobile phase, as determined by the minimum of the van der waals curve.

Advantageously, the thickness of the second porous material is supported by the walls of the capillary made of the first non-porous material.

According to another embodiment, the thickness of the second porous material is supported by the walls of the capillary tube made of the first porous material.

Advantageously, the conduit leading to the fluid passage or channel is less than 500 microns in diameter, preferably less than 250 microns, more preferably less than 50 microns.

According to a preferred embodiment, the conduit leading to the fluid passage or channel is less than 15 microns in diameter.

According to a preferred embodiment of the invention, the second porous material is chromatographic silica gel.

Advantageously, the specific surface area of the second porous material is between 50 and 800m²A/g, preferably between 70 and 600m²Between/g.

Advantageously, the specific surface area will be measured by nitrogen adsorption on a porous material.

The mobile phase velocity is defined as the velocity or superficial velocity when the tube is empty, that is to say the velocity at which the fluid flows regularly through the entire cross section of the packing.

The capillary duct is advantageously straight, but it is not excluded that the duct has a bend or an angle.

The cross-section is uniform from capillary conduit to capillary conduit and along the length of the capillary conduit.

The difference in cross-section can be conveniently determined by the relative standard deviation. The relative standard deviation represents the ratio of the standard deviation of the conduit diameter to the mean conduit diameter, expressed as a percentage. Advantageously, the average diameter of the individual conduits containing the first material is substantially constant, for example the standard deviation of the diameters of a sample of filler conduits is no more than 10% of the average diameter, preferably no more than 2% of the average diameter, more preferably no more than 1.0% of the average diameter. As used herein, the average of a set of values for variable X refers to the arithmetic mean E [ X ] thereof]. The standard deviation is defined as (X-E [ X ]])²Square root of the arithmetic mean of. Herein, a distribution refers to a set of values of variable X.

Advantageously, the diameter of the conduits does not differ more than 10% over the same conduit length.

Advantageously, the difference in conduit diameter over the same conduit length is preferably not more than 2%. More advantageously, the diameter of the conduits does not differ more than 1% over the same conduit length.

Advantageously, the average diameter of each conduit leading to a fluid pathway or channel is substantially constant, for example the standard deviation of the diameter relative to a sample of filler conduits is no more than 10% of the average diameter, preferably no more than 2% of the average diameter, more preferably no more than 1.0% of the average diameter.

Advantageously, the conduit extends through the packing, which minimizes pressure drop within the packing during chromatographic separation.

Advantageously, the total volume of the ducts leading to the fluid passages or channels represents more than 5% of the total volume of the packing, preferably more than 15% of said total volume, and more preferably more than 50% of the total volume of the packing. As used herein, "total volume of filler" refers to the volume occupied by the filler, including its pores and conduits; thus, the total volume can be calculated from the external dimensions of the filler. The channel volume was measured as follows: the number of channels x the average cross-sectional area of the conduit leading to the fluid passage or channels x the average length of the channels.

The volume calculation formula of the second material is as follows: the number of conduits x the average cross-sectional area of the stationary phase in the conduit x the average length of the conduit.

Advantageously, the volume of the capillary duct represents more than 5% of the total volume of the filler, preferably more than 15% of said total volume, more preferably more than 50% of the total volume of the filler. The catheter volume was measured as follows: the number of channels x the average cross-sectional area of the conduit x the average length of the conduit. A conduit refers to a conduit comprising a channel and a second porous material.

Advantageously, the second porous material occupies more than 2% of the volume of the filler material excluding the conduits, preferably more than 5% of said volume, more preferably more than 10% of said volume, in the filler material. "filler volume other than the conduit" refers to the difference between the total volume of filler and the volume of the portion of the capillary conduit leading to the fluid pathway or channel.

The conduit may have a cross-section of any suitable shape, such as circular, square, rectangular, hexagonal, star-shaped, slot-shaped, and the like. When a conduit has a non-circular cross-section, the conduit "diameter" refers to its hydraulic diameter.

In particular, the conduit has a circular cross-section.

In particular, the conduit has a regular hexagonal cross-section.

In particular, the duct is flat or in the form of a slot formed by two parallel planes.

Advantageously, the hydraulic diameter of the conduit is less than or equal to 250 μm. According to one embodiment, the hydraulic diameter of the conduit is less than or equal to 50 μm, or even less than or equal to 15 μm. Typically, the calculated hydraulic diameter is generally equal to the cross-sectional area of the conduit (unit: m)²) Four times divided by the circumference of the tube wetted by the mobile phase (unit: m).

Finally, the relative standard deviation of the thickness of the second porous material with respect to the cross-sectional area of the filler is preferably less than 10%, more preferably less than 5%, even more preferably less than 2.0%. In this case, the relative standard deviation characterizes the ratio of the standard deviation of the thickness of the porous material to its mean value, expressed in percentage.

The porosity of a material can be advantageously determined in chromatography in three ways:

1. the porosity of the organogel may be caused by swelling of the crosslinked gel in an organic, inorganic or aqueous solvent, wherein the swelling ratio is advantageously more than 2% of its volume, more preferably more than 10% of its volume.

