WO2000058010A1

WO2000058010A1 - System for washing particles out of a source into a receptacle

Info

Publication number: WO2000058010A1
Application number: PCT/EP2000/002592
Authority: WO
Inventors: David Reginald Harrison; Hunter Douglas Prain; Stephen Ramsey
Original assignee: Smithkline Beecham Plc
Priority date: 1999-03-27
Filing date: 2000-03-22
Publication date: 2000-10-05
Also published as: GB9907036D0; EP1165238A1; JP2002539935A

Abstract

A system for washing particles from for example a plate well (11) or reaction vessel, comprising a reservoir (1) for a washing liquid (2), a tubular conduit (3) along which the washing liquid (2) may flow to a particle washing probe (6) capable of being brought into communication with the well (11) or vessel, the probe (6) being capable of directing a stream of the washing liquid (2) into the well (11) or vessel source container to wash suspended particles from the well (11) or vessel; a particle recovery chamber (14) in communication with the exit conduit (13) into which the stream of washing liquid (2) and particles (26) flows and in which the particles (26) collect and e.g. suction means to drive the washing liquid (2) in a flow direction around the system.

Description

SYSTEM FOR WASHING PARTICLES OUT OF A SOURCE INTO A

RECEPTACLE

This invention relates to a system for washing particles out of a source to a receptacle. In particular the invention relates to a system for washing small polymeric beads from laboratory reaction vessels into a suitable receptacle. In recent years experimental laboratory organic synthetic chemistry has shifted from the use of large scale vessels such as classical flask, beakers etc to the use of small (typically 250 micron diameter or less) polymeric beads on the surface of which reagents are adsorbed and undergo reaction to form a desired product. Such beads are frequently used in combinatorial chemistry. Reactions using these beads are normally performed either in small "wells", typically of 5 ml or less capacity, typically less than 1 cm diameter, a number of such wells (typically 96) being formed in a plastic "plate", or alternatively in specialised reaction vessels adapted for use in large numbers together in an automated laboratory reactor.

Such automated laboratory reactors generally use a large number of small reaction vessels which can be fitted into an automated device which adds reagents and other media to each vessel, and performs other operations such as washing the vessels ant transferring their contents to other receptacles etc., under the control of a computer. The computer stores information relating to the contents of and the reagents etc. added to each such reaction vessel, and can consequently track the product through the system. One such automated laboratory reactor is the so called MYRIAD™ (from Mettler Toledo (GB)) system, which uses reaction vessels which for example typically comprise two small glass chambers linked by a connecting "U" tube, there being a glass sinter filter in the bottom of one of the chambers to retain the beads therein, the chambers having upper mouth openings for connection to the MYRIAD™ system. Other known automated laboratory reactors include the so-called ACT™ and IRORI™ systems

The use of such beads has created its own problems, e.g. those of handling such small beads, transferring them safely to other vessels, and washing them. A further problem is that of cleaning the numerous wells of such plates or the reaction vessels of such automated laboratory reactors after reaction has taken place and the experiment is over. In particular it is difficult to remove all of the residual beads from the wells and vessels. The beads often have specific surface chemical characteristics for the reaction they are used with, and in addition to simple cleanliness, the presence of residual foreign beads from an earlier reaction could introduce contamination of subsequent reactions. Sometimes such wells and vessels have sintered bottoms through which liquids may be passed but which retain beads, and the difficulty of cleaning is made more greater by beads becoming lodged in these sinters. Often it can take a laboratory worker several hours to thoroughly clean the numerous intricate reaction vessels by hand.

Some systems are known for washing reaction vessels such as microtitre well plates, for example as disclosed in EP 0 080 134, WO 87/01616, US 4,496,657 and US 4,493,896.

It is an object of this invention to provide a system which helps to solve these problems, and to provide a washing system which is simple in construction and particularly suitable for automation. Other objects of the invention will be apparent from the following description. According to this invention a system for washing particles from a particle source container to a particle recovery chamber comprises: a reservoir for a washing liquid which is suitable for suspending the particles in; a tubular conduit in communication with the reservoir and along which a stream of the washing liquid may be caused to flow from the reservoir, the conduit having an opening into the reservoir; a particle washing probe in communication with the tubular conduit at a position of the tubular conduit downstream of the opening, the particle washing probe capable of being brought into communication with the particle source container, and being capable of substantially liquid-tight engagement with the particle source container, the probe having an outlet opening for the washing liquid, and being capable of directing a stream of the washing liquid from the outlet opening of the probe into the source container, so as to suspend the particles in the stream of washing liquid, the probe having an exit conduit along which the stream of washing liquid and suspended particles may flow away from the source container; a particle recovery chamber in communication with the exit conduit at a position of the exit conduit downstream of the probe and into which the stream of washing liquid and particles may flow and in which the particles may collect; the system being provided with means to drive the washing liquid in a flow direction from the reservoir into the tubular conduit, into the transfer probe, out of the probe via the exit conduit carrying suspended particles and into the recovery chamber.

