Method for separation of radioactive sample using monolithic body on microfluidic chip

Abstract

The present invention relates to monolithic bodies, uses thereof and processes for the preparation thereof. Certain embodiments of the present invention relate to the use of a monolithic body in the preparation of a radioactive substance, for example a radiopharmaceutical, as part of a microfluidic flow system and a process for the preparation of such a monolithic body.

Claims

1. A process for separating an analyte from a radioactive sample, comprising: eluting the radioactive sample comprising the analyte through a chromatographic monolithic body, wherein: the chromatographic monolithic body is hermetically sealed within a polymer housing; the polymer housing comprises an inlet and an outlet and is prepared by molding a polymer around the chromatographic monolithic body; the chromatographic monolithic body, inside of the housing, is incorporated onto a surface of a microfluidic chip; the chromatographic monolithic body is selected from an inorganic monolithic body comprising functionalized silica and a normal phase monolithic body; and the microfluidic chip is part of a microfluidic flow system.

2. The process according to claim 1 wherein the inorganic monolithic body comprising functionalized silica is selected from: a cation exchange monolithic body; an anion exchange monolithic body; and a reverse phase monolithic body.

3. The process according to claim 1 wherein the inorganic monolithic body has a length of from 10 mm to 80 mm and a diameter of from 3 mm-5 mm.

4. The process according to claim 1 wherein the inorganic monolithic body has a length of from 10 mm to 80 mm and a width of from 2 mm-6 mm.

5. The process according to claim 1 wherein the radioactive sample is added to the inorganic monolithic body in a volume of 10 nl-100 ml.

6. A process for preparing a radiopharmaceutical, comprising: i) concentrating a radioisotope; ii) synthesizing the radiopharmaceutical; iii) purifying the radiopharmaceutical; and iv) analyzing the radiopharmaceutical; wherein at least one of steps i), ii) iii), and iv) comprises a process according to claim 1.

7. The process according to claim 6 wherein step i) is a process according to claim 1, the analyte is a radioisotope selected from [.sup.18F]fluoride, and [.sup.68Ga]gallium, or [.sup.68Ga] cation, and the radioactive sample is a radioactive solution produced from a cyclotron or a decay generator.

8. The process according to claim 6 wherein step ii) is a process according to claim 1, the analyte is a radiopharmaceutical precursor or protected form thereof and the radioactive sample is a reaction mixture.

9. The process according to claim 6 wherein step iii) is a process according to claim 1 and the analyte is a radiopharmaceutical selected from .sup.18F-FLT ([.sup.18F]fluorothymidine), .sup.18F-FDDNP (2-(1-{6-[(2-[.sup.18F]fluoroethyl)(methyl)amino]2-naphthyl}ethylidene)malonitrile), .sup.18F-FHBG (9-[4-[.sup.18F]fluoro-3-(hydroxymethyl)butyl]guanine or [.sup.18F]penciclovir), .sup.18F-FESP ([.sup.18F]fluoroethylspiperone), .sup.18F-p-MPPF (4-(2-methoxyphenyl)-1-[2-(N-2-pyridinyl)-p-[.sup.18F]fluorobenzamido]ethylpiperazine), .sup.18F-FDG (2-[.sup.18F]fluoro-2-deoxy-D-glucose), .sup.18F-FMISO ([.sup.18F]fluoromisonidazole) and .sup.18F-sodium fluoride.

10. The process according to claim 6 wherein step iii) is a process according to claim 6, the analyte is an impurity and the radioactive sample is a solution of radiopharmaceutical.

11. The process according to claim 10 wherein the impurity is selected from .sup.18F and endotoxin, and the inorganic monolithic body is a normal phase monolithic body.

12. The process according to claim 10 wherein the impurity is selected from acetylated [.sup.18F]FDG, acetylated [.sup.18F]FDM (fluoro-2-deoxy-D-mannose), acetylated ClDG (2-chloro-2-deoxy-D-glucose), mannose triflate and K222 (Kryptofix 2.2.2), and the inorganic monolithic body is a reverse phase monolithic body.

13. The process according to claim 10 wherein the impurity is selected from K222 and sodium hydroxide, and the inorganic monolithic body is a cation exchange monolithic body.

14. The process according to claim 10 wherein the impurity is selected from hydrochloric acid and a complexed metal radioisotope, and the inorganic monolithic body is an anion exchange monolithic body.

