WO2023135046A1

WO2023135046A1 - Functional microvalve

Info

Publication number: WO2023135046A1
Application number: PCT/EP2023/050147
Authority: WO
Inventors: Juliane DIEHM; Rafaela MEUTELET; Matthias Franzreb
Original assignee: Karlsruher Institut für Technologie
Priority date: 2022-01-17
Filing date: 2023-01-05
Publication date: 2023-07-20
Also published as: DE102022100987A1

Abstract

The present invention relates to slide valves comprising displaceable elements having a plurality of cavities, through which fluids can be selectively conducted, and static elements, with respect to which the displacement of the displaceable elements is carried out. The invention also relates to a kit comprising the elements and to uses.

Description

FUNCTIONAL MICROVALVE

All documents cited in the present application are fully incorporated by reference into the present disclosure (=incorporated by reference in their entirety).

The present invention relates to slide valves comprising slidable elements with a plurality of cavities through which fluids can be selectively passed, and static elements against which the slidable elements are displaced, a kit comprising the elements and uses.

State of the art

Valves can be used in many different ways and are relevant in many different areas.

There are solutions that use integration of chromatography columns into valves; sometimes called "lab-on-a-valve". In the field of lab-on-a-valve there are applications in which a chromatography column has been integrated directly into a central distribution valve. For example, the selected channel that is connected to a flow source , e.g. syringe pump, is connected and another channel is sealed with a frit. A bead reservoir is connected to another channel. The column is packed by first filling the permanently connected channel via the bead reservoir, then the valve on the second fritted channel is switched and the beads are transferred from one channel to the other.If a column is to be renewed, the beads can be removed from the column by increasing the flow rate and thus the pressure.This causes the beads to deform and can pass through the gap between the channel wall and the frit. Alternatively, an "in-valve column" can also be used for sample preparation, which is like a capillary filled with chromatography resin that is connected to a 6-port valve.

There are also solutions involving the integration of columns in microfluidic systems. There are already applications in the field of microfluidics in which chromatography columns are integrated directly into a microfluidic chip. However, these chips usually only contain passive elements. The lab-on-a-valve systems presented in the previous section are an exception integrated columns. There are also approaches in which stationary chromatography phases or extraction materials are integrated directly into the column housing, especially in the field of 3D printing, in which the housing and stationary phase are produced in one print. So far, however, these columns have not been further integrated into valves etc., but instead coupled with other components via connectors and capillaries.

There are also solutions within the framework of micro-simulated moving bed chromatography. Simulated Moving Bed Chromatography (SMB) is an established method for the continuous preparative separation of mixtures of substances.

Furthermore, multidimensional chromatography is known. Multidimensional chromatography is a technique that combines different types of chromatography to separate a single sample. There are already hardware variants that contain valves. On the one hand, there is the possibility of linking the columns via an external connection of several valves, thereby enabling sample transfer. The sample is guided through the various columns by switching the valves, whereby flow rates and buffer conditions can be adjusted for the individual columns. Another option is to integrate the columns into a microfluidic chip. The sample can be routed via integrated 2-way valves or via an external valve circuit, which regulates the flow rates in the various channels of the chip. In this case, the sample is transferred from one column to the other by a so-called "transfer cross".

In all processes, the separation performance and peak capacity can theoretically be increased by using orthogonal separation methods compared to a single column. In order to successfully put this into practice, the coupling of the individual columns and the sample transfer from one column to the other is of particularly high relevance, since peak-broadening effects, which can destroy the separation performance of the previous column, must be minimized. US Pat. Nos. 6,979,402 B1; US Pat. No. 6,997,213 Bl; WO 2017/155664 A1; U.S. 6,779,557 B2; US 9,726,301 B2; U.S. 8,807,164 B2;

US 2012/0116049 A1 or also US 6,136,198.

None of the prior art systems satisfactorily allow multiple

To flexibly connect columns within a microfluidic system: In the field of multidimensional chromatography, it is common to integrate several columns into one microfluidic chip, but the connections between the columns are rigid and consequently cannot be changed. At the same time, additional external valves are usually required for operation.

With lab-on-a-valve systems, columns have already been integrated directly into a valve channel, which means that the feed flow to the column can be changed directly. However, since that system is based on the use of a central distribution valve, it is not possible to connect several columns in the system. To do this, the fluid flow would always first have to be fed out of the valve and back into the valve.

There is still a need for improvement here with regard to the systems of the prior art.

The object of the present invention was to provide options for improving existing systems, in particular the systems should have increased flexibility and ease of maintenance.

Further tasks arise for the person skilled in the art from the following description.

These and other objects are solved within the scope of the present invention by the subject matter of the independent claims.

Preferred configurations emerge from the dependent claims and the following description.

In the context of the present invention, the term “comprise” also includes “consisting of”; This means that a corresponding list can contain (= include) other elements in addition to the elements explicitly mentioned, or it can contain exactly these elements (= consist of) (whereby insignificant elements such as screws, markings, etc. are not taken into account).

In the case of relative information such as up, down, left, right or the like, an observer standing upright on the ground in front of the object under discussion is assumed as the reference system within the scope of the present invention. In the context of the present invention, the expression “and/or” means that both elements mentioned in the context are included individually as well as the combination of the elements mentioned in the context.

In the context of the present invention, the term "fastening elements" preferably, but not exclusively, means screws (with nuts), in particular self-locking nuts.

In preferred embodiments, the present invention is based in particular, but not exclusively, on a simplified connection of a plurality of chromatography columns and a reduction in the dead volume between the columns. For this purpose, within the scope of the present invention, the chromatography columns are integrated directly into the valve, so that the column bodies are part of the valve. This eliminates the connection capillaries and connectors between the valve and columns, which reduces dead volume and simplifies the wiring.

In contrast to the previous state of the art, within the scope of the present invention several chromatography columns can be integrated into all components of a rotary valve system and the inflow and outflow of fluids between the columns can be implemented as desired.

The present invention therefore relates to slide valves, in particular SMB valves, comprising or consisting of, stacked one above the other, at least two displaceable elements (rotor) and at least one static element (stator), and optionally further elements. For the sake of simplicity, within the scope of the present invention, the slide valves are often referred to simply as valves in the following.

The term rotor for the displaceable element is used in particular when the displacement takes place about an axis of rotation. In the context of the present invention, however, the displacement does not have to be rotational, although this is preferred.

The individual elements do not necessarily have to be arranged one above the other in the same order as the component designations I), Ila) ... may suggest, but can take on different sequences (as long as this makes sense from a technical point of view). See below for examples of sequences. The first essential element I) of the slide valves according to the invention are at least two, or at least three, in particular two or three, displaceable, preferably rotatable, particularly preferably round, elements (rotor) each comprising a) at least one cavity with at least two connections per cavity, the Ports permit fluid flow through the at least one cavity, or b) at least one cavity without dedicated ports configured to receive inserts with at least two ports per insert, the ports permit fluid flow through the inserts, or c) at least one Cavity with at least two ports per cavity and at least one cavity without its own ports configured to receive inserts, preferably inserts with at least two ports per insert, wherein the ports allow fluids to flow through the inserts.

The cavities mentioned represent cavities with a defined volume, which in principle can have any shape. However, it is often useful and therefore preferred if the individual cavities in the valve according to the invention have the same dimensions in order to enable the greatest possible interchangeability of cavity inserts and better comparability of flows or test results. Cavity inserts are housings, in particular for accommodating (chromatography) columns, which are inserted into the corresponding cavities without their own connections to the displaceable elements I).

In preferred variants of the present invention, a displaceable element has in its center approximately square cavities without their own connections, which are therefore essentially indentations (approximately square means a deviation from the ideal square shape of at most 10%, preferably at most 5%, and in particular at most 2%.). These cavities can directly adjoin one another, so that they do not have any directly visible borders to one another. For example, this can be implemented as a recess with approximately square corner edges. Such a recess as an example for the cavities mentioned without their own connections is therefore the place at which, with the aid of inserts (housings), in particular (chromatography) columns, are inserted into the displaceable element. It can be in the context of present invention individual or all, preferably all, cavities are used. In addition, several (then thinner) inserts (housings), in particular (chromatography) columns, can be arranged per cavity. Furthermore, other symmetries or shapes and also other numbers of cavities without their own connections can be realized; preferred numbers of cavities per displaceable element are three, four, five, six, seven and eight, in particular four.

Cavity inserts that can be used according to the invention are preferably adapted to the shape of the cavities and, in some preferred variants, can comprise or consist of single-column inserts and single-column housings. The single-column inserts are inserted into the single-column housings in order to then form the assembled cavity inserts (in this example, single columns). By adapting the shape to the cavities, exact positioning is simplified. The assembled cavity inserts have connections which, in the simplest case, can be bores through which a fluid can flow.

However, other cavity inserts can also be used, for example those that are designed as a (chromatography) column or those that merely represent an (empty) housing, depending on the exact purpose being pursued.

Although only one cavity can be present, this one cavity is then particularly preferably subdivided or at least can be subdivided, for example by wall elements or the insertion of functional inserts, such as chromatography columns or the like.