Preferred embodiments of the system of the invention are described below.

Preferably a particle receptacle is provided into which particles collected in the particle recovery chamber may be caused to flow from the particle recovery chamber. Preferably the particle recovery chamber is provided with means to allow particles collected therein to be delivered to such a receptacle.

Preferably the source comprises a well in a plate, or a reaction vessel for an automated laboratory reactor, e.g. suitable for a MYRIAD™ automated laboratory reactor, of the type described above, and the probe is adapted to be brought into communication with such a well or reaction vessel.

The reservoir for the washing liquid may be any convenient vessel, for example a beaker, jar or bottle etc., which may be adapted if desired for use with the system of the invention. The reservoir may if desired be covered with a closure to minimise escape, contamination, fire hazards etc. The washing liquid may be any convenient suitably mobile liquid. Organic solvents such as methanol or et-hanol are particularly suitable, and in some cases water may be used.

Preferably over at least part of its length the tubular conduit comprises a flexible tube, e.g. of plastic, the flexibility enabling the probe to which it connects to be moved into position in a desired source container. Parts of the system such as the probe, recovery chamber etc. made of rigid materials such as glass, plastic or metal etc. may be provided with conventional connections to enable such a flexible tube to be connected. The opening of the tubular conduit into the reservoir is preferably at a point below the surface of the washing liquid when such liquid has been introduced into the reservoir, and for example be in or near the bottom of the reservoir. For example the conduit may dip into the reservoir from the upper part of the reservoir and extend to near the bottom of the reservoir. Preferably the probe has an outlet opening for the washing liquid in close proximity to an entrance opening of the exit conduit from the probe so that the particles may easily be washed into the entrance opening by the stream of washing liquid. A suitable construction of the probe is a co-axial or concentric arrangement of an outer and an inner tube, the outer tube communicating with the tubular conduit via which the washing liquid may be introduced into the probe, and the inner tube comprising the exit conduit by which the washing liquid, plus suspended particles, may exit from the probe.

The substantially liquid-tight engagement of the probe with the particle source container enables the washing liquid to enter the particle source container from the exit opening, bring particles in the container into suspension, then exit from the container via the exit conduit with no, or negligible leakage of the washing liquid. The probe is preferably made capable of engaging sealingly with the source, e.g. with the upper opening of a well of a plate, or the mouth opening of a reaction vessel of the type referred to above, by being shaped so as to fit sealingly into the source, e.g. the well or mouth opening in the manner of a plug. For example the outer profile of the probe may be generally conical in shape and of dimensions which enable it to fit plug-like into the opening of the well or the mouth of the reaction vessel. The probe may be provided externally with seal means, e.g. a soft plastic sleeve to enhance the seal between the probe and the source, and such a soft sleeve may also help to protect a glass reaction vessel from damage if the probe is inserted too firmly into the vessel. However in some cases a less than perfect seal between the probe and a source such as a well or a reaction vessel may be advantageous in allowing some entry of air into the well or vessel, which can cause mrbulence within the well or vessel, and this turbulence can help to dislodge beads in the well or vessel.

Preferably the inner tube in a construction where the inner and outer tubes are concentric or coaxial, extends in the longitudinal axis direction beyond the outer tube, so that the outer tube of the probe may engage with the opening of a well or the mouth of a reaction vessel, and the inner tube may extend downwardly into the interior of the well or vessel, e.g. to a point near the bottom of the well or reaction vessel. The specific dimensions of such a probe, e.g. a suitable profile for the conical part, and the distance to which the inner tube extends outside the mouth of the outer tube, will inter alia be determined in practice by the dimensions and shape of the source, e.g. a well or reaction vessel.

It will be appreciated that suitable dimensions and shapes of a probe, e.g. the dimensions of an outer mbe in the above-described concentric arrangement, or the distance to which the inner be extends outside the opening of the outer mbe, may be easily selected to fit any desired source, e.g. well or vessel. The system of the present invention may therefore be provided with a set of interchangeable probes each suitable for a particular use. It is preferred that the probe is moveable from one particle source container to another, e.g. sequentially from one well or reaction vessel to another. This facilitates use of the system of the invention to wash a number of such containers, for example when the containers are arranged in an array such as in a well plate or in an array of reaction vessels, e.g. on a table or arranged in an automated reaction apparams, allowing the probe to be simply moved from one container to the other to wash them sequentially. This also facilitates automation of the system, particularly if the system is controlled by a robot system which is capable of directing the probe to each of an array of containers. For example the position of each of the containers in the array may be stored in the robot's memory, and the robot may be capable of X- Y horizontal movement of the probe to individual containers, and vertical Z axis movement to insert the probe into each required container. The construction of such a robot system is well within the ability of a skilled engineer.