15. The process according to claim 6, wherein: step iii) is a process according to claim 1; the analyte is selected from [.sup.18F]fluoride, [.sup.18F]acetylated-FDG and [.sup.18F]FDG; and the inorganic monolithic body is selected from a reverse phase monolithic body and a normal phase monolithic body.

16. The process according to claim 6, wherein: step iii) is a process according to claim 1, and the analyte comprises [.sup.18F]fluoride, [.sup.18F]acetylated-FDG and [.sup.18F]FDG which are separated from each other by the inorganic monolithic body.

17. The process according to claim 6, wherein: step iii) is a process according to claim 1, and the analyte comprises [.sup.18F]FDG and [.sup.18F]FDM which are separated from each other by the inorganic monolithic body.

18. The process according to claim 6 further comprising, after concentrating the radioisotope, activating the radioisotope.

19. The process according to claim 18, wherein the radioisotope is activated by solvent exchange.

20. The process according to claim 6, wherein the radiopharmaceutical is synthesized by labeling a non-radioactive analogue of the radiopharmaceutical with the radioisotope.

Description

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

Brief Description of the Drawings

(1) Certain embodiments of the present invention will now be described herein, by way of example only, with reference to the accompanying non-limiting examples and drawings in which:

(2) FIG. 1 is an image of a monolithic body made according to certain embodiments of the present invention.

(3) FIG. 2 illustrates a mould for injection moulding for the preparation of a monolith module.

(4) FIG. 3 illustrates a mould for the preparation of a monolithic body.

(5) FIG. 4 illustrates a monolithic module comprising 2 monolithic bodies.

(6) FIG. 5 illustrates part of a microfluidic flow system comprising a monolithic module.

(7) FIGS. 6A and 6B illustrates a microfluidic chip for quality control comprising a monolithic module.

(8) FIG. 7 is a schematic diagram of a microfluidic system. The monolith is indicated by “deprotection”.

(9) FIG. 8A is an image of a monolithic module according to certain embodiments of the present invention. The monolith is encased in silicone within a mould. As shown in FIG. 8, the monolith is located in a mould and comprises tubing leading to and exiting the monolith.

(10) FIGS. 8B and 8C illustrate a cross section of three embodiments of a monolithic body having a double coating; and

(11) FIGS. 9A and 9B illustrates a microfluidic chip for quality control comprising a monolithic body according certain embodiments.

(12) In the Figures, like reference numerals refer to like parts.

(13) In order to incorporate an inorganic monolithic body into a microfluidic flow system for the separation of an analyte from a radioactive sample, the inventors have developed a process for preparing a monolithic module. Previously, a monolithic body could be prepared by a sol-gel process directly within a microfluidic channel or by heat shrink wrapping in PTFE for insertion into a microfluidic channel. However monolithic bodies prepared using prior art processes are often inconsistent in size and/or shape. The process developed by the inventors yields a monolithic module that can be easily and conveniently incorporated into a microfluidic flow system. The process is advantageous because the resulting monolithic modules and monolithic bodies contained therein have a consistent size and shape. The monolithic bodies prepared in this way are of a consistent size and shape and are hermetically sealed (except for the inlet and outlet) thus ensuring that the sample passes through the pores of the monolithic body and not along its outer interface of the monolithic body.

(14) A monolithic body may be prepared for example as described herein (see example 1) using a mould as illustrated in FIG. 3. The monolithic body may be functionalised as appropriate according to its intended use. Methods for monolith functionalisation are known in the art, examples of which are described herein (see example 2).

Example 1: Preparation of Monolithic Body

(15) A mould was designed using SolidWorks software which was also used to program the CNC machine. The CNC machine was then used to mill the mould out of PTFE. 0.282 g polyethylene oxide (PEO) was added to a 50 mL falcon tube and cooled with ice. 2.58 mL nitric acid (1 N) was added and the mixture stirred. 0.29 mL water was then added and the mixture left for 1 hour maintaining cooling. After 1 hour, 2.26 mL tetraethyl orthosilicate (TEOS) was added and stirring and cooling continued.

(16) The PTFE mould (see, for example, as illustrated in FIG. 3) in two halves was put together in a holder and heated at 40° C. for 1 hour, after which the holder was tightened to ensure no leakage. After 1 hour of stirring, the PEO/TEOS mixture was injected into the mould ensuring the mould was filled and all air escaped. A clamp with a parafilm layer was placed against the mould inlets and tightened to seal the mould, and the whole apparatus heated to 40° C. for 72 hours. After this time, the clamp was removed and the two halves of the mould carefully separated.

