Flow control apparatus for sample fluids

Abstract

A flow control apparatus for facilitating treatment of a fluid containing a sample for analysis, includes: a body having spaced ends and defining a fluid flow passage arrangement that extends between the ends. The fluid flow passage arrangement includes two flow paths that are configured in parallel, merge within the body at least once, and respectively contain a one-way check valve and a medium selected to treat or modify sample-containing fluid flowing therethrough.

Claims

1. A flow control apparatus for facilitating treatment of a fluid containing a sample for analysis, comprising: a body having spaced ends, and the body defines therein a fluid flow passage arrangement extending between said ends; the fluid flow passage arrangement including two flow paths that are configured in parallel, and respectively contain a one-way check valve and a medium selected to treat or modify sample-containing fluid flowing therethrough, the medium having a fluid input side and a fluid output side, the one-way check valve having a fluid input side and a fluid output side, and the apparatus configured so as to substantially prevent fluid flow into the fluid output side of at least one of the medium and the one-way check valve, wherein the fluid flow passage arrangement is configured such that the two flow paths are merged to form a common flow path on the fluid input side of the one-way check valve and the fluid output side of the medium, and wherein the fluid flow passage arrangement is configured such that the two flow paths are merged to form a fluid reservoir on the fluid output side of the one-way check valve and the fluid input side of the medium, and wherein the fluid flow passage arrangement is configured such that: (i) upon aspiration of a fluid through the common flow path in a direction toward the two flow paths, the one-way check valve opens to allow the fluid to pass from the input side to the output side of the one-way check valve, and the fluid is substantially prevented from flowing through the medium, and (ii) upon ejection of a fluid from the fluid reservoir toward the common flow path, the one-way check valve closes, to allow the fluid to pass from the input side to the output side of the medium, and the fluid is substantially prevented from flowing through the one-way check valve.

2. The flow control apparatus according to claim 1, wherein said flow paths open separately from one of said ends of said body at spaced ports.

3. The flow control apparatus according to claim 1, wherein said one-way check valve is a plug seal valve.

4. The flow control apparatus according to claim 3, wherein said plug seal valve includes an integral seal plug having respective axially adjacent portions of relatively larger and smaller cross-section, the latter defining a peripheral sealing surface that engages a complementary female surface, and the former defining a shoulder that biases the one-way check valve closed under pressure of the fluid.

5. The flow control apparatus according to claim 4, wherein the portions of relatively larger and smaller cross-section are generally cylindrical and: (i) the ratio of the diameter of the portion of larger cross-section to the diameter of the portion of smaller cross-section is in the range 2 to 4, and (ii) the ratio of the combined length of both portions to the length of the portion of smaller cross-section is in the range 1.25 to 2.5.

6. The flow control apparatus according to claim 1, wherein said medium has ends spaced along its respective passage and frits or sorbent terminations are provided at one of both of said ends of the medium.

7. The flow control apparatus according to claim 1, wherein said medium is a sorbent bed selected to trap targeted compounds from said fluid as it passes through the sorbent bed, for subsequent recovery from the bed by an elution solvent.

8. The flow control apparatus according to claim 7, wherein the sorbent bed is a solid stationary phase bed, for practising Solid Phase Extraction (SPE) or Micro Extraction by Packed Solvent (MEPS) of the targeted compounds.

9. The flow control apparatus according to claim 1, wherein said medium is selected from the group comprising filtering media, monoliths and immobilised biologically active materials.

10. The flow control apparatus according to claim 1, mounted within a barrel of a syringe, wherein said merged paths form a single duct communicable with a needle for the syringe, and said flow paths open separately into the interior chamber of said barrel.