2. This porosity may be related to the porosity of the material in the unsolvated state.

3. This porosity may be related to the porosity of the support on which the gel is deposited in the form of a thin layer.

According to the invention, the pore volume comprises the total volume of micropores, mesopores and macropores.

Material porosity refers to the porosity of the second material, but does not include the volume of the conduit leading to the fluid pathway or channel.

Advantageously, the porosity of the second material will be measured in the desolvated, dried state.

"mesoporous" refers to pores having a diameter between 2 and 50 nanometers; "macroporous" means pores greater than 50 nanometers in diameter; "microporous" refers to pores having a diameter of less than 2 nanometers.

The pore size referred to herein is measured by two different techniques, depending on the nature of the material tested: in the case of inorganic materials, in particular silica, the technique used for macropores and mesopores is mercury porosimetry, while the micropore uses the nitrogen adsorption technique; in the case of polymeric materials or materials based on inorganic matrices and provided with organogel coatings, the macropores are determined by mercury porosimetry, while the mesopores and micropores are determined by nitrogen adsorption techniques.

The invention will be described in more detail below with reference to the following figures.

In the example shown in fig. 1, the capillaries are straight, parallel and evenly distributed. The different conduits have as identical a morphology and a diameter as possible. Each conduit runs through the packing, that is to say its ends are advantageously open on each side 4, 5 of the packing, so that the fluid circulates from the inlet side 4 to the outlet side 5.

Thus, such packing materials may be used in chromatography columns.

Fig. 2 is a top view of the surface 5 of the packing of fig. 1 in direction 6. Openings for the respective capillary ducts 1 are formed in the organic gel 2.

According to one embodiment, the duct wall 10 is constituted by a solid continuous body made of a first material whose inner periphery supports a second porous material 11 (fig. 3). The portion of the conduit leading to the fluid path is constituted by the central channel of the capillary 12 or channel. The conduit may have a circular or hexagonal cross-section.

According to this embodiment, the catheter wall may be composed of a first non-porous material selected from:

glass

Silicon dioxide

Aluminosilicates, e.g. cordierite

Stainless steel

Organic polymers, such as polypropylene, polyethylene, PEEK, polytetrafluoroethylene or PTFE, polyvinylidene fluoride or PVDF.

According to another embodiment, the wall of the conduit is made of one of the materials from the above list having porosity.

Advantageously, the gel constituting the stationary phase is a second porous material and is an inorganic gel.

According to one embodiment, the gel constituted by the mineral is selected from:

silica gel

Activated alumina

Titanium oxide

Zirconia (zirconium oxide).

Advantageously, the gel constituting the stationary phase is a second porous material and is an inorganic gel constituted by silica gel.

Advantageously, the gel constituting the stationary phase is a second porous material and is an organogel. French patent application 1459175 to f.parameterier may be consulted to find a relevant description of organogels suitable for use in the present invention.

The manufacturing process of the filler according to the invention is extremely simple, consisting in using macroscopic capillaries made of stretchable material, such as glass, polymer or metal. The tube is stretched to a desired diameter and may be heated to fluidize the material. The diameter can therefore be up to 0.2 μm.

The interior of the tube is covered with a uniform film of stationary phase by pushing a liquid column of liquid precursor along the entire length of the tube. And depositing a thin film in which pores are formed by polymerizing with a crosslinking agent in the presence of a solvent and drying, and then by dissolving or drying.

The pipe obtained by the aforementioned method is cut into pipe sections of the same size and combined in parallel and can be sealingly bonded together. They can be inserted into a pressure-resistant structure and equipped with fluid inlet and outlet means, such as baking distributors and standard type connectors.

Chromatography is a special molecular separation method characterized in that it separates a mixture of chemical substances under the following opposing actions:

dynamic entrainment of these substances by the eluent stream,

retention of the immobilized phase with respect to these substances.

Preferably, the process is continued until the material is completely eluted from the stationary phase.

Chromatography is divided into two main categories: elution chromatography, affinity chromatography.

Figure 4 depicts an elution chromatography. According to this method, a continuous flow of mobile phase 28, possibly varying in composition and temperature with time, passes through a chromatographic column 21 filled with stationary phase 22. A quantity of material 23 to be separated is fed into the feed stream. Under antagonistic action, i.e. irreversible retention of immobilized relative chemical species and elution or entrainment of mobile phase, the species migrate along the column 21 at different rates and separate into elution bands or peaks 24, 25, 26, etc.

The separated material is separated by fractionating the fluid exiting the column to collect each elution zone from the elution solvent as it exits the column.

In a discontinuous process, the grading may be time-graded, while in a continuous annular rotating device, the grading may be angle-graded. It may include separation of a head fraction and a tail fraction of a simulated moving bed unit.

The chromatogram shows the concentration peaks of substances 24, 25, 26 at the column outlet as a function of time.