(17) The monolithic body formed in the mould was removed from the mould, rinsed with water and then soaked in water for 24 hours with regular replacement of the water to ensure the monolithic body was well washed.

(18) The silica-based monolith shows nanopore diameter of 16 nm, nanopore volume 0.7 cm.sup.3/g, and specific surface area 209 m.sup.2/g.

(19) The monolithic body was added to a mixture of 40 ml water and 10 ml ammonium hydroxide (5 M) and the mixture heated for 16 hours at 90° C. under reflux. After this time, the monolithic body was removed from the mixture and placed in water. The water was replaced regularly for the next 8 hours, after which the monolithic body was dried at 40° C. Finally the monolithic body was heated to 550° C. in a furnace for 3 hours. When cool the monolithic body was ready for use.

(20) For further details on the preparation of silica monoliths please see P. D. I. Fletcher, S. J. Haswell, P. He, S. M. Kelly, A. Mansfield, J Porous Mater. 2011, 18, 501.

Example 2: Functionalization of Monolithic Body

(21) 2.a. Preparation of Cation-Exchange Monolithic Body

(22) The desired amount of 3-mercaptopropyltrimethoxysilane is added to a solution containing 10 mL ethanol and 10 mL water, followed by the addition of a silica monolith. The mixture is refluxed overnight. The monolith comprising thiol surface groups is recovered and washed with water to remove unreacted reagents. The obtained silica monolith is oxidized by reaction with 10 mL hydrogen peroxide (30%) in 10 mL water and 10 mL methanol overnight at 60° C. The monolith is recovered and washed with water, and treated with 10 mL of 1 M H.sub.2SO.sub.4. The sulfonic acid modified monolith is washed with water and dried at 60° C. overnight.

(23) This cation-exchange monolith shows a CEC (cation exchange capacity) of 181 peq/g.

(24) 2.b. Preparation of Anion-Exchange Monolithic Body

(25) The desired amount of silica monolith is added to anhydrous toluene. To this is added a solution containing 0.12 mL methyltrichlorosilane and 0.3 M 3-chloropropyltrichlorosilane in anhydrous toluene. The reaction is conducted at 80° C. under nitrogen atmosphere for 24 hours. After this, the monolith is recovered and washed with dichloromethane, methanol, water and methanol to remove unreacted reagents and then dried at 60° C. overnight. Following this, the monolith is treated with N,N-dimethylethanamine in DMF at 80° C. for 24 hours to form positively charged groups on the surface of the silica monolith.

(26) 2.c. Preparation of Reverse Phase Silica Monolith

(27) The desired amount of silica monolith is added to a solution of 1.57 mmol octadecyltrimethoxysilane in toluene. The reaction is conducted at 80° C. overnight. The monolith is recovered and washed with toluene and dried at 60° C. overnight.

(28) For further details on the functionalization of silica monoliths please see C. S. Gill, B. A. Price, C. W. Jones, J Catal. 2007, 251, 145 or C. R. Silva, C. Airoldi, K. E. Collins, C. H. Collins, LCGL North America 2004, 22, 632.

Example 3: Synthesis of Silicon Nitride, Silicon Imido Nitride and Silicon Silicon Imide Monolithic Bodies

(29) Details for the preparation of certain silicon nitride materials can be found in WO 2006/046012 which describes a sol-gel procedure for the preparation of materials based on silicon nitride and silicon oxynitride. Monolithic bodies comprising silicon imido nitride, silicon imide and/or silicon nitride and processes for their preparation are disclosed in WO 2013/054129. Monolithic bodies comprising silicon imido nitride, silicon imide and/or silicon nitride as described herein can be prepared according to the preparation procedures described in WO 2006/046012 and WO 2013/054129.

(30) Silicon diimide mesoporous gel is optionally partially pyrolysed to form a silicon imido nitride, or completely pyrolysed to form a silicon nitride ceramic material.