In connection with the term chromatography column used in the present invention, sometimes abbreviated simply as "column", it should be pointed out that these columns are not in principle limited to a specific size, but only by the fact that they have to fit into the cavities to be used (Possibly with residual volume in the cavity), either in itself or using housings in which the columns are used.Such columns used in housing are particularly easy to handle, especially if the housing is adapted to the dimensions of the cavities, and can on Stock can be produced (also with different fillings/stationary phases or similar), so that columns can be easily exchanged (during operation).

If only one cavity is present, this therefore preferably represents a polyfunctional unit within the scope of the present invention, in particular by use several columns, each preferably in housings, so that functionally ultimately a plurality of cavities results.

It is therefore particularly preferred within the scope of the present invention if several chromatography columns of the same or different type (especially the same or different stationary phases) are arranged in the valve in at least one, preferably in all, displaceable element(s).

Within the scope of the present invention, the connections mentioned are sometimes also referred to as openings or inlets or outlets or connectors, which varies depending on the context. Connectors are in particular those openings that already have a device/equipment by means of which a connection to other parts, such as hoses, is made possible. However, this does not mean that the inlets/outlets or openings cannot (will) not be provided with appropriate devices/equipment.

The second essential element 11a) of the valves according to the present invention is at least one static, preferably round, element (stator) comprising at least one connection for fluid supply and at least one connection for fluid discharge.

This second element can additionally have one or more connections for fluid transmission.

In another variant of the present invention, the second essential element Ila) of the valves according to the present invention is at least one static, preferably round, element (stator) comprising at least one connection for fluid supply, at least one connection for fluid discharge, and one or more cavities for fluid transmission , preferably designed as (chromatography) column (s).

In this other variant, too, the second element can additionally have one or more connections for fluid transmission.

In the context of the present invention, the static element is arranged one above the other with sliding elements, so that the static element covers cavities and connections of the sliding elements, with connections of static and displaceable elements are brought into congruence by moving and thus a fluid flow through the static element into at least one, but in variants also several, cavity(ies) of the displaceable elements, through this cavity(ies) and again through another connection or other connections of the static element.

For this purpose, the static and displaceable elements are pressed together in such a way, in particular by fastening means, that the fluid(s) cannot flow between the contact surfaces of the elements, but only along the respective connections. For this purpose it is preferred if the respective connections (openings, inlets or outlets, connectors) of the elements are provided with seals or sealing elements. Examples of preferred seals are, for example, O-rings.

In variants of the present invention, the connections of the static element, which are used for the supply and discharge of fluids into the valve, are arranged on the side opposite a displaceable element. Additionally or alternatively, (the) connections of the static element, which are used to supply or discharge fluids into the valve, can be arranged on the peripheral sides of the static element.

The valve according to the invention can optionally include a preferably round, static cover plate III), which is arranged on the side of the uppermost of the at least two displaceable elements (rotors) opposite the stator. In this preferred variant, the uppermost displaceable element (the rotor) is clamped between the static element and/or at least one further displaceable element and the static cover plate. The cover plate is usually just a kind of "clamping aid" without its own connections or feed-throughs.

In variants, however, the cover plate can be replaced by a second static element. In these variants, a displaceable element can be used in special configurations, which has connections on the top and bottom, so that fluid streams can be routed through the valve and do not necessarily exit on the same side as they are introduced.

These cover plates can also have connections or, for example, spacer elements (facing outwards, ie away from the valve) or feet. In a further alternative of the present invention, the second essential element IIb) is a static, preferably round, element (stator) which has no connections for fluid (further) conduction. In this case, the connections of the first element I) are arranged in such a way that they are accessible from the outside, ie from the sides of the stack of valve elements used. In addition, in this case the element IIb) largely corresponds to a cover plate or base plate, which, however, can still optionally be present in each case.

For clarification, it should be pointed out once again that when the valves according to the invention are referred to as upper and lower sides (or similar), this refers to a structure comprising at least one sliding and static element, which are arranged one above the other, with the sliding element is considered "below" and the static element is considered "above"; the arrangements of the other elements, in particular of the second displaceable element, or plates then follow from this.

Furthermore, the valve according to the invention can optionally also have a, preferably round, static base plate IV) on the II), in particular Ila) or optionally III) opposite side of the stack of at least one I), II), in particular Ila) and optionally III) is arranged include.

According to the invention, these base plates can have the same shape and structure as the cover plates, but they can also have connections or, for example (outwards, i.e. directed away from the valve) spacers or feet. The bottom and top plates thus differ (essentially) only in that they are arranged on opposite sides of the valve.

In preferred variants, the valves according to the invention can also have devices or preparations V) for automatically driving the displacement of at least one, several or all of the elements I).

In some preferred variants, these are corresponding configurations of the outer peripheral surfaces of the respective rotatable element.

In preferred embodiments of the present invention, the facilities or devices V) are selected from the group consisting of: V) a) surfaces of the outer peripheral surface of the respective element I that are roughened or provided with a coating that increases grip (tackifyer);

V)b) a serrated structure of the outer peripheral surface of the respective

Elements I) (teeth),

V)c) Lever or shaft attachment point(s), lever, handles on the outer

peripheral surface of the respective element I);

V)d) a toothed structure of the inner peripheral surface of a (central) recess of the respective element I) (internal toothing),

V)e) at least one gear wheel in the (central) recess of the respective element I), a depression in the underside of the respective element I), or on the underside of the respective element I), this element then being in particular the lowest of the valve ;

V)f) Device for attaching driven components, preferably indentations into which such components can be inserted and/or provisions for the engagement of fastening means, preferably holes, in particular screw holes.

In variants V)a), V)b) and V)c), the drive is not part of the valve according to the invention per se, but a separate component that is made available separately. This can be, for example, a conventional belt drive, gear drives, for example gears mounted directly on a motor, or sliding motors or the like.

In the case of variant V)c), it must be taken into account that the displaceable element can then usually only be displaced by a certain amount; a complete displacement in the sense of a rotation can be implemented, but is often too complex; this variant is accordingly less preferred.

In variants V)d), V)e) and V)f), motors can be permanently installed on or in the valve.

In the event that a displaceable element (rotor) I) (the top one) in a valve according to the invention should or must be driven from above the valve, for example via device or device V)d), it is preferred that the Static element II), in particular Ila) (in its middle), and also if present base plate IV), and the further (s) displaceable (s) element (s) (rotor (s)) each have a recess by which the drive can be brought into engagement with the facilities or devices V)d).

The several displaceable elements (rotors) in a valve according to the invention can have the same or different devices or devices V). Of course, it must be taken into account that the respective devices or devices V) must be accessible, i.e. devices or devices V)d)/V)e)/V)f) that require a drive from above or below the valve should (must) not be inside.

Within the scope of the present invention, all displaceable elements can be shifted (rotated) manually, even if they have a facility or device V). It is therefore not absolutely necessary to provide an additional drive. Variant V)c) in particular is well suited for manual shifting.

In further preferred variants, the valves according to the invention can be designed without such “drive pre-installations or devices”, so that the displacement is then carried out purely manually. This can be advantageous, for example, if there is no or too little space for automatic adjustment devices is.

In preferred embodiments of the present invention, the relative movement, i.e. the displacement, in particular rotation, of I) (only one, several or all) in relation to the other elements takes place either manually or with the aid of a drive.

Due to the possibility that the displacement can take place very precisely when using a drive, in particular with electronic control, it is particularly preferred in some embodiments of the present invention to undertake the displacement (rotation) by a drive, in particular an electronically controlled drive. As said/indicated elsewhere in this description, the connections of the at least one static element are arranged in the valves according to the invention in such a way that they can be brought into alignment with all connections or selected connections of at least one displaceable element in order to selectively allow the transfer of Fluids between the elements to allow or prevent.

Within the scope of the present invention, displaceable or rotatable refers to the respective assembled valve, i.e. the respective displaceable element is displaceable or rotatable, independently of other displaceable elements, relative to the static element or elements, as well as other displaceable elements.

In this case, rotatable preferably refers to an axis of rotation C _m standing perpendicularly in the middle of the respective rotatable element, where m is the number of cavities in the element. This means that preferably the relative position of the whole element with respect to the valve is not changed, in particular the element is not rotated out of the valve (if the valve itself is not rotationally symmetrical (e.g. oval or rectangular), the composite valve has possibly no such axis of rotation, but a different symmetry group).

However, this does not necessarily mean that the rotatable element must have a round or m-cornered external (circumferential) shape, since the rotation is related to the cavities. Although a uniform outer circumference of the rotatable element is preferred because this is simpler in terms of manufacturing technology and can be advantageous for a rotational drive via belts or gear wheels, for example, the outer shape can also be irregular (for example also trapezoidal). It is preferred in variants if, when the rotatable element rotates, no part of this element protrudes beyond the edges of the (largest built-in) static element or cover plate/base plate when the valve is viewed from above. In this sense, it is also possible according to the invention, for example, to combine angular, displaceable, preferably rotatable, elements with round static elements or top/bottom plates or, conversely, round, displaceable, preferably rotatable, elements with square static elements or top/bottom plates (as well as independently of which round and/or angular shaped further sliding elements). As indicated, several displaceable, in particular rotatable, elements are used in the present invention for each valve. In further variants of the present invention, these can each or partially be separated from one another by static elements.