Preferably the particle recovery chamber comprises a vessel into which the exit conduit feeds, suitably via a connection that prevents leakage of the washing liquid. Preferably the exit conduit feeds into an upper part of the particle recovery chamber so that the suspension of liquid and particles collects in the lower part of the vessel. Preferably over at least part of its length the connection between the exit conduit and the particle recovery chamber comprises a flexible mbe, e.g. of plastic, again enabling the probe to be moved into place in a desired source container. The above-mentioned flexible tube of the tubular conduit and the exit conduit of the probe may be bundled together in a parallel track to facilitate movement of the probe. The use of the particle recovery chamber and a separate receptacle in which the particles may be received facilitates settling of the particles m the particle recovery chamber, after which the particles may be delivered to a receptacle in a relatively small quantity of the washing liquid Preferably the means to allow the particles to be delivered to the receptacle comprises a valve means in the particle recovery chamber, preferably in its lower part which when opened allows the liquid and particles to be released from the chamber, and then delivered to the receptacle. Preferably the means to drive the washing liquid comprises a means to apply suction to the particle recovery chamber so as to suck the washing liquid through the above-described flow path For example the system may be constructed so that the "house vacuum" as available in many laboratories is able to suck the washing liquid through the system, or alternatively a commercially available vacuum pump may be used An advantage of the use of suction is that in situations where the source, e g a well or the reaction vessels described above have a filter e g a sinter at their bottom (as is the situation with reaction vessels of the MYRIAD™ system) for example to enable liquid to enter the source through the filter whilst preventing loss of beads, the application of suction through the probe can cause some air or fluid to flow through the filter and to dislodge any beads which have become trapped in the filter However other drive means are not excluded, for example the application of positive pressure to the reservoir

In a preferred embodiment if suction is applied to the recovery chamber, the valve means may comprise a vacuum-sensitive valve, which may be operable by also providing a means to release the vacuum m the system, e g providing a means by which air may be allowed into the system to release the vacuum. Suitable valve means may include a ball valve or a flap valve in which a negative pressure in the recovery chamber holds the valve shut However ball and flap valves may be liable to trap particles such as beads between the ball or flap valve member and the valve seat when they close A preferred type of vacuum-sensitive valve is an "umbrella" valve, by which the application of suction to the chamber keeps the valve closed, but the release of vacuum causes the valve to open and thereby release the particles and washing liquid A suitable construction of "umbrella" valve comprises a conical valve member, with its apex pointing upwards and located external to the low pressure interior of the particle recovery chamber, which engages with a matching, preferably conical, valve seat rim around a downwardly facing opening at the bottom of the chamber, the apex of the cone pointing upwards. Reduced air pressure within the reservoir keeps the cone in place closing the opening, but when the reduced pressure returns toward atmospheric the cone falls out of engagement with the rim, so as to open the opening. The steep conical sides of such a valve member and seat help to prevent particles such as beads from settling on their surfaces and becoming trapped. As will be apparent such a conical valve member will need to be held in a suitable mount to prevent it falling away completely. For example the umbrella valve may have a stem extending from its base, retained slideably in a collar attached at the lower part of the chamber. It may be desirable in such a construction to enclose the umbrella valve stem to prevent particle such as beads from entering the space between the stem and collar and causing jamming of the valve. Other constructions of valve may also be used.

A suitable means to release the vacuum in the system may comprise a simple valve in the connection between the source of vacuum and the recovery chamber by which air may be allowed into the system. Alternatively or additionally a valve may be provided in the wall of the recovery chamber itself, or in the probe, or at other points in the system. Such valves may comprise simple openings provided with openable closures by means of which access into the interior of the system may be gained for cleaning, unblocking (if necessary) etc.

The receptacle may be any convenient location to which the particles may be delivered. Normally the receptacle comprises a container suitable for the particles and for the quantity of washing liquid that will normally accompany them as they leave the particle recovery chamber. The receptacle may for example comprise a beaker, jar, bottle or specially constructed or adapted vessel in a suitable downstream communication with the particle recovery chamber. In a preferred embodiment the receptacle and the washing liquid reservoir are the same vessel, so that the washing liquid may cycle through the system, i.e. leaving the reservoir via the tubular conduit and returning thereto via the delivery means by which the particles and liquid are delivered to the receptacle/reservoir. In such an embodiment it is usually necessary to provide a filter between the delivery means and the tubular conduit to prevent particles entering the conduit. Suitably such a filter may be provided at the opening into the reservoir of the tubular conduit and may comprise a sinter e.g. a glass sinter filter.