11. The flow control apparatus according to claim 1, provided as a separate unit attachable on the front of a syringe.

12. A syringe assembly for facilitating treatment of a fluid containing a sample for analysis, comprising: a syringe barrel and a complementary plunger; and a flow control apparatus in communication with a chamber defined by the barrel and the plunger, the flow control apparatus comprising: a body having spaced ends, and the body defines therein a fluid flow passage arrangement extending between said ends; the fluid flow passage arrangement including two flow paths that are configured in parallel, and respectively contain a one-way check valve and a medium selected to treat or modify sample-containing fluid flowing therethrough, the medium having a fluid input side and a fluid output side, the one-way check valve having a fluid input side and a fluid output side, and the apparatus configured so as to substantially prevent fluid flow into the fluid output side of at least one of the medium and the one-way check valve, wherein the fluid flow passage arrangement is configured such that the two flow paths are merged to form a common flow path on the fluid input side of the one-way check valve and the fluid output side of the medium, and wherein the fluid flow passage arrangement is configured such that the two flow paths are merged to form a fluid reservoir on the fluid output side of the one-way check valve and the fluid input side of the medium, and wherein the fluid flow passage arrangement is configured such that: (i) upon aspiration of a fluid through the common flow path in a direction toward the two flow paths, the one-way check valve opens to allow the fluid to pass from the input side to the output side of the one-way check valve, and the fluid is substantially prevented from flowing through the medium, and (ii) upon ejection of a fluid from the fluid reservoir toward the common flow path, the one-way check valve closes, to allow the fluid to pass from the input side to the output side of the medium, and the fluid is substantially prevented from flowing through the one-way check valve.

13. The syringe assembly according to claim 12, wherein said one-way check valve is arranged to substantially prevent flow along the flow path containing the one-way check valve.

14. The syringe assembly according to claim 12, wherein said flow paths open separately into said chamber.

15. The syringe assembly according to claim 12, wherein said one-way valve is a plug seal valve.

16. The syringe assembly according to claim 15, wherein said plug seal valve includes an integral seal plug having respective axially adjacent portions of relatively larger and smaller cross-section, the latter defining a peripheral sealing surface that engages a complementary female surface, and the former defining a shoulder that biases the one-way check valve closed under pressure of the fluid.

17. The syringe assembly according to claim 16, wherein the portions of relatively larger and smaller cross-section are generally cylindrical and: (i) the ratio of the diameter of the portion of larger cross-section to the diameter of the portion of smaller cross-section is in the range 2 to 4, and (ii) the ratio of the combined length of both portions to the length of the portion of smaller cross-section is in the range 1.25 to 2.5.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The invention will now be further described, by way of example only, with reference to the accompanying drawings, in which:

(2) FIG. 1 is an axial cross-section of a flow control apparatus according to an embodiment of the invention, in the form of a check valve cartridge fitted in the end of a syringe barrel;

(3) FIG. 2 is a cross-section on the line 2-2 in FIG. 1;

(4) FIG. 3 is a three-dimensional view of the valve plug of the plug seal check valve in the embodiment of FIGS. 1 and 2;

(5) FIG. 4 is a partially sectioned alternative embodiment in which the check valve cartridge is a separate attachable unit for mounting on the front of a syringe;

(6) FIG. 5 is a further alternative embodiment with a different configuration of passages within the body of the check valve cartridge;

(7) FIG. 6 depicts the four operational states (A to D) of the check valve cartridge of FIGS. 1 and 2 during the operation of a syringe for an SPE application;

(8) FIG. 7 is a graph illustrating the elution profile and carryover for a target compound in an SPE application, the graph also showing, for comparison purposes, a standard elution profile and carryover in a MEPS application.

(9) FIG. 8 is an axial cross-sectional view of a pipette tip incorporating a flow control apparatus similar to the embodiment of FIG. 1; and

(10) FIG. 9 is an axial cross-sectional view of a further embodiment in which the one-way valve is a ball valve.

DESCRIPTION OF EMBODIMENTS OF THE INVENTION

(11) The syringe assembly 10 illustrated in FIGS. 1 and 2 includes a tubular syringe barrel 12 of annular cross-section, a reciprocable plunger 14, and a forwardly projecting hollow syringe needle 16. The front end of barrel 12 has a return lip 13 that locates a flow control apparatus in the form of a check valve cartridge 20. Cartridge 20 may be a press fit in the end of the barrel or otherwise secured in position, eg with adhesive.

(12) Cartridge 20 comprises a generally cylindrical body 22 of a suitable inert material having spaced ends comprising end-faces 24,25. The body 22 is moulded or machined to define therein a fluid flow passage arrangement 30 extending between end-faces 24,25.

(13) Passage arrangement 30 includes an axially extending bore 32 in body 22 of uniform diameter dimensioned to receive, in a press fit, syringe needle 16. This bore 32 opens at end-face 24, which abuts the return lip 13 of the front of syringe barrel 12. Passage arrangement 30 is completed by a pair of flow paths 34,36 in body 22 that are configured in parallel, merge within body 22 into the inner end of bore 32, and open separately at end-face 25 at respective ports 35,37. Flow paths 34,36 thereby communicate the interior of syringe needle 16 with the interior of syringe barrel 12 in a parallel flow arrangement.

