Fraction collector

Abstract

The present disclosure refers to a fraction collector for fractionating liquid into liquid containers, optionally arranged in cassettes, the fraction collector comprising a housing, a tubing connector for liquid connection to a tube for supplying the fraction collector with liquid, at least first and second holders each configured for direct or indirect support of a plurality of liquid containers, and at least one outlet, optionally a dispensing nozzle, in liquid communication with the tubing connector and for dispensing liquid into the liquid containers, wherein the outlet and the first and second holders are housed in the housing, and the first and second holders differ as to their vertical position, wherein the fraction collector is configured such that liquid is collected in liquid containers at different vertical positions.

Description

FRACTION COLLECTORTECHNICAL FIELD

[0001] The present invention concerns a fraction collector, the use thereof for chromatography, and a chromatography system comprising said fraction collector.BACKGROUND OF THE INVENTION

[0002] A fraction collector is a device, e.g. used in chromatography systems to collect eluted samples, in particular molecules, as they elute from the chromatography column.

[0003] The fraction collector may be a vital component in chromatography systems, providing automated, precise, and customizable collection of eluent fractions, which enhances the efficiency and accuracy of the separation process.

[0004] Existing fraction collectors have limited capacity and if large capacity is needed, a large bench space may be needed for the fraction collector.

[0005] Another problem with existing fraction collectors may be that it is hard to access the vessels which have already been processed during an ongoing run.

[0006] There has been a need and desire to improve liquid fractionation as to capacity and / or efficiency, in particular space- and / or time-wise.SUMMARY OF THE INVENTION

[0007] The present invention solves the above problems and provides a fraction collector for continuously fractionating liquid into liquid containers, optionally arranged in cassettes, the fraction collector comprising a housing, a tubing connector for liquid connection to a tube for supplying the fraction collector with liquid, at least first and second holders each configured for direct or indirect support of a plurality of liquid containers, and at least one outlet which may also be referred to as dispensing means, optionally a dispensing nozzle, in liquid communication with the tubing connector and for dispensing liquid into the liquid containers, wherein the outlet and the first and second holders are housed in the housing, and the first and second holders differ as to their vertical position, wherein the fraction collector is configured such that liquid is collected in liquid containers at different vertical positions and wherein the fraction collector is arranged such that at least one of the at least first and second holders in which liquid collection is completed can be accessed without interrupting the liquid collection ongoing in the liquid containers in another holder of the at least first and second holders.

[0008] Optionally, a fraction collector of the invention may be defined as follows: A fraction collector for fractionating liquid into liquid containers, optionally arranged in cassettes, the fraction collector comprising a tubing connector for liquid connection to a tube for supplying the fraction collector with liquid, at least first and second holders each configured for direct or indirect support of a plurality of liquid containers, wherein the first and second holders differ as to their vertical position, wherein the fraction collector is configured such that liquid is collected in liquid containers at different vertical positions.

[0009] A fraction collector of the invention may represent a multi-level fraction collector, as the holders are provided at different levels / floors, i.e. at different vertical heights. A fraction collector of the invention may be seen as a multifloor fraction collector, i.e. a fraction collector having multiple platforms with height differences. The holders are at different levels in height, i.e regarding the direction of gravity, often referred to as z-direction.

[0010] Fractionating may refer to dividing a larger amount of liquid into relatively small fractions / amounts of liquid and is followed by collection of the smaller fractions of liquid.

[0011] The holders are for directly or indirectly (e.g via a cassette) support / holding of liquid containers, in particular at least in parts in a horizontal plane. As such, the liquid containers may be held, by a fraction collector of the invention, at horizontal planes at different vertical locations A holder may also be referred to as a support or tray

[0012] At least two holders may be provided, optionally more than first and second holders. Optionally, all holders are at different levels / vertical locations.

[0013] A holder may hold / support a cassette / cartridge which includes the liquid container(s) The cassette may be configured to adapt the height (i e vertical location) of the liquid container(s)

[0014] The fraction collector of the invention is configured to collect liquid fractions (size) of 100 pl to 250 ml. Additionally or alternatively, the fraction collector may be configured to subsequently collect a plurality of fractions (e.g. 10-600).