It may also be advantageous to provide a means by which a second wash liquid, for example provided from a second, alternative, reservoir, e.g. a container of clean washing liquid or a different washing liquid may be sent through the probe. For example the system of the invention in which the receptacle and the washing liquid reservoir are the same may be provided with means to switch the system to obtain the second washing liquid from the second, alternative reservoir. This may for example be achieved by providing a valve in the tubular conduit between the reservoir and the probe, by means of which the probe may be connected optionally to the reservoir or the alternative second reservoir. It may also be advantageous to include means to stop the flow of wash liquid to the probe, i.e. from the reservoir or the alternative reservoir mentioned above, and preferably to allow air to enter the tubular conduit upstream of the probe, when or shortly before the probe is disengaged from the particle source container. This can have the advantage that loss of residual wash liquid in the probe, which has not yet been removed from the particle source container via the exit conduit, may be avoided. This means may be located in the tubular conduit between the reservoir and the probe, and may be a valve, by means of which air may be introduced and the flow of wash liquid stopped.

In another embodiment of the invention, a plurality of probes as described above may be connected in parallel via suitable manifolds and valve arrangements apparent to those skilled in the art to one or more tubular conduits and exit conduits so that the system may be used to wash a number of sources substantially simultaneously or serially without having to move the probe from one source to another immediately after washing a first source to allow a second source to be washed. Alternatively two or more of such a plurality of probes may be moveable together from one source to another. All of the component parts of the system of the invention may be made of materials commonly used in laboratory apparams, e.g. glass, plastics or metals which are inert relative to the washing liquid, the particles and any substances adsorbed thereon. Soft plastics materials may be particularly suitable for parts of the probe which are likely to come into contact with for example fragile glass reaction vessels, and/ or such parts may be spring loaded to absorb any potentially damaging impact. For example part of the probe, particularly the inner mbe of the above- mentioned concentric mbe probe, may comprise telescopically slideable concentric sleeves, and such sleeves may be spring loaded to absorb such impacts when the probe is inserted into a reaction vessel or well in a plate. The system may be made of separate component parts which are connectable by for example standard laboratory connectors and flexible plastic tubes. The system may of course be adapted for automated operation, and the various valves referred to herein may be electrically operated, e.g. solenoid, valves. In particular automated operation of the system may be linked to the operation of an automated laboratory reactor system.

As further aspects the present invention provides the following:

A system insertable into a vessel or well and able to make a substantially liquid-tight connection with the sides of the mouth of the vessel or well, and provided with a conduit by means of which a transfer liquid may be directed into the vessel or well to wash particles out of the vessel or well, and provided with an exit conduit via which the particles may leave the vessel or well carried by a stream of the washing liquid.

A particle transfer probe adapted for use with the system of the invention.

A method of transferring particles, in particular beads as described above, from a source, particularly a well in a plate as described above, using the system of this invention.

The invention will now be described by way of example only with reference to the accompanying drawings.

Fig. 1 schematically shows the system of the invention and its method of use.

Fig. 2 shows a longitudinal section through the umbrella valve of the system shown in Fig. 1. Fig. 3 schematically shows a reaction vessel as used in a MYRIAD device, and part of a probe.

Referring to Fig. 1 , a system comprises a reservoir 1 being a beaker, and containing a washing liquid 2, being methanol. The beaker 1 may alternatively be a closed vessel, e.g. a covered jar. A mbular conduit 3 extends into the reservoir 1 and has an opening 4 submerged in the liquid 2 and near the bottom of reservoir 1. The opening 4 is provided with a sintered glass filter 5. The part of the conduit 3 which dips into the liquid 2 is a rigid glass mbe with the sinter 5 at its end, and this rigid mbe is connected, using a standard laboratory connector at 3A to a flexible plastic mbe 3B by which the conduit 3 is flexibly continued.

The conduit 3 extends to communicate at 3C with a particle transfer probe 6. This probe 6 comprises two concentric tubes, being an outer mbe 7 and an inner mbe 8. The outer and inner tubes 7, 8 are made of glass, and the probe 6 is integral in construction although it may equally well be made in connectable parts. The outer mbe 7 communicates with the mbular conduit 3, and the inner mbe 8 acts as the exit conduit. The inner and outer tubes 7, 8 have respective openings 9, 10. The inner mbe 7 extends downwardly axially beyond and outside of the opening 10 of the outer mbe 7. The part 6 A of the probe 6 adjacent to the opening 9 is shaped externally into a generally conical shape so that it can fit into and engage sealingly in a male-female relationship with a generally cylindrical well 11 in a plate 12, the well 11 being one of many (not shown) in the plate 12. With the conical part of the outer mbe 7 engaged with the well 11 the lowest part of the inner mbe 8 extends deep into the well 11, the length to which the inner mbe 8 extends beyond the opening 10 so that the opening 9 is near the bottom of the well 11. It will be appreciated that the profile of the part 6A and the length of the inner mbe 8 may be designed such that the probe 6 can engage with other types of source 11, e.g. the mouth openings of reaction vessels, such as MYRIAD™ reaction vessels. Additionally the part of the inner mbe 8 which extends beyond the opening 10 may for example be provided with a soft exterior, for example to prevent damage to a well 11 or reaction vessel in the event of accidental impact.