In this way, a wide variety of sequences of (displaceable and static) elements can be implemented, resulting in a flexible valve (system) that can be adapted to a wide variety of requirements.

Some examples of sequences included according to the invention, but by no means even approximately all possible ones, are (R=displaceable, in particular rotatable, element, S=static element; D=cover plate; B=base plate; in each case from bottom to top):

1RRRS; DRRRS; DRRRSB (three times R, once S)

2RSRS; DRSRS; DRSRSB (alternating twice R and twice S)

3RSRSRS; DRSRSRS; DRSRSRSB (alternating three times R and three times S)

4RSRRRS; DRSRRRS; DRSRRRSB

5 RRRSRRRS; DRRRSRRRS; DRRRSRRRSB (1 doubled)

6RRS; DRRS; DRRSB (twice R, once S)

7RRRRS; DRRRRS; DRRRRSB (four times R, once S)

8 RSSRS

9 RSSD; BRSSD

According to the invention, these stacking sequences can of course also be further combined with one another, in which case preferably no cover plates or base plates are arranged on the combination surfaces.

As already mentioned, the valves according to the invention can therefore consist of only at least two displaceable elements and a static element, or several of these, in addition to parts such as seals, drive or the like, and optionally additionally comprise cover and/or base plates.

In preferred variants of the present invention, the components I), II), in particular IIa), III), IV) have a common axis of rotation which lies vertically in the center of the stack of the elements present, with the elements preferably all being round or approximately round , In particular round, are designed. In this context, approximately round means a deviation from the ideally round shape of at most 20%, preferably at most 10%, more preferably at most 5% and in particular at most 2%.

As already described, it is preferred in some variants according to the invention that, in addition to I), Ila) and III) or IV), or I), III) and IV) are also present.

In some variants according to the invention, it is preferred that Ila) is firmly connected to III) and/or IV) via appropriate fastening means. As already explained, this also applies if several displaceable and/or static elements are arranged.

As already explained, it is essential for these fixed connections that the intervening displaceable, preferably rotatable elements I) can still be displaced, in particular can be rotated about the axis of rotation, but at the same time there is fluid-tightness between the elements and, if applicable, top/bottom plates, such that no Fluids flow between the contact surfaces, but only between connections provided in front of them.

In preferred embodiments of the present invention, the displaceable (rotatable) elements I) have at least two cavities; in some variants, this embodiment is preferred to that with a cavity (even if this is divided).

It is particularly preferred if at least two of these at least two cavities are filled with the same or different materials or inserts containing such materials, with the materials being able to interact with the substances running in the fluid (dissolved and/or suspended in the fluid) (i.e. for Examples are in particular stationary phases in chromatography, the fluid would then be the eluent and the substances running in the fluid (dissolved and/or suspended in the fluid) are those that are to be (off) separated by chromatography).

If two or more cavities are present in a displaceable (rotatable) element I), in the case of a round or uniformly polygonal element I) in particularly preferred configurations they have the same dimensions and are uniformly distributed around the center, so that the round or uniformly polygonal Element has an axis of rotation C _n perpendicular to its center, where n is the number of cavities. In preferred embodiments of the present invention, different flow paths are generated by the relative movement of the individual elements in relation to one another (=displacement). In further preferred embodiments of the present invention, at least one flow path through at least two cavities is changed by the relative movement of the individual valve elements with one another.

In preferred embodiments of the present invention, there is also the possibility of supplying and/or removing fluid streams between the cavities.

In preferred embodiments of the present invention, the cavities are configured such that materials, preferably materials for performing a chromatographic separation, in particular for stationary phases for chromatography, can be introduced or inserts, preferably comprising chromatography columns, can be used.

In addition, in further preferred embodiments of the present invention, optional frits/filters/nets/grids can be used to retain the materials, if necessary, in the cavities and/or at their inlets and/or outlets.

Furthermore, in preferred embodiments of the present invention, the cavities have a cylindrical shape or a geometry that deviates from the cylindrical shape. This means that the cavities can be adapted to the planned application within the scope of the present invention. For example, it is possible to incorporate the cavities directly during production and to determine their shape accordingly, which works particularly well when production is carried out using additive manufacturing techniques, in particular 3D printing. For example, the cavities can be designed around, in order to then either only be filled with sample fluid or, in other preferred embodiments, used and designed as (chromatography) columns, for which they are then in particular filled with a stationary phase, for example in the form of small balls (beads/beadlets) can be filled. In other embodiments, the cavities, as also described elsewhere in this description, can be designed and shaped in such a way that separately produced (chromatography) columns, if necessary with the aid of appropriately adapted and shaped housings.

Accordingly, in various configurations according to the invention, it is preferred that individual or all elements I), II), in particular Ila), III), IV), if appropriate V), are produced by means of additive manufacturing processes, in particular 3D printing.

In the context of the present invention, particularly suitable 3D printing methods are those that work with resin-based starting material, preferably digital light processing (DLP), stereolithography (SL) or poly/multijetting. With these methods, liquid-tight components can be obtained, preferably with relatively (for 3D printing techniques) smooth surfaces. The choice of material depends to a large extent on the respective application; acrylate-based plastics are preferred; these can be heavily fluorinated, e.g. to improve the sliding properties on the sealing surface and for increased chemical resistance.

In preferred embodiments of the present invention, the cavities have a volume of 10 nanoliters to 10 milliliters, preferably 1 microliter to 1000 microliters. This volume is the volume that can be used by the (chromatography) column, i.e. the (effective) column volume.

In the context of the present invention, in particularly preferred configurations, one or more cavities can be filled with structures of defined geometry, in particular produced by 3D printing, with different cavities preferably being filled with different materials for interaction with dissolved substances, or different cavities with the same materials for Interaction are filled with dissolved substances.

In variants of the present invention, the cavities are preferably filled with materials for carrying out a chromatographic separation, it being possible for the filling to take place inside or outside the valve.

Furthermore, in preferred variants of the present invention, frits/filters/nets/grids, preferably frits, are introduced to hold back the materials, if necessary, either in the cavity or between the individual valve elements. Another subject of the present invention is also a kit for the production of slide valves, in particular for SMB processes, comprising i) various slide elements, preferably round, (rotors) comprising a) at least one, preferably at least two, cavity (s) with at least two ports per cavity, the ports allowing the flow of fluids through the at least one cavity, or b) at least one cavity without its own ports configured to receive at least two inserts with at least two ports per insert, the ports allowing the flow of fluids through which allow inserts, or c) at least one cavity with at least two connections per cavity and at least one cavity without its own connections configured to accommodate inserts, ii) static elements, preferably round, (stators) comprising at least one connection for fluid supply, and at least one Port for fluid removal, optional one or more cavities for fluid transfer, optional one or more ports for fluid transfer, iii) static top plates, preferably round, iv) static bottom plates, preferably round, vi) inserts configured to fit into the cavities of i) b) to be used, preferably designed as chromatographic columns, wherein the individual elements of the kit are configured to be able to be connected to one another to form a slide valve, the connections of the static elements ii) are arranged in such a way that they can be connected to the connections or selected connections of the movable elements i) can be brought into congruence.

The individual elements correspond to the elements of the valve according to the invention described above as follows: i)=I); ii) = Ila), iii) = III), iv) = IV).

The kit according to the invention is based in particular on the fact that different slide elements and static elements are each of the same size or at least have coordinated dimensions, in particular with regard to Fastening elements, preferably screws (with nuts), in particular self-locking nuts, and axis of rotation C _m ., are included.

For this purpose, the kit includes, on the one hand, different sets of elements i) in different sizes and with different configurations, in particular different numbers and dimensions of cavities.

Accordingly, the kit includes, on the one hand, different sets of elements ii) in different sizes and with different configurations, in particular connections (openings, inlets or outlets, connectors).

Likewise, the kit includes different sets of top plates and base plates in different sizes and configurations. In variants, the relative number of these can be lower because, for example, several provisions for fastening means can be arranged on a larger cover plate

In preferred configurations, the kits according to the invention can also include motors v), with which the rotor or rotors can be moved.

In preferred configurations, the kits according to the invention can also include housings vii), into which the valves can be inserted.

In preferred configurations, the kits according to the invention can also include holders viii), which can hold the valves or individual parts.

It should be pointed out that the kits according to the invention are also suitable for the variant of the present invention which uses the static element IIb) instead of the static element IIa). In this case, starting from the kit, it is possible and sufficient to select and install one (more) top or bottom plate.

Furthermore, the subject of the present invention is the use of the slide valves according to the invention or of slide valves produced by means of the kits according to the invention in the field of multi-column chromatography or in the coupling of chromatography methods with other processes.