[0015] The liquid container may e g include tubes and / or wells, optionally positioned in rows and / or a 2D matrix arrangement or any other arrangement. The liquid container may be referred to as a reservoir or vessel (e.g tubes, plates, bottles). The liquid containers may be constituted as tubes mounted in a rack or as recesses formed in a plate.

[0016] The idea underlying the present invention increases the capacity of the fraction collector and at the same time is a more efficient use of space and / or time for liquid fractionation by uniting at least first and second holders, optionally a plurality of holders, in a same, single housing, while positioning the at least first and second holders at different vertical positions. The housing is common to the liquid containers held by the at least first and second holders. This may allow for more efficient use of space, in particular in the vertical direction, when a multi-level fraction collector of the invention is compared to multiple single-level fraction collectors positioned next to each other (in the horizontal direction). This provides a basis for a space-saving fraction collector with larger capacity.

[0017] For example, the first and second holders, optionally a plurality of holders, may, at least in parts, be on top / underneath (below) each other (i.e at least an overlap of the first and second holders in vertical direction; optionally the first and second holders being shifted relative to each other in the vertical direction, optionally not in the horizontal direction). The first and second holders may be stacked, such that a stack of at least two holders is provided in a fraction collector. The first and second holders may be seen as upper and lower holders, respectively, on top of / below each other.

[0018] A single tubing connector for a tube supplying the liquid containers held by the at least first and second holders, in particular, by all holders, may be provided. A common tubing connector and common tube may be advantageous, as no separate / individual liquid connection needs to be established for the supply of liquid at different vertical positions. This may in particular be beneficial in terms of flushing of liquid and delay of liquid flow. More specifically, liquid fractions may be dispensed in a continuous sequence in the liquid containers at different vertical positions, avoiding interrupts and losing of fractions in the tube. This may, however, not be possible when positioning / stacking separate, single-level fraction collectors on top of each other.

[0019] According to some embodiments, an optional accumulator with a chamber may be arranged to collect the liquid flow during the time interval for switching the outlet between the at least the first and second holders, so that continuous fractionation may be facilitated. An example accumulator (i.e. a liquid holding means) is described in WO 2010144036 A1 , the content which is incorporated as a whole, in particular in connection with the liquid holding means 31 described therein.

[0020] Optionally, the outlet, more optionally the dispensing nozzle, is a common outlet for dispensing the liquid into the liquid containers, supported by the at least first and second holders. In other words, the containers at the first and second holders, optionally all holders, i.e. at the different vertical positions, share a common outlet / nozzle This further facilitates dispensing liquid in a continuous sequence in the liquid containers at different levels. Specifically, switching from one nozzle to another nozzle may be avoided, which may eliminate the situation of losing liquid in the tube for the previous nozzle.

[0021] Optionally, the fraction collector further comprises a compartment extending at least between the first and second holders at least in parts in the vertical direction and connecting the at least first and second holders. Thecompartment may extend vertically, optionally exclusively vertically. The compartment may provide a spatial connection (e.g a cavity) between the first and second holders, optionally all holders. The compartment may in particular join the various holders, i e levels In one embodiment, the compartment may be located at a side of the fraction collector.

[0022] Optionally, the at least first and second holders are moveable in at least the vertical direction. In this embodiment, the (optionally all) holders are moveable, while the liquid outlet may be stationary at least in the z- direction This embodiment may be seen as realizing the “paternoster” principle The underlying idea is to reach, by means of a same outlet, liquid containers at different holders, i.e. at different vertical locations.

[0023] Optionally (additionally or alternatively,) the outlet is moveable at least in the vertical direction, such that the fraction collector is configured to adapt the vertical position of the outlet to the at least first and second holders The underlying idea is to reach, by means of a same outlet, liquid containers at different holders, i e at different vertical locations. The outlet can further be arranged to be movable in the horizontal plane when the liquid containers in each floor, i.e. in the horizontal plane, are positioned in rows and / or a 2D matrix arrangement, as already implemented in prior art. In other words, the common nozzle is arranged to be movable in a 3-dimensional direction and to dispense liquid to the liquid containers held by the at least first and second holders arranged in multiple floors This embodiment may be seen as an alternative to the “paternoster” principle embodiment. However, the two embodiments are not mutually exclusive.