(14) Each flow path 34, 36 comprises a first duct portion 34a,36a extending parallel to the axis 11 of the syringe barrel and needle, a second duct portion 34b,36b extending radially to link portion 34a,36a to bore 32, and an enlarged chamber portion 34c,36c that respectively contains a one-way check valve 40 and a medium 50 selected to treat or modify fluid flowing through the medium.

(15) In this embodiment, one-way check valve 40 is a plug seal valve including a valve plug 42 as shown in FIG. 3. Valve plug 42 is an integral moulding in a suitable rubber and consists of a first portion 44 of larger cross-section and a second portion 46 of smaller cross-section. In this case, plug portions 44,46 are solid coaxial cylinders. Larger plug portion 44 defines a cylindrical surface for seating and sealing the valve onto a cone sealing seat 45 at the junction between the chamber portion 36c and the axially parallel duct portion 36b of flow path 36. Smaller diameter portion 46 of the valve plug 42 provides a tail that defines a shoulder 47 by which the plug is biased closed onto the cone seat by fluid pressure.

(16) It has been found that there are optimum dimensions for the diameter and length of the two cylindrical portions of the valve plug to obtain optimum operation. The larger diameter portion 44 effects pressure differential for sealing and aspiration back pressure. Its length ensures that the plug remains parallel in the valve during operation. The relative diameter of the smaller portion 46 determines spring) force and its length will effect the normally closed position of the valve. The valve must allow opening (flow) at low differential pressures to ensure that sample is not drawn into the sorbent bed during aspiration. Conversely the valve ideally allows sealing during dispensing at very low flowrates (low differential pressure) to enable a wide range of applications

(17) Adopting a and c as the respective diameters of the smaller and larger portions 44,46,b as the overall length of the plug and d as the length of the larger diameter portion, the ratio c/a is conveniently in the range 2 to 4 while the ratio b/d is conveniently in the range 1.25 to 2.5. One example of an effective set of dimensions is c=1 mm, a=0.4 mm, b=4 mm and d=2.5 mm.

(18) A suitable material for the plug 42 is a silicone rubber. Rubber hardness and constitution should be chosen to combine low flow rate sealing with chemical inertness so as not to interfere with, contaminate or absorb compounds from the sample fluid. A suitable material is a 40 duran hardness fluorosiloxane chosen for softness and chemical resistance.

(19) The check valve depicted in FIGS. 1 to 3 has been found to perform reliably in flow rates ranging from 20 L/min to 5 mL/min. Operation of the valve and flow paths were checked using dye solutions under a microscope. The plug seal valve also showed acceptable opening pressure, resulting in minimal back flow into the sorbent bed 50. The valve reliably closed immediately on liquid dispensing to ensure that substantially no sample was lost.

(20) Medium 50 is typically a media bed that may comprise or contain but is not limited to SPE packing materials, SPE disks, sorbents, filtering media, monoliths and immobilised biologically active materials. Medium 50 is retained in chamber portion 36c of flow path 36 between frits or sorbent terminations 52,53, one of which is flush with the end face 25 of the valve cartridge body.

(21) It will be appreciated that check valve cartridge 20 can alternatively be provided as a separate self-contained unit 120 that can be attached on the front of a syringe, as illustrated in FIG. 4. In this arrangement, cartridge body 122 has a two-part body and is fitted within an outer housing 160 which is press fitted or screw threaded onto a syringe end fitting 162. Bore 132 can receive the syringe needle 116 as before, while housing 160 and fitting 162 include an axially located duct arrangement communicating flow paths 134, 136 with the interior of the syringe barrel. Additional radial grooves are provided in the end face 125 of body 122 to provide fluid communication between this duct arrangement and the flow paths 134, 136.

(22) It will also be understood that the parallel flow paths, one-way check valve and treatment medium can be incorporated into a single piece plastic moulded, machined or 3D printed syringe barrel.

(23) FIG. 5 illustrates a further embodiment in which body 220 is a single piece and flow path 234 is co-axially aligned with bore 232.

(24) The particular operational advantage of the illustrated embodiment is that when the syringe plunger is retracted to aspirate fluid into the syringe through needle 16, the reduced pressure in the syringe opens valve 40, 140, 240, and there is then sufficient restriction to flow through the media bed 50 to substantially prevent any flow through the bed when the valve is open. On the other hand, once the fluid has been drawn into the syringe and the plunger of the syringe is depressed, the check valve defaults to its closed position, assisted by the pressure generated in the syringe barrel by the back pressure due to restriction of flow through the media bed. With the valve closed, the dispensed fluid will flow only through the bed to exit through the needle of the syringe.