The slide valves according to the invention or the slide valves produced using the kits according to the invention can also be used for (bio)chemical analyses, in particular those with small sample volumes, preferably for the analysis of environmental samples the food industry, in the (bio)pharmaceutical industry, in the chemical industry, in medical diagnostics.

In variants of the present invention, it may be preferable to insert the individual (chromatography) columns individually into the cavities of the displaceable element, in particular columns in housings into the cavities without their own connections, in order to be able to manufacture the columns individually and also to be able to replace them if necessary.

In preferred embodiments of the present invention, the columns are accordingly packed individually and only then integrated into the valve. This procedure makes it possible, among other things, to exchange the columns individually and to use them, for example, for further experiments / comparative experiments.

This variability and ease of maintenance is one of the great advantages of the present invention.

Within the scope of the present invention, the cavities mentioned can be used as such if, for example, the cavities are/are filled with materials that can interact with the substances flowing into the fluid (substances dissolved and/or suspended in the fluid). In such a case, the interacting materials can be present in the cavities as a slurry or in powder form. Alternatively, however, the cavities can also be used indirectly by using cavity inserts, which can then be designed, for example, as empty inserts or as (chromatography) columns.

For the sake of simplicity, the cavities are sometimes not referred to as such in the descriptions of the figures, but rather as column(s), which at the same time describes the respectively selected function of the relevant cavity.

In particularly preferred configurations of the present invention, the cavities with at least two connections per cavity of the displaceable elements I) are designed as (chromatography) columns and the cavities without their own connections of the displaceable elements I) are designed as cavities with inserted (chromatography) columns or cavity inserts ; in the latter case, the (chromatography) columns or cavity inserts used provide the necessary connections. The present invention thus relates, in other words, to rotary valves consisting of a plurality of elements which are connected to one another so that they can be moved (rotated) relative to one another, the elements having fluidic channels and, in some cases, cavities. At least two cavities are preferably filled with materials that can interact with the substances flowing into the fluid (substances dissolved and/or suspended in the fluid). Different flow paths can be generated by the relative movement of the individual valve elements with one another.

The flow path through at least two cavities is changed by the relative movement of the individual valve elements with one another, and in preferred variants there is the possibility of supplying and/or removing fluid flows between the cavities.

A preferred variant of the present invention is a slide valve, in particular an SMB valve, comprising, arranged in a stack one above the other, I) at least two displaceable elements (rotors), each comprising a) at least one cavity or at least two cavities, preferably at least two cavities, for example two Cavities, with at least two connections per cavity, the connections allowing the flow of fluids through the at least one cavity, or b) at least one cavity or at least two cavities, preferably at least two cavities, for example two cavities, configured without their own connections for receiving at least two inserts with at least two connections per insert, the connections allowing fluids to flow through the inserts, or c) at least one cavity or at least two cavities, preferably at least two cavities, for example two cavities, with at least two connections per cavity and at least one cavity without its own connections configured to accommodate inserts,

Ila) at least one static element comprising at least one connection for fluid supply and at least one connection for fluid discharge, optionally one or more cavities for fluid transmission, optionally one or more connections for fluid transmission, III) optionally a static cover plate, which is arranged on the side opposite the static element (stator) of the displaceable element (rotor) furthest from the static element (stator),

IV) optionally a static base plate which is arranged on the Ila) or optionally III) opposite side of the stack of I), Ila) and optionally III),

V) optional means or preparations for automatically driving the displacement of the element I), wherein the terminals of the at least one static element are arranged in such a way that they can be brought into register with all terminals or selected terminals of at least one displaceable element in order to selectively Transfer of fluids between the elements to enable or prevent.

A particularly preferred variant of the present invention is a slide valve, in particular an SMB valve, comprising, stacked one above the other,

I) two displaceable elements or three displaceable elements each comprising a) at least two cavities with at least two connections per cavity, the connections allowing the flow of fluids through the at least one cavity, or b) at least one cavity without its own connections configured to accommodate at least two inserts with at least two ports per insert, the ports allowing the flow of fluids through the inserts, or c) at least one cavity with at least two ports per cavity and at least one cavity without dedicated ports configured to receive inserts,

Ila) at least one static element comprising at least one connection for fluid supply and at least one connection for fluid discharge, optionally one or more cavities for fluid transmission, optionally one or more connections for fluid transmission,

III) optionally a static cover plate, which is arranged on the side opposite the static element (stator) of the displaceable element (rotor) furthest from the static element (stator), IV) optionally a static base plate which is arranged on the Ila) or optionally III) opposite side of the stack of I), Ila) and optionally III),

V) optional means or preparations for automatically driving the displacement of the element I), wherein the terminals of the at least one static element are arranged in such a way that they can be brought into register with all terminals or selected terminals of at least one displaceable element in order to selectively Transfer of fluids between the elements to enable or prevent, and wherein the two displaceable elements or the three displaceable elements are arranged directly one on top of the other.

In principle, the slide valves according to the invention can be used wherever (bio)chemical analyzes are carried out with small sample volumes. In preferred variants, they are used for the analysis of environmental samples (drinking water, pollution, etc.) in the food industry, in the (bio) Pharmaceutical industry, in the chemical industry, used in medical diagnostics.

In further variants, the slide valves according to the invention are used in the field of multi-column chromatography or when chromatographic methods are coupled with other processes.

The slide valves according to the invention are therefore advantageous for all manufacturers and users of (process) analytics in the areas mentioned above.

Last but not least, the present invention also relates to methods for carrying out chromatographic investigations, in particular SMB, using or using the slide valves according to the invention or valves produced from kits according to the invention.

Of course, these methods also have the advantages described, which result from the valves and/or kits according to the invention. All or some of the various described embodiments of the valves of the present invention may be used in these methods. The direct integration of columns and valve into a single assembly within the scope of the present invention results in the following advantages, among others:

Complex circuits can be implemented more easily since connections between the columns can be changed without external wiring. More compact design: Especially in applications where many different flow paths are required, the number and size of fluid connectors can be the limiting factor in terms of the system footprint. The integration of several components into one component eliminates the need for these connectors.

The dead volume is reduced: As a logical consequence of the first two points, there is inevitably a lower dead volume in the overall system. This is advantageous for many analytical procedures as it minimizes dispersion effects.

Various multi-column chromatography methods are represented, for example, by simulated moving bed (SMB) chromatography or multidimensional chromatography. While SMB focuses on continuously solving a specific separation task, multidimensional chromatography focuses on combining different separation mechanisms. In addition, a method can be used as multi-column chromatography MCC (multi-column chromatography), in which a sample is repeatedly passed through columns of the same construction (usually through two in alternation) in order to achieve the highest possible separation efficiency and limitations, which with a single long column, such as excessive pressure losses across the column, can occur. For all of these methods, the present invention offers increased flexibility and thus a larger area of application on a microfluidic scale.

If, in the description of the slide valves or kits according to the invention, parts or the entirety are marked as "consisting of", it is to be understood that this refers to the essential components mentioned. Self-evident or inherent parts such as lines, valves, screws, housings, measuring devices , storage tanks for raw materials/products etc. which would not substantially change the slide valves or kits are not excluded. A particularly preferred embodiment of the slide valves according to the invention is the variant shown in FIG.

Another particularly preferred embodiment of the slide valve according to the invention is the variant shown in FIG. 10 with two displaceable elements.

Another particularly preferred embodiment of the slide valve according to the invention is the variant shown in FIG. 11 with three displaceable elements.

Another variant embodiment of the slide valve according to the invention that is preferred according to the invention is the variant shown in FIG.

A particular advantage of the present invention is that the dead volumes can be significantly reduced compared to the systems of the prior art. In the valve systems of the prior art, on the one hand, the valves themselves have a certain dead volume, and on the other hand, in the systems of the prior art, the volume of the connecting capillaries is added.

A prior art system thus has a certain dead volume, to which is added the volume of the connecting capillaries, adding up to a total dead volume; this corresponds to the volume of all connecting channels between the columns (e.g. four) used for the SMB, regardless of whether these are in the form of channels in the valve or as connecting capillaries. The more compact design through integration of the columns in the valve not only eliminates the dead volume of the capillaries, but the dead volume of the valve system can also be reduced and is then only a fraction of the dead volume of the systems of the prior art.

According to the invention, for example, reductions in the dead volume of more than 80% are possible.

In the context of the present invention, not every displaceable element (every rotor) has to have cavities; it is also possible for one or more rotors to have only fluidic connections, for example; but preferably at least one displaceable element has cavities, preferably at least two displaceable elements have cavities. Furthermore, within the scope of the present invention, the various elements, in particular the displaceable elements, can have the same axis of rotation, but do not have to.

Furthermore, within the scope of the present invention, the displaceable elements can be moved independently of one another in the same direction, or several or all can be moved in the same direction (with the same or different amounts).

Within the scope of the present invention, either the fluidic connection at one pair of seals or at several seals can change at the same time during a movement. The connection can be changed at the seal pairs during a process at different times per seal pair and the distance between the changes does not have to be uniform.

It should also be noted again that both displaceable elements (rotors) and stators can be made up of several disks (stacks). These stacks can (but don't have to) move as one piece and in that case can be considered as one element. Furthermore, it should be pointed out again that the complete system can also be integrated into other fluidic systems (for example "SMB on a chip").