[0024] Optionally, the fraction collector comprises vertical movement means moveable at least between the first and second holders at least in the vertical direction and directly or indirectly mounting the outlet. The vertical movement means may provide for movement at least in the vertical direction and may include a rod, a screw drive, a piston, a scissor lift, a belt, a robot etc.. Since the vertical movement means mount the outlet, e.g nozzle, the vertical movement means allows for movement of the outlet in the vertical direction, i.e. in height The movement means may provide for movements individually / separately in the vertical and horizontal directions, or may combine movements in vertical and horizontal directions, e.g. by means of a robot with rotary joints.

[0025] Optionally, the movement means is positioned in the compartment, optionally at a side of the housing This may allow for movement of the outlet at a side of the housing.

[0026] Optionally, the movement means comprises a robot and / or a substantially vertical rack for vertical movement of the outlet and an arm for horizontal movement of the outlet. In some embodiments, this allows for a simple and efficient realization of a movement of the outlet in space.

[0027] Optionally, the arm is moveable in a horizontal plane, the arm further optionally being rotatable for radial movement of the arm and / or linearly displaceable for linear movement of the arm. This may support that the outlet may target the liquid containers along Polar or Cartesian coordinates.

[0028] Optionally, the arm is horizontally collapsible and configured to reduce its horizontal dimension, such that the fraction collector is configured such that the arm is, in a collapsed state, moveable in the vertical direction within the housing, optionally inside the compartment and / or along the rack. This may provide a space-saving embodiment.

[0029] Optionally, the fraction collector further comprises at least first and second openings, optionally doors, for individual access to the first and second holders, respectively. In some embodiments, each holder, i.e. level of holder, may have its own, individual door / access. This may, in some embodiments, allow for access to another floor / holder in which fractionation has been finished and provide the possibility to replace filled liquid containers with empty liquid containers, and thus may support “endless fractionation” to the effect that fractionation does not need to be interrupted / stopped for exchange of liquid containers, i.e. replacement of filled containers by empty containers for further collection of liquid fractions.

[0030] With the arrangement of the common tubing connector, the movement of the dispensing means and the total fractionation volume divided into different parts / floors that can be accessed and replaced individually without interrupting the fractionation in another part / floor of the fraction collector, continuous fractionation can be provided by the fraction collector herein.

[0031] Optionally, the fraction collector is configured to be liquidly connected in series to another fraction collector of the invention, optionally positioned horizontally next to each other. This may further increase the collecting capacity of liquid

[0032] Optionally, the fraction collector may comprise a switch valve close to the nozzle for handling liquid connection, optionally to the other fraction collector, when connected in series to another fraction collector.

[0033] The invention is also directed to the use of the fraction collector of the invention for chromatography appliances, wherein the liquid fractionated is liquid obtained by chromatography

[0034] The invention is also directed to a chromatography system comprising a fraction collector of the invention. Specifically, the chromatography system may further comprise a chromatography apparatus, in particular having a tubing outlet for directly or indirectly connecting to the tubing connector of the fraction collector of the invention for supply of liquid to the fraction collector, which liquid was obtained by chromatography

[0035] The following disclosure relates to an (auto)sampler for sampling of liquid, in which the same principles as disclosed above for the fraction collector may be implemented and which may optionally also be part of a chromatography system. Basically, inversion of the fluid flow in a fraction collector corresponds to an (auto)sampler, i e dispensing liquid vs withdrawing liquid Specifically, a sampler may have an inlet that is moveable in the vertical direction (z-movement) for the inlet to go down (to lower and optionally dive) into the liquid containers, e.g. with a suction needle. Specifically, the following is summarized:

[0036] Sampler, optionally automatic, for sampling / collecting liquid from liquid containers, optionally arranged in cassettes, the sampler comprising a housing, a tubing connector for liquid connection to a tube for withdrawing liquid, at least first and second holders each configured for direct or indirect support of a plurality of liquid containers, and at least one inlet, which may also be referred to as sampling / withdrawing means, optionally a tip, in liquid communication with the tubing connector and for sampling liquid from the liquid containers, wherein the at least first and second holders for holding a liquid container is housed in the housing, wherein the sampler is optionally configured such that liquid is collected from liquid containers including a z-movement of the inlet, optionally at different vertical positions. The inlet is moveable at least in the vertical direction, such that the sampler is configured to adapt the vertical position of the inlet for liquid sampling relative to the liquid container. Optionally, the inlet is a common inlet for withdrawing the liquid from the liquid containers. Optionally, the sampler further comprises a compartment extending at least in the vertical direction. Optionally, the holder is moveable in at least the vertical direction. Optionally, the sampler comprises vertical movement means moveable at least in the vertical direction and directly or indirectly mounting the inlet. Optionally, the movement means is positioned in the compartment, optionally at a side of the housing. Optionally, the movement means comprises a robot and / or a substantially vertical rack for vertical movement of the inlet and an arm for horizontal movement of the inlet. Optionally, the arm is moveable in a horizontal plane, the arm further optionally being rotatable for radial movement of the arm and / or linearly displaceable for linear movement of the arm. This may support that the inlet may target the liquid containers along Polar or Cartesian coordinates. Optionally, the arm is horizontally collapsible and configured to reduce its horizontal dimension, such that the sampler is configured such that the arm is, in a collapsed state, moveable in the vertical direction within the housing, optionally inside the compartment and / or along the rack.BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Fig. 1 schematically shows a fraction collector according to an embodiment of the invention, forming together with a chromatography apparatus a chromatography system according to an embodiment of the invention.

[0038] Fig. 2(a) schematically shows a fraction collector having a vertically moveable outlet and stationary holders, according to an embodiment of the invention.

[0039] Fig. 2(b) schematically shows a fraction collector having moveable holders, according to an embodiment of the invention.

[0040] Fig. 3 schematically shows parts of a fraction collector according to an embodiment of the invention.

[0041] Fig 4 schematically shows a fraction collector having a robot as movement means according to an embodiment of the invention.

[0042] Fig. 5(a) to (d) show holders of, cassettes for, and / or liquid containers for a fraction collector according to an embodiment of the invention.

[0043] Fig 6 schematically shows two fraction collectors according to an embodiment of the invention connected in series, forming together with the chromatography apparatus a chromatography system according to an embodiment of the invention.DETAILED DESCRIPTION OF THE INVENTION

[0044] The present invention relates to a fraction collector 1. The fraction collector 1 is comprised in a chromatography system 8 further including a chromatography apparatus 13, as shown in Fig 1 The chromatography system 8 is used for chromatography appliances, wherein the liquid fractionated is liquid obtained by chromatography. The fraction collector 1 comprises a housing 4, a tubing connector 6 for liquid connection to a tube 7 for supplying the fraction collector 1 with liquid. The tube 7 fluidly connects the chromatography apparatus 13 and fraction collector 1

[0045] At least first and second holders 2, in Fig. 1 : three holders 2 as an example, are provided, wherein the holders 2 are provided on top of each other, i.e. are stacked holders 2, in the z-direction. The holders 2 are housed in the housing 4 and differ as to their vertical position in z direction.

[0046] With continued reference to Fig 1 , the fraction collector 1 further comprises three openings / access doors 11 as an example, more general: at least first and second openings 11 and respective doors, for individual access to the respective holder 2. Hence, each of the holder 2 is accessible individually by a door / opening 11 .

[0047] Fig. 2(a) shows a fraction collector 1 having a vertically moveable outlet / nozzle 5. Hence, the outlet 5 is in liquid communication with the tubing connector 6 and for dispensing liquid into liquid containers 14 (not shown in Fig1 ) supported by the holders 2. According to the embodiments shown in Fig.2(a), the holders 2 each support two liquid containers 14. The fraction collector 1 is configured such that liquid is collected in liquid containers 14 at different vertical positions in z direction in view of different vertical positions of the holders 2 Here, each holder 2 is configured for direct or indirect support of liquid containers 14

[0048] The fraction collector 1 comprises a vertical compartment 10 extending between the holders 2 in the vertical direction z and spatially connecting the holders 2. A movement means 9 is (partially or) in its entirety positioned inside / within the compartment 10, here at a side of the housing 4 (not shown in Fig. 2(a)).