The exit conduit 8 extends to connect at 8B with an exit mbe 13. The mbe 13 is conveniently a flexible plastic mbe similar to the mbe 3B. Conveniently the mbe 3B and 13 may be bundled together e.g. by clips (not shown) so that they can be handled together as a single conduit line of two parallel plastic tubes to allow the probe 6 to be engaged with a selected well 11 , and moved when desired to another well 11. (In this respect it should be noted that the layout of the system is shown schematically, and the lengths of the various lengths of bing is not to scale, so that for instance the mbe 3B may be similar in length to the mbe 13). Typically the probe 6 may have an outside diameter of 1-2 cm, tapering in the conical region to allow a tight engagement with the well 11. or the mouth of a reaction vessel.

The connections 3C and 8B allow easy disconnection of the probe 6 for e.g. cleaning and/or replacement with another probe having dimensions suitable for another source of the beads, e.g. a different well or vessel.

The mbe 13 leads to a particle recovery chamber 14. Typically the volume of the chamber 14 may be ca. 100-250 ml. The chamber 14 is a generally mbular cylindrical vessel made of glass, and at its upper end has an entry manifold 15 also made of glass, the connection between the chamber 14 and manifold 15 being for example via a standard laboratory glassware fitting. Passing through the manifold 15 is an entry port 16 being a glass mbe opening into the upper part of the chamber 14, and extending outside of the manifold 15 to form a connection at 13A with the flexible exit mbe 13 leading from the probe 6. At its lower end the chamber 14 is provided with an exit opening 17 fitted with an umbrella valve 18, the construction and operation of which is shown in more detail in Fig. 2.

The umbrella valve 18 comprises a conical valve member 27 which engages with a circular valve seat rim 29 around the downwardly facing opening 17 at the bottom of the chamber 14, the apex of the cone 27 pointing upwards. Reduced air pressure within the reservoir 14 keeps the conical valve member 27 in place against valve seat 29 closing the opening 17 as shown in Fig. 2A, but when the reduced pressure returns toward atmospheric the conical valve member 27 falls out of engagement with the rim as shown in Fig 2B, so as to open the opening 17. The conical valve member is held in a suitable mount 32 to prevent it falling away completely. The valve 18 is thus such that if there is a negative pressure within the chamber 14, the external atmospheric pressure keeps the valve 18 closed, but if the pressure within the chamber 14 is at or close to atmospheric the valve 18 opens to allow any content 19 in the chamber to drain out through the opening 17. The umbrella valve 18 is made of plastic e.g. Teflon™ and is fitted by a screw connector to the openings 17.

Positioned immediately below the opening 17 is the reservoir 1, so that when the valve 18 is open the contents 19. comprising beads together with a quantity of the washing liquid drains into the reservoir 1. The reservoir 1 in the construction shown in Fig. 1 therefore also functions as the receptacle for the beads 26.

The manifold 15 is also provided with a connection 20 by means of which a vacuum may be applied to the interior of the chamber 16. The connection 20 is provided with a valve 21 by means of which the interior of the chamber 14 may be connected via outlet 22 to the atmosphere rather than the vacuum source, so as to release the vacuum in chamber 14. and consequently to open the valve 18. The chamber 14 is also optionally provided with an vacuum release valve 23. In its simplest form the valve 23 may simply comprise a side opening closeable by a bung, or in a more sophisticated form may comprise a valve. Opening the valve 23 provides another way to release the vacuum by allowing air to enter the chamber 14 to restore atmospheric pressure therein. Additionally a side opening 23 may provide a convenient access to the chamber 14, e.g. for introduction of washing liquid and clearing blockages etc. The system is also optionally provided with a valve 24, connectable via line

25 to another reservoir (not shown) of a second washing liquid, which may the same or a different washing liquid to the liquid 2. This valve 24 may also be used to stop the flow of washing liquid and to introduce air into the outer mbe 7 of probe 6.