(25) A typical operational flow sequence will now be described, with reference to FIGS. 6A to 6D, for an application where the media bed is an SPE medium chosen to trap targeted compounds from a sample liquid onto the bed. Drawback of the syringe plunger 14 opens the valve 40 and aspirates sample liquid into the barrel chamber 15 via flow path 34. The liquid does not pass through the medium or bed 50 (FIG. 6A). When the plunger 14 is depressed to close the valve, the sample is directed out through the sorbent bed 50, trapping targeted compounds on the bed (FIG. 6B). After brief contact with rinse fluid in the syringe needle, the syringe assembly is then moved to access an elution solvent. Here drawback of the syringe plunger 14 again opens the valve 40 and allows elution solvent to enter the barrel without traversing the sorbent bed (FIG. 6C). Finally, the plunger 14 is depressed to close the valve and solvent is directed through the sorbent bed 50, eluting the trapped compounds as it passes (FIG. 6D).

(26) It will be appreciated that fraction collection and multiple solvent elution operations are also feasible.

(27) Because the aspiration steps draw fluid through the check valve path and only the dispensing steps force fluid through the medium path, the reason for a minimum particle size restriction in media beds is removed. This permits the use of smaller particle sized media, for example down to as little as 1 micron diameter. The advantage of smaller media particle size is much higher compound capacity before saturation/breakthrough occurs and a much narrower band of eluted compound. The result is a nearly true chromatographic separation. The higher sample concentration in the elution band gives much greater sensitivity for analytical analysis.

(28) These outcomes are illustrated in the graph of FIG. 7, which depicts an experimental SPE elution profile and SPE carryover for the embodiment of FIGS. 1 and 2 in comparison to the standard MEPS solution profile and MEPS carryover.

(29) With the increased capacity and single directional flow of the sample through the bed the targeted compounds are focused in a narrow band at the top of the bed and when they are eluted with the elution solvent, the sample components can come off in a very narrow band or in a small volume. This small elution volume means the concentration of the targeted sample compounds can be very high, in fact higher than conventional SPE and even MEPS. This eliminates the need to concentrate the sample ready for analysis as is always necessary in conventional SPE.

(30) For example, it has been demonstrated that 10 ml of sample can be processed down to 10 microliters of eluent containing the targeted compounds. This is a concentration factor of 1000:1 and can be achieved in minutes.

(31) The flow characteristics of the device are such that there is minimal dead volume and good Gaussian elution profiles of the sample compounds can be achieved from the SPE cartridge.

(32) The cleaning of a syringe, particularly in an automated system, is limited to filing and dispensing solvent multiple times. Conventionally, with each cycle of filling and dispensing, materials in the syringe flow path are diluted. With this check valve design, there is a one direction flow at all times through the areas of the syringe where contamination can occur, so the process is a purge of the syringe which is far more efficient cleaning process than repeated dilutions.

(33) While originally designed for SPE applications, the ability to use small particle sorbent materials enables the check valve cartridge to be used as a pseudo liquid chromatography column where partition separation can be altered for various SPE media.

(34) Combined with an automated system, the configuration of the invention can be programmed to elute and collect defined partition bands for concentration or targeted pre-analytical separation.

(35) Often a liquid chromatography system is used as the sample preparation step for mass spectrometry involving specialised high pressure solvent delivery systems and valving systems. There are some sample analysis types where a syringe with a check valve cartridge as illustrated with SPE media can perform the same function as the sophisticated LC system.

(36) FIG. 8 illustrates a further embodiment generally similar to that of FIGS. 1 and 2, but with a ball valve 440 as the one-way check valve. Other possible forms of the check valve include, without limitation, flap valves, duck bill valves, and umbrella valves.

(37) FIG. 9 illustrates how the inventive concept is readily extendable to a disposal pipette 510 tip. Such tips can have a variety of volumes, materials and shapes, and can subsequently be used on a standard or modified pipettor. Again, after the fluid has been drawn into the barrel side 512 of the tip, the pipettor is depressed, the check valve 540 defaults to the closed position assisted by the pressure generated in the syringe component by the back pressure due to restriction of flow through the media bed 550. With the valve closed, the dispensed liquid from the pipettor tip can only flow through the media bed 550 and exit through the tip outlet 500.