Example 4: Preparation of Monolithic Module

(31) 4.1 Preparation of Monolithic Module Using a Two Mould Process

(32) Once functionalised, the monolithic body must be hermetically sealed to ensure that, when administered, fluid flows through the monolithic body and not around the monolithic body, for example at the interface between the monolithic body and housing. This can be achieved by forming a monolithic module according to an aspect of the invention. In particular, the monolithic body may be placed in the first of two moulds as shown in FIG. 2 with half of the monolithic body held in a recess (31). The monolithic body is secured in place by a protrusion (32) at each end of the monolithic body which extends to the centre of the primary axis of the monolithic body and remains in contact during a first moulding step. Molten polymer is injected into the first mould and allowed to set forming a first module part over the monolithic body. This resulting first module part with integrated monolithic body is placed in a second mould with the module surface opposite the monolithic body and module sides held within a recess. Molten polymer is injected into this second mould over the exposed monolithic body surface and bonds to the surface of the first module part. After setting, the complete monolithic module is annealed in a furnace. Inlet and outlet holes (41) can be moulded into the monolithic unit during the moulding process or may be machined into the monolithic module. A monolithic module prepared by this process (FIG. 4) comprises a monolithic body (42) which is hermetically sealed except for the inlet and outlet (41).

(33) 4.2 Preparation of a Monolithic Module Comprising a Silicone Moulding

(34) MDX4-4210 biomedical silicone was prepared by mixing 1 part of curing agent with 10 parts by weight of base elastomer. The mixture was then exposed to a vacuum of about 710 mm Hg for approximately 30 minutes to remove any trapped air from the silicone. A monolithic module was prepared by moulding MDX4-4210 biomedical silicone around a monolithic body. A monolithic body was placed in a mould and positioned such that there was a distance of at least 1 mm from the surface of the monolithic body to the surface of the mould. The mould was provided with air holes to release air trapped within the uncured silicone. The mould was also provided with holes for tubing which tubing held the monolithic body in place and allowed for adjustment of the monolithic body within the mould (see FIG. 8).

(35) The silicone mixture was added to the mould to completely cover the monolith and also the tubing provided within the mould and cured at 55° C. for 2 hours.

(36) The resulting module was found to comply with leakage and stability requirements at a flow rate of 1 ml/min. Chemical compatibility was observed with acetonitrile and sodium hydroxide. No volume change was observed following immersion of the module in acetonitrile for 20 hours at 24° C. Volume changes following immersion in sodium hydroxide were observed as follows: +9% volume increase at 50% concentration for 7 days at 70° F. −2% volume increase at 20% concentration for 7 days at 70° F. +1.2% volume increase at 20% concentration for 3 days at 212° F.

Example 5: Use of Monolithic Body to Isolate .SUP.68.Ga

(37) A cation exchange monolith has been used to quantitatively trap and recover .sup.68Ga from a decay generator. Use of a commercial cation exchange resin has only recovered about 50% .sup.68Ga.

(38) An aqueous radioactive substance for example .sup.68Ga solution is passed through a cation-exchange monolith column so that the .sup.68Ga is trapped on the monolith. The monolith is then washed with organic based solution and the column eluted with a small volume of organic based solution to release at least 95% .sup.68Ga.

(39) By addition of the required reagent i.e. DOTA, NOTA or DTPA to the obtained .sup.68Ga solution, excellent labelling yield can be obtained, for example 99% for DOTA (20 μM DOTA, 95° C., 10-20 min), 99% for NOTA (100 μM NOTA, room temperature, 10 min), and 96% for DTPA (20 μM DTPA, 95° C., 20 min).

(40) After labelling/or synthesis of radiotracer the reaction mixture then passes through a reverse phase (C18) monolithic column for purification.

Example 6: Synthesis of Radiotracer [.SUP.18.F]FDG

(41) 0.2-0.3 mL of an aqueous solution of .sup.18F is passed through an electrode trapping cell at a flow rate of 0.2 mL/min under a constant electric potential (14-20 V) applied between carbon and Pt electrodes. The cell is then flushed with anhydrous MeCN (0.5 mL/min, 1 min) while the voltage is disconnected. 0.1 mL of organic based solution containing the K222 and KHCO.sub.3 in MeCN—H.sub.2O (1-10%) is passed through the cell at flow rate of 0.1 ml/min under a reversed potential (2-4 V) while the cell is heated to a preset temperature of 80° C. and the released solution is stored in a sample loop. The released solution containing .sup.13F, K222 and KHCO.sub.3 is pushed by MeCN at flow rate of 0.02 ml/min to mix with 0.1 ml of mannose triflate solution (0.02 mL/min) inside a Y-micromixer then together entering a microreactor (volume 0.05 mL) heated at 100° C. The reaction solution is mixed with a flow of H.sub.2O (0.04-0.12 mL/min) then passed through a C18-monolith column for trapping the labelled precursor. The monolith is washed with water and dried with N.sub.2. A 0.4 ml of 2 N NaOH solution is loaded into the monolith and hydrolysis is maintained at room temperature for 2 min and the product [.sup.18F]FDG is eluted out with 1-5 mL of water, which is passed through cation-, anion-, silica- and C18-monoliths for purification of [.sup.18F]FDG. This process is shown schematically in FIG. 7.