Referring to Fig 3, a typical reaction vessel for a MYRIAD system is shown schematically (overall 40). The vessel 40 comprises two compartments 41, 42 linked at their bottoms by a U mbe 43. In the lower part of one compartment 41 is a sintered glass filter 44. The compartments 41 , 42 have respective mouths 45, 46, formed in a connection head block 47. The lower part of a probe 48 is shown, having an outer mbe 49 with a conical end 410, which can mate sealingly with either of the two mouths 45, 46. The probe 48 has an inner mbe 411 which extends beyond the open lower end of the outer mbe 49. The probe 48 may conveniently be made of plastics materials, particularly the lower end of inner mbe 411 to minimise the risk of damage to vessel 40, which in the case of MYRIAD vessels, can be expensive to replace. The lower end of inner mbe 411 may for example be of a flexible bellows construction (not shown) to enhance its flexibility. Alternatively part of the inner mbe 411 may be provided in the form of telescopically sliding sleeves which are spring loaded relative to each other (not shown) to help to absorb undesirable and potentially damaging impacts between the lower end of the mbe 411 and the vessel 40, e.g. the sinter 44.

In use the system of the invention operates as follows. The system is assembled as described above and as schematically shown in Fig. 1. The reservoir 1 is loaded with a washing liquid 2 such as methanol, with the conduit 3 dipping into the liquid 2 with its opening 4 and the filter 5 immersed in the liquid 2.

The probe 6, 48 is sealingly engaged with a selected well 11 in a plate 12, or with the mouth 45, 46 of a reaction vessel 40, the well 11 or vessel 40 containing small polymeric beads 26 ca. 100 microns in diameter, having been used in a combinatorial chemistry reaction. In the vessel 40 such beads will normally only be intentionally present in compartment 41. The sealing engagement is achieved by inserting the conical end of the probe 6, 48 in a plug fashion into the well 11 or mouth 45, 46.

If present, the valve 22 is closed. The valve 21 is then set to connect the chamber 14 to a vacuum source, and a vacuum is then applied to the chamber 14 via the vacuum connector 20.

The application of a vacuum to the chamber 14 causes suction to be transmitted through the assembly so that the washing liquid 2 is sucked from the reservoir 1 through the filter 5 and along the conduit 3. The vacuum also holds valve 18 closed. The liquid 2 enters the probe 6, 38 passes down the outer mbe 7, 38 and into the well 11 or vessel 40. This flow of liquid washes the beads 26 from the well 11 or vessel 40 into the exit conduit i.e. the inner mbe 8, 411. The seal formed between the probe 6. 8 and the well 11 or mouth 45, 46 ensures that suction is communicated to the interior of the well 11 or compartment 41 or 42. The seal between the probe 6. 48 and the well 11 or mouth 45, 46 may be enhanced if necessary by the fitting of a resilient sleeve (not shown) around the part of the probe 6, 48 which comes into contact with the well 11 or mouth 45, 46. If the well 11 or the reaction vessel 40 has a sintered bottom 43 then the suction applied in this way to the sinter 43 may help to dislodge beads 26 caught in the sinter.

The stream of washing liquid 2 and beads 26 flows up the exit conduit 8, 411 and along the mbe 13 to enter the chamber 14 via the entry port 16. A suspension of beads 26 and liquid 2 collects at 19 in the bottom of the chamber 14, with the beads 26 eventually separating out.

When it is apparent to the user, e.g. by seeing through the glass walls of the chamber 14, that no more beads 26 are being collected in chamber 14, and consequently that well 11 is empty of beads 26, the probe 6 may be lifted out of the well 11 or vessel 40 and inserted into another well (not shown) containing beads. Alternatively, e.g. in an automated system the probe 6 may be inserted into the well 11 or the reaction vessel 40 for a time known in practice (which can be experimentally determined) to be sufficient to clear the well 11 or reaction vessel 40 of beads 26. Additionally or alternatively means (not shown) may be provided e.g. to detect the cessation or diminution of a flow of beads 26 in the conduit 13.

The action of lifting the probe 6, 48 out of the well 11 or the reaction vessel 40 allows air to enter the system via the openings 9, 10 of the probe. The breaking of the vacuum causes the suction of liquid 2 out of the reservoir 1 to stop, and also causes the umbrella valve 18 to open, allowing the liquid 2 and beads 26 in the chamber 14 to fall into the reservoir 1. In some cases removal of the probe 6, 48 from well 11 or a reaction vessel 40 may of itself be sufficient to release the vacuum, but it is preferred to release the vacuum by opening the valve 21 to the atmosphere, or if the valve 22 or 23 is present to open one of these. The use of the valves 21, 22 or 23 in this way is preferred to avoid the formation of an air locks. When the probe 6, 48 is re-inserted in a well 11, or a reaction vessel 40 the vacuum is regenerated throughout the system, so that the suction of washing liquid 2 from reservoir 1 recommences and the above-described process is repeated. The filter 5 allows liquid 2 to pass, but not beads 26, so that the latter accumulate in the reservoir 1 whilst the liquid 2 recycles. It will be apparent that there are alternative ways of operating the system.