In addition, it should be mentioned again that the cavities of the valves according to the invention are not only filled with column inserts or direct absorber material, but also, for example, with capillaries (especially when manufacturing the valve with 3D printing techniques, in order to reduce contact with 3D printing material, or channel diameter to reduce) can be filled.

Because the valves according to the invention always have at least two displaceable elements (rotors) that can be moved relative to one another, there are also the following advantages over the valves of the prior art, for example:

Regarding SMB, not all ports need to be switched at once, it can also be switched asynchronously. This allows special cases of SMB processes, such as the Varicol process, to be made possible with just one rotary valve. For this purpose, previous systems used either several decentralized valves (e.g. US Pat. No. 6,136,198) or at least two rotary valves (e.g. WO 2017/155664 A1). As a result, the dead volume and the system costs can be further reduced by the present invention. In addition, it becomes possible to integrate several SMB systems into one plant in order to carry out complex and multi-component separations.

This also has many advantages for non-SMB applications, since, for example, fractionation processes can be carried out much more flexibly. In addition, versatile interconnections can be implemented, e.g. to rinse individual columns, etc.

In contrast to known systems with several rotors (e.g. US 6,779,557 B2 or US 9,726,301 B2), where the advantage is that they can realize versatile connections to material flows outside the valve, the valves of the present invention make it possible that different functions are taken over in the valve itself by the different links, which is not possible with the valves of the prior art, which moreover do not relate to chromatography.

Miniaturized SMB systems are known from US Pat. No. 8,807,164 B2, with which processes such as the Varicol process can also be carried out—however, pneumatically controlled membrane valves are used instead of slide valves. As a result, a simple SMB process does not require a valve as in the context of the present invention, but at least 8 valves, in the case described even 72. This makes the control much more complex and expensive, and the susceptibility to errors is significantly higher simply because of the high number of valves the dead volume of the system (even if the structure is kept comparatively compact) is still significantly larger than in the systems of the present invention.

The individual parts of the device/systems/valves according to the invention are functionally connected to one another in a manner known and customary in the art.

The various configurations of the present invention, for example—but not exclusively—those of the various dependent claims or individual configurations described in the figures can be combined with one another in any way, provided such combinations do not contradict one another. The embodiments of the present invention explained in more detail below with reference to the figures represent various preferred embodiments. Many of the features or embodiments shown below in individual figures can be combined with features and embodiments shown in other figures or the rest of the description, in particular where the Features are described accordingly. For example, different rotor configurations shown in the figures can be combined in a valve according to the invention. Moreover, the figures are not to be interpreted as limiting and are not true to scale. Furthermore, the figures do not contain all the features that have the usual devices/plants, but are reduced to the features that are essential for the present invention and its understanding, for example screws, brackets, etc. are not shown or not shown in detail.

The same reference symbols/numbers mean the same or equivalent device parts; for better understanding and clarity, some reference numbers are provided with letters which indicate the location shown (e.g. R for rotor, this feature is then found in the rotor = a displaceable element of the present invention) - however, the numbered elements in each case are the same or equivalent, for example holes Dl, Ria, Sl, S1-0V.

It should be noted that although the figures show preferred round embodiments of the valves according to the invention, the invention is in no way limited to these round examples. It is also covered by the present invention that the valves have a polygonal, for example rectangular or for example hexagonal, or for example octagonal or n-cornered basic shape. Furthermore, elliptical basic shapes are also suitable.

In the following, exemplary embodiments according to the invention for individual components of a sliding valve according to the invention, in particular for SMB, with integrated columns are shown in FIGS. The special feature of this system according to the invention is that the columns are first manufactured individually and then inserted into the rotor (Figure lb, lc). This allows the columns to be exchanged individually and it is possible to use the columns with the appropriate adapter (Figure 5) as a single column (e.g. for characterization experiments) or columns with the same characteristics can be used for an SMB. These factors facilitate the design of the SMB and increase the predictability of the experimental results.

FIG. 1a shows a stator S of a valve V according to the invention in an oblique view (above) and in an oblique view from below (lower part of the figure). You can see the bores S1 for pressing the rotor R and stator S by means of suitable fastening elements, preferably screws (with nuts), in particular self-locking nuts. The fluid connectors for external material flows S2 are also shown. For example, hoses can be connected to these connectors, through which fluids can then be conducted to the respective cavities 13 of the valve V, which are usually occupied by chromatography columns 13 . On the sides (referenced only on the right-hand side) of the stator S, means S3 for aligning the rotor R and the stator S are shown. In the simplest case, this can be a bore. With the help of this device and the corresponding counterpart (R3) on the rotor R, the two parts can be reliably aligned in relation to each other. Numeral S4 points to an O-ring groove which is arranged on the rotor-side ends of the fluid connectors and which serves to seal the contact points of rotor R and stator S. In this way, when moving (rotating) the rotor R, fluid is prevented from escaping unintentionally. Accordingly, these O-ring grooves S4 are essentially depressions in the stator S (or on/in the rotor-side ends of the fluid connectors and/or on/in the connecting channel openings S7), into which a seal is (or can be) inserted. In this respect, the present invention is not limited to this specific embodiment; rather, another form of seal can also be used. In FIG. 1a, however, this is indicated as round lines around the rotor-side openings of the fluid connectors or the openings of the connecting channels S7 (but only numbered once for the sake of clarity). The area of the stator S that comes into contact with the rotor R is denoted by S5. Similar to device S3, a device S6 can optionally be provided in the middle of the stator, which serves as a centering aid for rotor R and stator S. This centering aid is preferably designed as a pin and/or annular centering groove (shown here as an annular centering groove). Furthermore, S7 also indicates where a connecting channel can be located, with which two cavities 13, that is to say in particular chromatography columns 13, can be connected to one another. This Connection channels can be simple bores or curved hollow tubes or the like.

In the upper part, FIG. This is denoted as well R9 and is the location where chromatography columns 13 are loaded into the rotor R. In the example shown and its quasi-square design, four places for chromatography columns 13 are therefore available. In this case, individual or all depressions R9 can be used. In addition, several (then thinner) chromatography columns 13 can be arranged per well R9. Furthermore, other symmetries or shapes can be selected for the depressions R9 and consequently other numbers of depressions R9 can also be implemented; preferred numbers of depressions R9 per rotor R are three, four, five, six, seven and eight, in particular four. In the assembled state of the valves V according to the invention, these depressions R9 form cavities 13 together with the rotor R located above them or the stator located above them, which cavities 13 can be used per se or, preferably, by using chromatography columns 13 . In this rotor R, bores Ria are also illustrated, which are used to connect to a motor coupling (not shown) for rotating the rotor R (via appropriate fastening means). In the example shown, these are arranged in the middle around a recess. Although this recess is illustrated as a circle, this does not necessarily have to be the case. Also illustrated here are devices (e.g. bore) for aligning rotor and stator (the stator, which is not shown here, then has corresponding counterparts, with bores in the rotor pins or similar would be arranged in the stator). The circle segments outside of the depressions R9 shown represent the contact surfaces R5 of the rotor R to the stator S (not shown here) (or other rotors).

The lower part of FIG. lb shows the rotor R shown above in FIG. The circle segments outside of the columns R13 shown represent the contact surfaces R5 of the rotor R to the stator S. Finally, a device R3 for aligning the rotor R and the stator S is also labeled R3. FIG. 1c shows examples of columns that can be used according to the invention. RIO shows a single column insert RIO with an optional O-ring cord groove (for better pressure stability, shown by a double edge line) in the figure above. Such single-column inserts RIO are then used in single-column housings Rll (third representation from above), which are preferably adapted to the shape of the cavities (this simplifies the exact positioning), and then used as assembled single columns R13 in the cavities or recesses R9 become. The assembled individual columns R13 are shown in the bottom part of FIG. 1c, on the left in a top view and on the right in a view from below, with connections to the stator S, shown here as points R12, then being shown on the right. In the simplest case, these connections can be bores through which a fluid can flow. Finally, as the second view from above, a sectional view through the individual column housings R11 with inserted columns R13 is shown (sectional view along the line CC in the third view from the top). One can clearly see how the connections R12 lead out downwards from the housing Rll and on the other hand are connected to the columns R13 used.

Figure ld shows a cover plate D for the valves V according to the invention. This (if it is used) is attached to the side of a rotor R facing away from the stator S and then by attaching fastening elements, preferably screws (with nuts), in particular self-locking nuts , Pulled together and fixed through the holes Dl and tighten the fasteners, the valve according to the invention (where the rotor R between the stator S and / or further rotor R and cover plate D remains movable (rotatable)). In this respect, the cover plate D is essentially a plate with bores D1 for receiving the fastening means, wherein the cover plate D can have a recess in the middle if the rotor R is to be driven from this side; if the rotor R is to be driven, for example, by toothed wheels or belts which act on its outer sides, such a recess is not necessary.