(42) As described herein, a monolithic body and/or a monolithic module (FIG. 4) may be incorporated into a microfluidic flow system (FIG. 5), for example into a microfluidic chip for quality control (FIG. 6). Quality control analysis of a sample may be required prior to administration to a patient.

(43) FIG. 4 illustrates a monolithic module comprising a first monolithic body and a second monolithic body which may be incorporated into the chips of certain embodiments described herein. The monolithic module may be injection moulded.

(44) FIG. 5 illustrates how a microfluidic module may be incorporated into a microfluidic chip. The first intersecting channel is connected to an upstream portion of the first separation element 1150 such that fluid, e.g. the sample, in the first intersecting channel can flow through the first separation element. In the exemplified embodiment, the first separation element is a strong anionic exchange (SAX) monolithic liquid chromatography column. In one embodiment, the first reaction zone is comprised in a modular component 1155 which is secured to the upper surface of the upper planar structure such that the first intersecting channel is in fluid communication with the first separation element. Thus, the modular component comprises an inlet 1165 and a flow channel which are in fluid communication with the first intersection channel and the first separation element. Similarly, the modular component comprises an outlet 1175 downstream from the first separation element which is in fluid communication with the channel 1180 in use to allow the sample to flow from the first separation element to the channel 1180. The first separation element comprises a monolithic body.

(45) A second intersecting channel is in fluid communication with a second separation element 1170. The second separation element comprises a monolithic body which may a silica monolith or a C18-modified silica monolith. The second separation element 1170 is connected at a downstream end region thereof to a further microchannel 1210 which is in turn fluidly connected to an outlet (not shown). The module may comprise an inlet port 1185 which is in fluid communication with the second separation element. The module may also comprise an outlet port 1195 which is in fluid communication with a microchannel 1210.

(46) An embodiment of a chip and system is shown in FIG. 6. The microfluidic chip (3000) includes a first microchannel 3010 which is in fluid communication with an inlet port 3020. A sample fluid can be introduced into the microfluidic chip through the inlet port 3020.

(47) The first microchannel 3010 comprises a first valve element 3040 which can control movement of a fluid e.g. the sample into the first microchannel.

(48) The chip illustrated in FIG. 6 comprises an additional microchannel 3050, referred to as a sample channel. The sample channel is in fluid communication with the sample inlet port 3020. The sample channel intersects the first microchannel. The first valve element may be a multidirectional valve which controls movement of the sample either to the sample channel or the first microchannel depending on the requirement of the user.

(49) The sample channel is in fluid communication with an outlet 3060. Aptly, the sample channel is not connected to any further inlets. As such, no reagents are added to the sample in the sample channel and the sample may be suitable for administration to a patient in need thereof. Whether the sample is administered will be dependent on the outcome of the one or more tests carried out by the system of embodiments of the present invention and determination of the characteristics of the sample.

(50) The sample channel may be in fluid communication with one or more detection channels as described herein. A first detection channel 3070 is provided which can be used to determine a characteristic such as for example clarity and/or appearance of the sample.

(51) A second detection channel 3080 may be provided downstream from the first detection channel.

(52) The first detection channel and the second detection channel may be in fluid communication via a portion of the sample channel which is provided in the lower planar structure. Thus, in use, a sample is flowed along the sample channel, down the first detection channel, along the sample channel in the lower planar structure and then upwardly along the second detection channel. The sample then exits via the outlet 3060.

(53) Aptly, the first microchannel comprises a plurality of valve elements which can be used to direct flow of the sample and/or reagents and/or solutions from the first microchannel to other areas of the microfluidic chip. In addition the valve elements can be used to isolate portions of a fluid in the first microchannel from other areas of the first microchannel. Aptly, the valve elements are provided in series.

(54) Thus, the first microchannel 3010 may comprise a second valve element 3100, a third valve element 3110, a fourth valve element 3120, a fifth valve element 3130, a sixth valve element 3140 and a seventh valve element 3145. Ultimately, the number of valve elements may depend on how many tests are to be provided on the chip and thus how many detection zones portions of the sample are to be directed to.