FIG. 5 depicts affinity chromatography capable of separating molecules, ions or biomolecules. A continuous flow of solvent 30 containing the molecules 27 to be separated enters a chromatographic column 21 filled with a stationary phase 22, said stationary phase 22 having a high affinity for the molecules to be separated. Under the action of this high affinity, the molecules are constantly immobilized on the stationary phase until saturation. This fixing is almost irreversible under the conditions of the first stage. In this case, the changing front 31 of the concentration of molecules 27 is a progressive peak-valley towards the outlet. The column is saturated when the concentration of molecules 27 in the solvent at the outlet end of the column becomes higher.

In the second stage, the characteristics (pH, ionic strength, etc.) or properties of the elution solvent 29 are changed to reduce or eliminate the affinity of the molecules 27 for the stationary phase 22 and to dissolve the molecules in the solvent 29. The molecules 27 elute from the solvent 29 exiting the column 21 until the solvent is exhausted. The column 21 is then subjected to a regeneration treatment and is ready for a new cycle.

The chromatogram shows the time-dependent concentration profile of substance 27 at the outlet of the column during the fixing and elution phases.

Figure 6 shows van der waals' curves for a polycapillary packing, wherein the thickness of the porous stationary phase on the inner circumference of the conduit is variable, according to the arrangement depicted in figure 3. The van der waals curve relates the efficiency characteristics expressed in terms of theoretical plate height of the chromatography packing to the mobile phase velocity of the elution chromatography. It can be seen that these van der waals curves have a minimum or optimum efficiency. The abscissa represents the stationary phase velocity (unit: mm/s) measured on a cross section of the conduit including the thickness of the porous material. The ordinate represents the height of the theoretical plate (unit: μm). It can be seen that at high speeds due toThe thickness of the stationary phase deposited on the walls is smaller and therefore the van der waals curve becomes more parallel to the abscissa. This constitutes a significant feature of the invention, enabling operation at higher flow rates and hence higher yields of chromatographic bed, while maintaining higher efficiency than a granular bed. These curves are given for a diameter of a circular cross-section pipe having a value of 10 microns and leading to a fluid passage or channel. The seven curves in fig. 6 correspond from top to bottom to the thickness of the porous material covering the entire tube wall and are equal from left to right (unit: microns):

10.1

5.6

3.7

2.5

1.7

1.1

0.7

TABLE 1

Figure 7 shows the comparative yield ratio per volume of column between a multi-capillary packing and a particulate packing according to the present invention. The control may conveniently be performed at the minimum of the van der waals curve. This control is done for the same pressure drop of the column and the same number of plates between the two packings. It can be seen that the curve exhibits a very significant maximum value at the lower thickness of the stationary phase on the wall of the pipe, said value being between 0.005 and 1.0 times the hydraulic radius of the empty pipe through which the fluid passes. Under such conditions, the yield of the polycapillary filler is 50 times higher than the yield of the particulate filler.

The calculated volume yield is the flow rate of the mobile phase flowing through the filler per volume, converted into the amount of porous material present in said volume.

Table 1 above shows the characteristic magnitudes presented by the curves in fig. 7.

Fig. 8 shows the same ratio as in fig. 7 under a broader range of operating conditions. For a given dimensionless pressure drop (30-2400, with an optimum of 200 for the van der waals curve), the different curves or bands represent the ratio of the column unit volume control yield for porous materials varying in thickness between 10.057 μm and 0.003 μm (the diameter of the conduit leading to the fluid passage or channel is equal to 10 μm).

The gain factors applicable to the ratios given in figure 8 as the reference velocity (or pressure drop) of the particle bed increases are listed in table 2 below.

This comparison is more advantageous for the packing according to the invention, since the particle bed is operated at high speed elution.

Pressure drop	Factor(s)
		200	1
300	1.3691427
		600	3.88484339
1200	16.1266904
		2400	88.3237398

TABLE 2

Advantageously, the present invention employs an elution chromatography method.

Elution chromatography may be achieved by any known technique, such as discontinuous column chromatography, radial or axial continuous loop chromatography, simulated moving bed.

Advantageously, the chromatography used may be affinity chromatography.

Advantageously, the chromatography used may be an ion exchange method.

Specifically, the porous material may be formed by a gel sol method.

This sol-gel process may also be based on aluminosilicates, such as clays, without departing from the scope of the invention.

Advantageously, the porous material of the filler according to the invention will consist of silica gel.

Advantageously, such a gel will be deposited on the walls of the duct by impregnation, in the form of a liquid precursor.

Liquid precursor refers to any liquid that forms a silica gel under the conditions of the manufacturing process, such as an aqueous alkali metal silicate solution, a silica sol, a water-soluble alkoxysilane.

The deposition may be achieved by dipping or wetting of the inner wall of the conduit to deposit a liquid film of the precursor, removing and draining excess liquid, and acidifying, hydrolysing, drying or calcining the deposit.

This can also be achieved by chemical vapour deposition, for example by allowing gaseous hydrofluoric acid to act on the pure silicon dioxide walls.

Modification may be performed by any known surface treatment, such as silanization with octadecyl trialkoxysilane, octyl trialkoxysilane, aminopropyl trialkoxysilane, and the like.

Examples of such treatments applicable to silica gels and organogels can be seen in reference [1 ].