Figure le shows an assembled valve V according to the invention consisting of stator S, two rotors R and cover plate D (in the order given above one another). Although it is not illustrated in FIGS. 1a to 1e, a base plate B can of course also be arranged on the other side of the valve; However, it should be noted here that inlets or fluid connectors S2 remain accessible, which generally requires that these are arranged comparatively far in the middle—or on the outer peripheral edge of the stator S.

In the configurations according to the invention according to FIG. 1a to FIG.

Figure 2 shows an example (simplified to one movable element for the drawing) the difference between the micro-SMB described in the prior art (indicated by a) in the upper part of the figure) and the corresponding interconnection according to the present invention (in the lower part of the Figure labeled b)). In both parts, a static element/stator S is shown at the top and a movable element/rotor R is shown at the bottom. The inventive integration of the columns 13 in the valve V, more precisely in the rotor R, eliminates the need for connecting channels (represented by cross-striped rectangles) in the valve and additional external capillaries (represented by arrows). This significantly reduces the dead volume. Possible placement points for any frits are denoted by 14 (for the sake of clarity only on the right columns, which in turn are numbered only in the left part with 13 for the sake of clarity). By means of such frits it is possible to hold the stationary phase in the columns 13, even if this consists only of a bed; In addition, a filter effect can be achieved so that only sufficiently small particles/substances reach the column itself (i.e. the stationary phase) and the remaining components are trapped. In further variants of the present invention, sufficiently fine-meshed filters, nets or grids can also be used instead of the frits. In addition, the frits/filters/nets/grids can be exchanged, for example in the event that they become clogged, so that the entire column does not always have to be replaced (which means cost advantages and material savings). It should be pointed out again that for the sake of simplicity only one rotor is shown in this figure; in the case of the valves according to the invention with at least two displaceable elements (rotors), the same effects naturally also occur, although they are then increased. FIG. 3 shows a highly schematic example of a structure for a micro-SMB system using a valve according to the invention. This exemplary structure includes four containers for each diluent, extract, sample and raffinate, as well as a container for waste, a multi-channel pressure control unit for microfluidics 15 with a pressure control probe PCR per channel, four flow sensors FCR, two UV sensors QR, two conductivity sensors LR and one (screwed together) valve V according to the invention with four integrated columns 13 (for example distributed over two rotors, each with two columns 13 or distributed over one column in the first rotor and three columns 13 in the second rotor). Such a setup can (but is not mandatory) be used for investigations such as the example shown below.

FIG. 4 shows the results obtained in the example described below. For this purpose, the concentrations in the (inflow and outflow) streams of the system used are shown in FIG. A more detailed description can be found below in the example.

Figure 5 illustrates packing adapters for packing individual columns separately. At the top is a plan view showing the pack adapter lid on the left and the main body (or base) on the right. P9 designates a depression for inserting an individual column and PI bores for pressing the individual parts by means of appropriate connecting elements, preferably screws (in one example, these bores go through all parts and then the individual parts are pulled together or screwed together by tightening screws/nuts, for example). pressed, or in another example the bores only go through one part and in other part a threaded groove is cut into which a screw can be screwed, or in still another example clamping rods are passed through the bores and then all parts of clamped together on the outside via the clamping rods. Other variants are possible). P2 designates connectors for external fluid flows. A single column is thus placed in the depression P9 of the lower part, then the cover is put on and the lower part and cover are fixed to one another by means of the connecting elements. The column can then be connected and filled or operated via connectors P2. In the second line, the same pack adapter is shown again in a side view. The third line shows the pack adapter on the left in a top view and on the right in a bottom view. You can see the holes PI and in the left part the Connectors P2 (not numbered for clarity). The cuts through the adapter parts along the respective cutting lines AA and BB are then shown in the bottom line of FIG. In the section along AA of the cover, passage openings for fluids are then also shown, which are marked with arrows.

With these adapters it is possible to use the columns independently of the valve according to the invention, whereby a single column can be packed with the adapter or used as a column independent of the valve, depending on whether a frit is used in the feed stream of the adapter.

In the following, in Figures 6 to 11, exemplary embodiments according to the invention of rotor disks, in which chromatography columns are integrated (Figures 6 to 8), base plates/cover plates (Figure 9) and assembled valves from these rotors and base plates/cover plates (Figures 10 and 11) illustrated. Different designs of the rotor disks are shown as examples, which, for example, only have columns (FIG. 6), additional bypass channels that can also be used for direct sample injection ("sample loop") (FIG. 7) or additional microfluidic elements for flow control ( Figure 8). Numerous other configurations are conceivable. To compress the rotor disks, for example, the cover and base can be identical (Figure 9); in this case, fluid can be supplied and removed from both sides (top and bottom). Figure 10 shows the assembled components of a valve according to the invention with two displaceable elements (rotors) and Figure 11 shows the assembled components of a valve according to the invention with three displaceable elements (rotors). The rotor discs can be rotated, for example, via gear wheels or a belt drive. The valves according to the invention allow the flexible connection of different chromatography columns or sample loops without any dead volume.

FIG. 6 shows a possible variant of the rotor R of the valves V according to the invention. The teeth 24 of the outer circumference of the rotor R immediately catch the eye in this variant. Such teeth make it possible to drive the rotor R via a toothed belt or toothed belt. However, this possibility does not rule out the possibility of the rotor being driven from below by a motor that acts, for example, via the center hole. To that extent it is within the scope of the present invention It is quite possible and includes producing rotors R with teeth 24 and, if necessary, further devices for motor contacting and then driving them (for example depending on local possibilities) either by gearwheels/belts or by motors acting at a different point. Otherwise, the basic functionality of the rotor R in FIG. 6 corresponds in principle to that shown in FIG. 1b, for example. Although only three chromatography columns 13 are illustrated here in FIG. 6, four or more (or fewer) are just as possible. Furthermore, the columns 13 are only indicated here (dashed); the columns are designed here as an integral part of the rotor plate (accessible for example via additive manufacturing, in particular 3D printing), but the rotors shown in FIG. 1b can also be provided with teeth 24 in order to make the drive options more flexible. Returning to FIG. 6, the inlet 21 and outlet 22 of the cavity or column 13 are shown, which in this case show the possibility of the cavity/column 13 being supplied with fluid from one surface and drained from the other side. According to the invention, however, it is just as possible to arrange both the inlet 21 and the outlet 22 on one (of the same) surface side. In addition, number 20 illustrates an optional recess into which an (inlet) frit 14 can be inserted if desired (cf. also FIG. 2 and the description for possible positioning of frits or filters/nets/grids). Finally, a centering bore 23 is also shown in the middle, by means of which (and other centering means, such as rods or the like) rotor R and stator S as well as cover plate D can be centered. However, this centering bore 23 can also, alternatively or additionally, be used as an attachment point for a centrally arranged motor (or a means that transmits the rotation of a motor, such as a shaft).

FIG. 7 illustrates a similar exemplary embodiment of the present invention as FIG. 6. In contrast to FIG. 6, which only illustrates cavities/columns 13, additional passage channels (bypass channels) 25 are shown in FIG. Loop") can be used, illustrated. With these, it is possible, if the rotor R is positioned with them via appropriate fluid receptacles (for example sample containers, additional columns, eluent collection containers, etc.), to dose fluids while bypassing the cavities/columns 13, for example in the eluent or other columns targeted specific, individual eluted fractions are provided with an indicator or the like.

FIG. 8 is another exemplary embodiment of the rotors according to the present invention, similar to FIGS. 6 and 7, but here additional microfluidic elements for flow guidance are illustrated. On the one hand, a splitter 26 for dividing a fluid flow between two cavities/chromatography columns 13 is shown. As can be seen in the lower part of FIG. 8, fluid can be fed into the splitter 26 from above, as a result of which the fluid then reaches both adjacent cavities/columns 13 (shown in a V-shape). This can be used, for example, to use different columns (i.e. essentially different stationary phases) at the same time, which can be useful for example, but not only, for screening experiments. Likewise, a direct outlet is illustrated at 22a, which can be used to split a fluid flow; it is illustrated here that a fluid fed into the inlet 21 partly reaches the upper cavity/column 13 shown horizontally and partly directly to the outlet 22a—this is therefore also a variant of a splitter. It should be noted that these two illustrated microfluidic elements are not the only conceivable/usable ones. For example, it is also possible within the scope of the present invention, instead of the splitters 26 illustrated here for dividing into two cavities/columns 13, splitters for dividing into three or four or more cavities/columns 13 are also possible; accordingly, the direct outlet 22a can also be connected to a splitter for splitting into two, three, four or more cavities/columns 13 (and not just one as illustrated).

In addition to being driven in rotation by a toothed belt or gear wheels, the rotors R of the present invention, as illustrated, for example, in FIGS 1 engaging elsewhere than the outer periphery of the rotors R, or rotated by hand, or by (non-toothed) belts, solely with sufficient friction between belt and rotor outer peripheral surface.