[0049] The outlet / nozzle 5 is moveable in the vertical direction z, such that the fraction collector 1 is configured to adapt the vertical position of the outlet 5 to the respective position of the holders 2. The outlet / nozzle 5 is a common outlet for dispensing the liquid into the liquid containers 14. Hence, by moving the outlet 5 to the corresponding liquid container 14, liquid can be filled in all liquid containers 14, while the liquid containers 14 are stationary.

[0050] The outlet 5 is moved by means of the movement means 9. The vertical movement means 9 is moveable between the holders 2 in the vertical direction z and directly or indirectly via further entities mounts the outlet 5

[0051] The movement means 9 comprises a substantially vertical rack 9c for vertical movement of the outlet s, and an arm 9b as well as a beam 9a for horizontal movement (in the horizontal plane xy) of the outlet 5. The outlet 5 is provided at the arm 9b and moveable in an x-direction in which the arm 9b extends. The arm 9b is moveable along a y-direction along the beam 9a, which extends in the y-direction. The beam 9a is moveable in the vertical z-direction along the vertical rack 9c The arm 9b is, hence, linearly displaceable for linear movement of the outlet 5.

[0052] Fig. 2(b) schematically shows a fraction collector 1 having moveable holders 2. The holders 2 are i.a. vertically moveable and reflect a paternoster configuration. In this embodiment, the liquid containers 14 together withthe holders 2 are fed towards the outlet 5, which is stationary in the z-direction (but moveable in x-and y-directions). More specifically, the liquid containers 14 are fed towards the outlet 5 which makes linear movements along the beam 9a and the arm 9b in the horizontal directions xy, while remaining at the same height, i e z-position Of course, these principles are the same as those for the fraction collector 1 of Fig. 2(a). According to some other embodiments, the fraction collector 1 shown in Fig.2(a) and Fig.2(b) may be implemented in combination, i e. both the liquid containers 14 and the outlet 5 are moveable in the z-direction and in the x-and y-directions.

[0053] Fig 3 shows an embodiment in which the arm 9b is horizontally collapsible and, accordingly, configured to reduce its horizontal dimension, such that the fraction collector 1 is configured such that the arm 9b is, in a collapsed state, moveable in the vertical direction z within the housing 4 and inside the compartment 10 In its collapse state, the arm 9b is also moveable along the rack 9c in the z-direction. In this embodiment, the arm 9b is rotatable for radial movement of the arm 9b in the horizontal plane xy The outlet 5 is stationary relative to the arm 9b Alternatively, the movement means 9 may be configured as shown in Fig. 2(a), namely for linear movements in the xy-plane In some other embodiment, the outlet 5 is movable along the arm 9b in the horizontal xy.

[0054] Fig. 4 schematically shows movement means 9 comprising a robot for movement of the outlet 5 in x,y,z- directions Each of the holders 2 can be reached by the outlet 5 by means of movement of the robot 9 The robot 9 may be located at a side of the fraction collector 1.

[0055] As stated above, With the arrangement of the common tubing connector, the movement of the outet and the total fractionation volume divided into different parts / floors that can be accessed and replaced individually without interrupting the fractionation in another part / floor of the fraction collector, continuous fractionation can be provided by the fraction collector herein.

[0056] Fig. 5(a) to (d) show configurations pertaining to the holders 2, liquid containers 14 and cassettes 3. More specifically, Fig 5(a) shows a holder 2 in which plural liquid containers 14 in the form of rectangular bottles are provided. Fig 5(b) shows two cassettes 3, for support by one or two holders 2 and for receipt of one or more liquid containers in the form of well-plates 14. Fig. 5(c) shows another type of cassettes, namely two cassettes 3 for receipt of tube-shaped liquid containers 14, as indicated. Fig. 5(d) shows again another type of cassettes, namely two cassettes 3 receiving liquid containers 14 in the form of small tubes. As liquid containers 14 may be arranged in cassettes 3, the cassettes may help to adjust the vertical position of the liquid containers, in particular relative to the outlet 5. Liquid containers may be configured as vessels, such as tubes, plates, bottles etc.

[0057] Fig. 6 schematically shows a chromatography system 8 comprising two fraction collectors 1 liquidly connected in series to each other and positioned horizontally next to each other. Upstream of the fluid flow through the two fraction collectors 1 , the chromatography apparatus 13 is provided. The fraction collector 1 comprises a switch valve 12 for handling liquid connection between the two fraction collectors 1 , when connected in series.