For example a separate reservoir 1 and receptacle for the beads leaving the chamber 14 via valve 18 may be used. In such an alternative construction such a receptacle (not shown) may be positioned under valve 18 so that beads and washing liquid 19 drain into the receptacle (not shown) in a manner analogous to the way in which in the illustrated construction they drain into reservoir 1. For example the chamber 14 itself may comprise the receptacle and beads 26 may be collected therein. However this may lose the advantage that the separation of the beads 26 by settlement in chamber 14 before they are drained off via valve 18 into a separate receptacle allows the beads 26 to be collected in a relatively small quantity of wash liquid. If the valve 24 is present, the probe 6 may be connected via line 25 to a reservoir (not shown) of a clean solvent whilst applying suction to probe 6, 48 via conduit 13, so that the well 11, or the reaction vessel 40 may be washed with clean solvent, which ultimately is collected in the reservoir 1. For example each well 11, or reaction vessel 40 may be washed initially with liquid 2 until all the beads 26 are believed to have been removed, followed by a clean solvent wash. If valve 23 is present it may be opened to allow the chamber 14 to be washed with clean solvent to remove any residual beads 26, for example to prevent them becoming lodged in valve 18.

The above described process may be used to sequentially remove beads 26 from d e multiple wells 11 of a plate 12, or from one or more vessels 40 and transfer them to a desired receptacle 1. Beads 26 collected in the receptacle 1 may be disposed of or alternatively and preferably regenerated chemically so that they may be re-used again.

In another mode of use the probe 6, 48 may be inserted into well 11 or vessel 40 without the outer mbe 410, 7 making a seal with the well 11 or mouth 45, 46, i.e. so that air may enter the well 11 or vessel 40, and no suction is applied to the wash liquid. In such a simation material such as liquid, beads etc may be sucked from the well 11 or vessel 40 into chamber 14.

In another mode of use valve 24 is used to shut off the flow of wash liquid and to admit air, shortly before the probe 6. 48 is disengaged from well 11 or vessel 40. The flow of air releases the vacuum which would otherwise hold the probe 6, 48 in place in well 11 or vessel 30, tends to flush liquid out of well 11 or vessel 40, and also helps to clear outer mbe 8, 49 of any washing liquid before the probe 6, 48 is disengaged. This can help to prevent spillage of washing liquid from outer mbe 8, 49 when the probe 6, 48 is disengaged.

Referring to Fig. 2 the construction and operation of the umbrella valve 18 is shown in more detail. The umbrella valve 18 comprises a conical valve member 27 with its apex uppermost, and having a cylindrical valve stem 28. The valve member 27 seals against a circular valve seat 29 having correspondingly conical sides, the valve seat being formed in a valve mounting 30 which is attachable to the opening 17 of the chamber 14 by means of a suitable connector (not shown). At the bottom of the valve mounting 30 is an opening 31. The stem 28 is slideably retained within a collar 32, which is connected to the rim of opening 31 by means of spider legs 33. In Fig. 2A the valve 18 is shown in its closed configuration, with the valve member 27 held by reduced pressure in the chamber 14 in a sealing engagement with valve seat 29. Beads 26 are therefore unable to pass through the valve 18.

As shown in Fig. 2B, when the pressure in the chamber 14 increases as a consequence of air entering the chamber 14, the valve member 27 drops, with its stem 28 sliding in the collar 32, so as to disengage from valve seat 29 and open the valve. The base of the conical member 27 seats on the upper surface of the collar 32. Beads 26 and liquid 19 can then flow through the opening 17 and out through the valve opening 31 between spider legs 33. Around the collar 32 is fitted a seal 34 with its bottom covered by a sinter 35 which prevents beads 26 from becoming caught between the stem 28 and the collar 32. When a vacuum is reapplied to the chamber 14 the conical member 27 returns to the position shown in Fig. 2A.

Claims

Claims.