FIG. 9 shows a further variant according to the invention for a cover plate D, which of course can also be used as a base plate B on the other side of the valve can be arranged. In this figure, the cover plate/base plate D/B is additionally provided with connections S2 for external fluid connectors in addition to the bores D1 for the introduction of fastening means (as described above). Flow channels 27 are also illustrated in this figure following these connectors S2. Such flow channels can of course also be present in the other embodiments when connectors S2 are placed on cover plate/base plate D/B or stator S (but for the sake of clarity they are not always shown in the figures). Depending on the exact design of connectors S2 and flow channels 27, an exact distinction is not always possible, or they can merge continuously - in this respect, as already mentioned in the description, connectors S2 and inlet 21 are partially synonymous within the scope of the present invention (unless explicitly stated otherwise or defined in more detail). Although two connectors S2 are shown here, this is not the only possibility according to the invention. One, three, four or more connections S2 can just as easily be provided. The exact number or the exact configuration of the cover/bottom plate will of course be selected depending on the rotors used/planned. In such a configuration, the cover D acts as a stator at the same time. If, moreover, top plates/bottom plates D/B with connections S2 are arranged on both sides of a rotor R, in particular as shown in FIGS will be realized; With such an arrangement it is of course also possible to use one of the top plates/bottom plates D/B only as a cover and not to use the connections S2. In this respect, a valve that has a cover plate D and a base plate B according to FIG. 9 is very flexible in its application.

FIG. 10 illustrates the view of a fully assembled valve V according to the present invention, in which two rotors R, with teeth 24 on the outer peripheral edge, are arranged one above the other. A cover D, as also shown in FIG. 9, is illustrated at the top in this figure. However, this can also be a stator S, which has corresponding connections, or the cover D has the function of a stator S in this illustrated, exemplary embodiment—or vice versa. Furthermore, a cover plate D or base plate B is illustrated as the bottommost part in the figure; this can be a top/bottom plate as illustrated in FIG (then the valve of this embodiment would have two equal sides), but it can also be a cover plate as illustrated in Figure lc or a simple round disk with corresponding bores Dl, but care must then be taken that the lowest rotor R is designed in such a way that whose outlets either end in the area of the recess of the cover plate (according to FIG. 1c), or whose outlets are directed upwards and the fluids are then directed upwards again (through the other rotors). In the middle of this valve V there is also a centering axis Z, with the help of which the individual components can be centered precisely one above the other and which serves as the axis of rotation (of the rotors).

FIG. 11 illustrates the view of a fully assembled valve V according to the present invention, in which three rotors R, with teeth 24 on the outer peripheral edge, are arranged one above the other. A cover D, as also shown in FIG. 9, is illustrated at the top in this figure. However, this can also be a stator S, which has corresponding connections, or the cover D has the function of a stator S in this illustrated, exemplary embodiment—or vice versa. Furthermore, a cover plate D or base plate B is illustrated as the bottommost part in the figure; this can be a top/bottom plate as illustrated in FIG. 9 (then the valve of this embodiment would have two equal sides), but it can also be a top plate as illustrated in FIG. 1c or a simple round disc with corresponding bores D1, however Care must then be taken to ensure that the lowest rotor R is designed in such a way that its outlets either end in the area of the recess in the cover plate (according to figure lc), or that its outlets are directed upwards and the fluids then flow upwards again (through the other rotors) are routed. In the middle of this valve V there is also a centering axis Z, with the help of which the individual components can be centered precisely one above the other and which serves as the axis of rotation (of the rotors).

In the following, exemplary embodiments for a further, different variant according to the invention are shown in FIGS. 12 to 15; In this variant, the stator has one or more cavities for fluid transmission in addition to connections for fluid supply and discharge.

In this variant, a zero dead volume injection valve is shown. In this valve, only one cavity filled with separating material is used in the stator, whereas the rotor furthest away from the stator has cavities, these are (or are) only filled with sample, but do not contain any stationary phase; between these two one or more further rotors are arranged for connection.

In the field of chromatography, it is of great interest to keep the dead volume between the injection and the column as small as possible so that the sample is injected in a liquid volume that is as compact as possible.

It is expressly pointed out that FIGS. 12 to 15 represent a simplified version, since FIG. 15 in particular would otherwise be too confusing. According to the invention, at least one further rotor (R ₂ -0V) belongs between the stator S-OV and the rotor R-OV, the cavities of which (or whose) are completely filled with sample and/or separating material, and which the cavities of the rotor R-OV and Stator connects S-OV with each other, for example outlet S0-0V with the inlet for 13-R-OV.

FIG. 12 shows the stator S-OV of the zero-dead-volume injection valve OV, viewed from above (upper part of the figure) and seen from below (lower part of the figure) with corresponding external (microfluidic) connectors (21-OV, 22- OV, 21-OVa, 22-OVa) and an integrated well 13-S-OV, which is preferably a chromatography column. The corresponding further components correspond to those described above. The inlet of the chromatography column is designated with 21-OV and the outlet with the number 22-OV. Similarly, 21-OVa and 22-OVa denote an inlet and an outlet, which, however, are not connected to the cavity/chromatography column 13-S-OV, but to the channels or channels adjoining them through the stator S-OV lead through to cavities in the rotor S-OV of the zero dead volume injection valve 0V. Also shown are bores S1-0V for fastening, preferably by means of screws, in particular with (self-locking) nuts, for axial compression (fastening/fixing) of the rotor and stator, which function as described above. The lower part of the figure shows the contact surface S14- 0V to the additional rotor(s) R ₂ -0V, which lies between S-OV and rotor R-OV, and at the outlet of the cavity/chromatography column 13-S-OV an optional recess 20-0V is again illustrated, in which, for example, a frit (or filter/mesh/grid) can be inserted if this is necessary or desired.

The cavity/chromatography column 13-S-OV can preferably be produced together with the entire stator S-OV using additive manufacturing processes, in particular 3D printing; the shape, depending on what you want, is particularly easy to achieve. Figure 13 shows the rotor R-OV of the zero dead volume injection valve 0V which is furthest away from the stator S-OV, in which cavities 13-R-OV of different sizes, in particular designed as sample loops Ps-OV, are integrated (the additional rotors in between As mentioned, R2-OV are not shown for the sake of clarity). These cavities 13-R-OV/Ps-OV can be curved as shown here, but they can also have any other shape, for example angled or serpentine; however, a curved shape is preferred. These cavities 13-R-0V/Ps-0V preferably differ in terms of their diameter and possibly their curvature (if they are curved), the distance between their cavity ends remains (preferably) constant (the length of the cavity also depends on the radius of curvature and is therefore variable). In this way it is ensured that different quantities or volumes of the samples can be located in the respective cavities 13-R-0V/Ps-0V without the geometry or the construction of the stator S-OV with the respective connection positions being affected of inlets and outlets would have to be changed. At the respective ends/exit points from the rotor R-OV of the respective cavities 13-R-OV/Ps-OV, cutouts for the arrangement of frits (or filters/nets/grids) can also optionally be provided here.

The cavities 13-R-0V/Ps-0V can preferably be produced together with the entire rotor R-OV using additive manufacturing methods, in particular 3D printing; the shape, depending on what you want, is particularly easy to achieve. The rotor R-OV can have gears 24-R-OV (not shown) and can be rotated by them (e.g. by means of gears or toothed belts). Instead of being driven in rotation by a toothed belt or gear wheels, the rotor R-OV can of course also be driven by a motor, for example acting from below, which acts at a different point than the outer circumference of the rotor R-OV, or it can be turned by hand, or by (non-toothed) belts, solely via sufficient friction between the belt and the outer peripheral surface of the rotor.

The cover D-OV of the zero dead volume injection valve 0V shown in FIG. 14 is used for pressing rotor R-OV and stator S-OV (and intermediate rotors R ₂ -0V, not shown) with fasteners, and this also has bores D1 accordingly -0V for fasteners, preferably screws, especially with (self-locking) nuts. The cover plate D-OV is shown here as a continuous plate, without a cut-out in the middle. Depending on the exact way by means of which the rotor OV (and the at least one, not shown 2-OV) is to be rotated, a central recess can also be provided here, into which a motor (directly or indirectly via shafts or the like) can engage can. However, if the rotor R-0V has teeth 24-R-OV and this is to be used to rotate, no recess needs to be provided, just as not if the rotor is to be rotated using belts, but only with sufficient friction (or even by hand).

The upper part of FIG. 15 shows an oblique plan view of the arrangement of the parts S- 0V, R-OV and D-OV for one of the zero dead volume injection valve 0V - for the sake of clarity the part(s) belonging to the complete valve intermediate rotor(s) R2-OV are not shown for clarity. The lower part shows a top view, with the stator S-OV being shown transparently, so that the position of the cavities/sample loops 13-R-0v/Ps-0V in the rotor R-OV in relation to the inlets and outlets of the stator S -OV, and in particular also in relation to the cavity/chromatography column 13-S-OV in the stator. You can see that a sample loop, referred to here as Ps-I-OV, is in the "inject" position, i.e. it is in contact with the cavity/chromatography column 13-S-OV in the stator S-OV. This means , that a fluid from the sample loop Ps-I-OV can be introduced (injected) into the cavity/chromatography column 13-S-OV. Another sample loop, referred to here as Ps-L-OV, is located in the "Load"- position, meaning that it can be filled with fluid (or, alternatively, fluid can be removed therefrom) through the connectors of the stator; intermediate rotor(s) would be designed to make these precise connections.