[0058] For an autosampler, the outlet 5 serves as inlet, i.e for withdrawing liquid from the liquid containers 14 Hence, compared to the fraction collector 1 of the disclosure, the liquid flow is inverted, i.e. in the opposite direction. Any of the Figures 1 to 6 and the corresponding description thereof shall apply for an autosampler, while the outlet 5 is replaced by an inlet and / or functions as an inlet.List of reference signs1 Fraction collector2 Holder3 Cassette4 Housing5 Outlet6 Tubing connector7 Tube8 Chromatography system9 Movement means9a Beam9b Arm9c Rack10 Compartment11 Opening12 Switch valve13 Chromatography apparatus14 Liquid container

Claims

Claims1. A fraction collector (1 ) for continuously fractionating liquid into liquid containers (14), optionally arranged in cassettes (3), the fraction collector (1 ) comprising a housing (4), a tubing connector (6) for liquid connection to a tube (7) for supplying the fraction collector (1 ) with liquid, at least first and second holders (2) each configured for direct or indirect support of a plurality of liquid containers (14), and at least one outlet (5), optionally a dispensing nozzle, in liquid communication with the tubing connector (6) and for dispensing liquid into the liquid containers (14), wherein the outlet (5) and the first and second holders (2) are housed in the housing (4), and the first and second holders (2) differ as to their vertical position (z), wherein the fraction collector is configured such that liquid is collected in liquid containers (14) at different vertical positions (z) and wherein the fraction collector is arranged such that at least one of the at least first and second holders in which liquid collection is completed can be accessed without interrupting the liquid collection ongoing in the liquid containers in another holder of the at least first and second holders.

2. Fraction collector of claim 1 , wherein the outlet, optionally the dispensing nozzle (5), is a common outlet for dispensing the liquid into the liquid containers (14), supported by the at least first and second holders (2).

3. Fraction collector of claim 1 or 2, further comprising an optionally vertical compartment (10) extending at least between the first and second holders (2) in the vertical direction (z) and connecting the at least first and second holders (2).

4. Fraction collector of any of the preceding claims, wherein the at least first and second holders (2) are moveable in at least the vertical direction (z)5. Fraction collector of any of the preceding claims, wherein the outlet, optionally the nozzle (5), is moveable at least in the vertical direction (z), such that the fraction collector is configured to adapt the vertical position of the outlet (5) to the liquid containers (14) on the at least first and second holders (2).

6. Fraction collector of claim 5, further comprising vertical movement means (9) moveable at least between the first and second holders (2) at least in the vertical direction (z) and directly or indirectly mounting the outlet (5).

7. Fraction collector of claim 6 when claim 5 depends on claim 3, wherein the movement means (9) is positioned in the compartment (10), optionally at a side of the housing (4).

8. Fraction collector of any of the preceding claims, wherein the movement means (9) comprises a robot and / or a substantially vertical rack (9c) for vertical movement of the outlet (5) and an arm (9b) for horizontal movement of the outlet (5).

9. Fraction collector of claim 8, wherein the arm (9b) is moveable in a horizontal plane (xy), the arm (9b) optionally being rotatable for radial movement of the arm (9b) and / or linearly displaceable for linear movement of the arm (9b).

10. Fraction collector of claim 8 or 9, wherein the arm (9b) is horizontally collapsible and configured to reduce its horizontal dimension, such that the fraction collector (1 ) is configured such that the arm (9b) is, in a collapsed state, moveable in the vertical direction (z) within the housing (4), optionally inside the compartment (10) and / or along the rack (9c)11. Fraction collector of any of the preceding claims, wherein the fraction collector further comprises at least first andsecond openings (11 ), optionally doors, for individual access to the first and second holders (2), respectively.

12. Fraction collector of any of the preceding claims, wherein the first and second holders (2) are configured to support two or more cassettes (3) for holding the liquid containers, wherein the holders (2) each receive at least one cassette (3) 13. Use of the fraction collector of any of the preceding claims for chromatography appliances, wherein the liquid fractionated is liquid obtained by chromatography.14 Chromatography system including a chromatography apparatus (13) and a fraction collector (1 ) of any of the preceding claims.

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