1. A system for washing particles from a particle source container to a particle recovery chamber which comprises: a reservoir for a washing liquid which is suitable for suspending the particles in; a mbular conduit in communication with the reservoir and along which a stream of the washing liquid may be caused to flow from the reservoir, the conduit having an opening into the reservoir: a particle washing probe in communication with the mbular conduit at a position of the mbular conduit downstream of the opening, the particle washing probe capable of being brought into communication with the particle source container, and being capable of substantially liquid-tight engagement with the particle source container, the probe having an outlet opening for the washing liquid, and being capable of directing a stream of the washing liquid from the outlet opening of the probe into the source container, so as to suspend the particles in the stream of washing liquid, the probe having an exit conduit along which the stream of washing liquid and suspended particles may flow away from the source container; a particle recovery chamber in communication with the exit conduit at a position of the exit conduit downstream of the probe and into which the stream of washing liquid and particles may flow and in which the particles may collect; the system being provided with means to drive the washing liquid in a flow direction from the reservoir into the mbular conduit, into the transfer probe, out of the probe via the exit conduit carrying suspended particles and into the recovery chamber.

2. A system according to claim 1 characterised in that a particle receptacle is provided in communication with the particle recovery chamber and into which particles collected in the particle recovery chamber may be caused to flow from the particle recovery chamber.

3. A system according to claim 2 characterised in that the particle recovery chamber is provided with means to allow particles collected therein to be delivered to the receptacle.

4. A system according to claim 1 characterised in that the probe is adapted to be brought into communication with a well in a plate, or a reaction vessel for an automated laboratory reactor.

5. A system according to any one of claims 1 to 4 characterised by a probe having a co-axial or concentric arrangement of an outer and an inner mbe, the outer mbe communicating with the mbular conduit via which the washing liquid may be introduced into the probe, and the inner mbe comprising the exit conduit by which the washing liquid, plus suspended particles, may exit from the probe.

6. A system according to any preceding claim characterised in that the probe is capable of engaging sealingly with the source by being shaped so as to fit sealingly into the source in the manner of a plug.

7. A system according to claim 6 characterised by the outer profile of the probe being generally conical in shape and of dimensions which enable it to fit plug-like into the opening of the source.

8. A system according to any of claims 5, 6 or 7 characterised in that the inner mbe extends in the longimdinal axis direction outside of the outer mbe through the opening therein.

9. A system according to any preceding claim characterised in that the particle recovery chamber comprises a vessel into an upper part of which the exit conduit connects so that the suspension of liquid and particles collects in the lower part of the vessel.

10. A system according to any preceding claim characterised by a valve means in the lower part of the receptacle which when opened allows the liquid and particles to be released from the chamber.

11. A system according to any preceding claim characterised in that the means to drive the washing liquid comprises a means to apply suction to the particle recovery chamber so as to suck the washing liquid through the flow path.

12. A system according to claim 10 or 11 characterised in that the valve means comprises a vacuum-sensitive valve.

13. A system according to claim 12 characterised in that the vacuum-sensitive valve is operable by a means to release the vacuum in the system.

14. A system according to claim 12 or 13 characterised in that the vacuum- sensitive valve is an umbrella valve, by which the application of suction to the chamber keeps the valve closed, but the release of vacuum causes the valve to open and thereby release the particles and washing liquid.

15. A system according to claim 14 characterised in that the umbrella valve comprises a comcal valve member which engages with a matching conical valve seat rim around a downwardly facing opening at the bottom of the chamber, the apex of the cone pointing upwards.

16. A system according to any one of claims 11 to 15 provided with a valve in the connection between the source of vacuum and the recovery chamber by which air may be allowed into the system.

17. A system according to any one of claims 11 to 16 provided with a valve in the wall of the recovery chamber itself.

18. A system according to any preceding claim characterised in that the receptacle and the washing liquid reservoir are the same vessel.

19. A system according to claim 18 characterised in that the liquid cycles through the system, leaving the reservoir via the mbular conduit and returning thereto via the delivery means by which the particles and liquid are delivered to the receptacle/reservoir.

20. A system according to any preceding claim characterised by a means by which wash liquid from a second, alternative, reservoir may be sent through the probe.

21. A system according to claim 20 characterised by a valve in the mbular conduit between the reservoir and the probe, by means of which the probe may be connected optionally to the reservoir or the alternative reservoir.

22. A system according to any one of the preceding claims characterised by means to stop the flow of wash liquid to the probe, when or shortly before the probe is disengaged from the particle source container.

23. A system according to any preceding claim characterised by a plurality of probes connected in parallel via manifolds and valve arrangements to one or more mbular conduits and exit conduits so that the system may be used to wash a number of sources substantially simultaneously or serially.

24. A system insertable into a vessel or well and able to make a substantially liquid-tight connection with the sides of the mouth of the vessel or well, and provided with a conduit by means of which a transfer liquid may be directed into the vessel or well to wash particles out of the vessel or well, and provided with an exit conduit via which the particles may leave the vessel or well carried by a stream of the washing liquid.

25. A particle washing probe adapted for use with the system as claimed in any one of the preceding claims.

26. A method of transferring particles from a source to a receptacle using a system as claimed in any one of claims 1 to 24.