Example:

The invention will now be further elucidated with reference to the following non-limiting example.

Using a test setup with a flow source and process sensors, as is also illustrated in FIG. 3, samples were examined with a valve according to the invention comprising four columns and two rotors. The columns were filled with Cytiva Sephadex G-25 F chromatography material. The aim of the test experiment was to desalt bovine serum albumin (BSA) from ammonium sulfate (AS). A mixture with 2 g/L BSA and 200 mM AS was chosen as the feed solution (sample). The BSA protein should be drawn off in the raffinate port of the system and the AS in the extract.

To carry out the test, the valve according to the invention was used as an SMB valve and an SMB process was carried out in a known manner at room temperature and ambient pressure.

At the end of the experiment, the raffinate solution had an AS concentration of 32 mM and a BSA concentration of 1 g/L. The BSA yield is thus 61% with a dilution factor of 50%. At the same time, 82% of the AS could be depleted.

In summary, Figure 4 shows the concentrations in all the influent and effluent streams of the system. The concentrations are plotted on the ordinate and the application or withdrawal points of the respective fluid are plotted on the abscissa, with the respective columns and flow velocities specified under the coordinate system. The direction of switching of the columns is indicated and the switching time tschait was 276 seconds.

It can be seen from the data that the valve of the present invention is very effective. The applicability of the slide valves according to the invention for the operation of a micro-SMB could thus be successfully demonstrated.

Reference list:

13 (chromatography) column

14 frit

15 multi-channel pressure control unit for microfluidics (with pressure control sensors PCR)

16 conductivity meters

FCR flow sensors

QR UV sensors

LR conductivity sensors

20 (optional) recess for inserting a frit

21 inlet (of the chromatography column) 22 outlet (of the chromatography column)

22a direct outlet to split the flow stream

23 center hole

24 teeth for (belt) drive

25 pass-through channel for column bypass or sample injection

26 device (splitter) for splitting a flow stream into (two)

chromatography columns

27 flow channel

D cover plate

Dl hole for pressing the rotor and stator using fasteners (e.g. screws) / for inserting screws or other fasteners for external pressing

P pack adapter

PI bore (of the pack adapter) for pressing the individual parts

P2 connector (of the pack adapter) for external fluid flows

P9 Indentation (of the pack adapter) for inserting a single column

R Rotor

Ria connection holes for the motor coupling to rotate the rotor

R3 Device (e.g. bore) for aligning rotor and stator

R5 Contact area of assembled rotor (with (four) single columns inserted) to stator

R9 Cavity (of the rotor) for inserting the columns

RIO use of the single column with optional O-ring (string) groove for better pressure stability

R12 connecting channel to the stator

R13 composite single column

S stator

51 bore (in the stator) for pressing rotor and stator

52 fluid connectors for external material flows (e.g. hose connections)

53 Device (e.g. bore) for aligning rotor and stator

54 O-ring groove for sealing the contact points of rotor and stator

55 contact surface to the rotor

56 (optional) centering aid for rotor and stator

57 (optional) connecting channel between two columns V (composite) valve (with integrated columns)

Z centering axis

OV zero dead volume injection valve

13-OV cavity (of rotor or stator)

20-0V recess (for fries or similar)

21-OV Inlet of the chromatography column 13-OV in the stator S-OV

21-OVa Inlet for sample loop Ps-OV

22-OV Outlet of the chromatography column 13-OV in the stator S-OV

22-OVa outlet for sample loop Ps-OV

D-OV Zero dead volume injection valve cover plate

D1-0V holes for fasteners

Ps-OV Zero dead volume injection valve rotor R-OV sample loop

Ps-I-OV sample loop on the "Inject" position

Ps-L-OV sample loop on the "Load" position

R-OV Zero dead volume injection valve rotor

S-OV Zero dead volume injection valve stator

S1-0V Holes for fasteners

S14-0V Zero dead volume injection valve rotor R-OV contact area

Claims

Expectations:

1. Slide valve, in particular SMB valve, comprising, stacked one above the other,

I) at least two displaceable elements, each comprising a) at least one cavity with at least two connections per cavity, the connections allowing the flow of fluids through the at least one cavity, or b) at least one cavity without its own connections configured to accommodate inserts with at least two ports per insert, wherein the ports allow fluids to flow through the inserts, or c) at least one cavity with at least two ports per cavity and at least one cavity without dedicated ports configured to accommodate inserts, in particular inserts with at least two ports per Insert, wherein the connections allow fluids to flow through the inserts, lla) at least one static element comprising at least one connection for fluid supply and at least one connection for fluid discharge, optionally one or more cavities for fluid transmission, optionally one or more connections for fluid transmission, or llb) a static element that has no connections for fluid (further) conduction,

III) optionally a static cover plate, which is arranged on the opposite side of the static element of the displaceable element furthest away from the static element,

V) optional devices or preparations for automatically driving the displacement of the element I),

44 wherein the ports of the at least one static element are arranged to be registerable with all ports or selected ports of at least one displaceable element to selectively allow or prevent the transfer of fluids between the elements, and wherein the cavities are configured so that

Materials introduced for performing a chromatographic separation or

Inserts can be deployed and optional,

Frits for retaining the materials, if necessary, can be inserted into the cavities and/or at their inlets and/or outlets. Slide valve according to claim 1, characterized in that in addition to I) Ila) and III) or IV), or I), III) and IV) are present, the components I), Ila), and optionally III), IV) a have a common axis of rotation, which lies vertically in the middle of the stack of existing elements, with the elements in particular all being designed round or approximately round, and that Ila) is firmly connected to, if present, III) and/or IV) via appropriate fastening means , but intermediate(s) I) is still rotatable around the axis of rotation. Slide valve according to one of Claims 1 or 2, characterized in that at least one of the displaceable, preferably rotatable, elements I) has at least two cavities, preferably at least two cavities of these at least two cavities are filled with the same or different materials or inserts containing such materials where the materials can interact with the substances running in the fluid.

45 Slider valve according to one of Claims 1 to 3, characterized in that different flow paths are generated by shifting the individual elements relative to one another and preferably at least one flow path is changed through at least two cavities by shifting the individual valve elements relative to one another. Slider valve according to one of Claims 1 to 4, characterized in that there is the possibility of supplying and/or removing fluid streams between the cavities. Gate valve according to any one of claims 1 to 5, characterized in that the cavities are configured such that

Introduced materials for stationary phases for chromatography or

Inserts comprising chromatography columns, can be used and are optional,

Frits for retaining the materials, if necessary, can be inserted into the cavities and/or at their inlets and/or outlets. Slider valve according to one of Claims 1 to 6, characterized in that the cavities have a cylindrical shape or the cavities have a geometry that deviates from the cylindrical shape. Slider valve according to one of Claims 1 to 7, characterized in that the cavities have a volume of 10 nL to 10 mL, preferably 1 pL to 1000 pL. Slide valve according to one of Claims 1 to 8, characterized in that individual or all elements I), IIa), III), IV), optionally V), are manufactured by means of additive manufacturing processes, in particular 3D printing. Slider valve according to one of Claims 1 to 8, characterized in that the displacement of I) in relation to the other elements takes place either manually or with the aid of a drive.

46 Kit for producing slide valves, in particular for SMB processes, comprising i) various slide elements comprising a) at least one cavity with at least two connections per cavity, the connections allowing fluids to flow through the at least one cavity, or b) at least an unported cavity configured to receive liners with at least two ports per liner, the ports permitting the flow of fluids through the liners, or c) at least one cavity with at least two ports per cavity and at least one unported cavity configured for accommodating inserts, ii) static elements comprising at least one connection for fluid supply and at least one connection for fluid removal, optionally one or more cavities for fluid transmission, optionally one or more connections for fluid transmission, iii) static top plates, iv) static bottom plates, vi) Inserts that are configured to be inserted into the cavities of i)b), preferably designed as chromatographic columns, the individual elements of the kit being configured to be able to be connected to one another to form a slide valve, the connections of the static elements ii) so are arranged so that they can be brought into registry with the terminals or selected terminals of the displaceable elements i). Kit according to claim 11 additionally comprising one or more of the following elements v) motors with which the rotor or rotors can be moved, vii) housings in which the valves can be inserted. viii) include brackets which can hold the valves or individual parts. Use of a slide valve according to one of Claims 1 to 10 or of a slide valve produced with a kit according to Claim 11 or 12 in the field of multi-column chromatography or in the coupling of chromatography methods with other processes. Use according to Claim 13 for (bio)chemical analyses, in particular those with small sample volumes, preferably for the analysis of environmental samples, in the food industry, in the (bio)pharmaceutical industry, in the chemical industry, in medical diagnostics. Method for carrying out chromatographic investigations, in particular SMB, using or by means of a slide valve according to one of Claims 1 to 10 or a slide valve produced with a kit according to one of Claims 11 or 12.