(55) The first microchannel may comprise an approximately 90 degree change in direction (3030) between the first valve element and the second valve element.

(56) A first intersecting channel 3150 may be provided on the chip. The first intersecting channel 3150 is in fluid communication with a further inlet, referred to herein as the second inlet port 3160. The first intersecting channel intersects the first microchannel at a junction between the second valve element 3100 and the third valve element 3110.

(57) As described herein, each intersecting channel may be provided with a pair of valve elements which prevent flow of fluid from the detection zones during filling of the first microchannel with the sample. Aptly, one of the pair of valve elements is provided in the intersecting channel upstream of the junction between the intersecting channel and one of the pair is provided downstream from the junction. The valve elements, indicated by 3500a, 3500b, 3500c, 3500d, 3500e and 3510a, 3510b, 3510c, 3510d and 3510e are placed in a closed position when the first microchannel is filled with the sample. Once flow of the sample or portion thereof to a detection zone is desired, the valves of the intersecting channel can be opened to provide a fluid flow path to the detection zone.

(58) Downstream from the junction, the first intersecting channel is in fluid communication with a reagent inlet port 3260. Further downstream from the reagent inlet port 3260, the first intersecting channel comprises a serpentine mixing portion 3270a. The first intersecting channel is in fluid communication with a detection zone 3280. The detection zone aptly comprises a third detection channel 3285 which extends at least partially through the thickness of the chip and provides a pathlength between a source and a detector.

(59) A second intersecting channel 3170 is provided on the chip. The second intersecting channel is in fluid communication with an inlet port 3180, referred to as a third inlet port. The second intersecting channel intersects the first microchannel 3010 at a junction between the third valve element 3110 and the fourth valve element 3120. In the illustrated embodiment, the second intersecting channel has a similar structure to the first intersecting channel. The second intersecting channel is in fluid communication with a second reagent inlet port 3290 at a position downstream from the junction. The second intersecting channel comprises a serpentine mixing zone 3295 in which a portion of the sample and a reagent introduced via the second reagent inlet port can be mixed together prior to entering the detection zone.

(60) The chip may also comprise a third intersecting channel 3190. The third intersecting channel is in fluid communication with an inlet port 3200, referred to as a fourth inlet port. The third intersecting channel intersects the first microchannel at a junction between the fourth valve element 3120 and the fifth valve element 3130. The third intersecting channel is in fluid communication with a third reagent inlet port 3300 at a position downstream from the junction. The second intersecting channel comprises a serpentine mixing zone 3305 in which a portion of the sample and a reagent introduced via the second reagent inlet port can be mixed together prior to entering the detection zone.

(61) One or more valve elements 3310, 3320, 3330 may be provided to control flow of a fluid in the first, second and/or third intersecting channels to the detection zone. Thus, the valve elements can be used to selectively move fluid e.g. a mixture of a portion of the sample and a reagent from one but not the other intersecting channels. Thus, only one mixture of sample and reagent is directed to the detection zone and into the detection channel at a time.

(62) The microfluidic chip may additionally comprise one or more inlet ports for introducing a solution e.g. a washing solution or a standard solution through the detection zone. These inlet ports 3350, 3360 and 3370 are aptly provided upstream to the valve elements thus enabling flow of a fluid introduced through these inlet ports to the detection zone be controlled.

(63) The detection zone may comprise an outlet 3340 for removing fluid which has travelled along the detection channel.

(64) In alternative embodiments, each of the first, second and third intersecting channels may be in fluid communication with a detection channel. That is to say in place of the third detection channel depicted in FIG. 6, a plurality of detection channels, each connected to a single intersecting channel, may be provided. In such embodiments, determination of a plurality of characteristics using the detection channels may take place simultaneously.

(65) The chip may also comprise a fourth intersecting channel 3210 which intersects the first microchannel at a junction between the fifth 3130 and sixth valve elements 3140. The fourth intersecting channel 3210 is aptly in fluid communication with an inlet port 3220, referred to as a fifth inlet port, provided upstream from the junction. The fourth intersecting channel is in fluid communication with a further detection zone 3520 which comprises a second separation element 3270b. The second separation element is a monolithic body. The second separation element is as described above. The second separation element may be comprised in a separate module which is provided on the upper surface of the upper planar surface in use. The separation module is a monolithic module. The second separation element is in fluid communication with a microchannel 3420 which flows to a detection zone which also comprises an electrochemical cell 3410. The electrochemical cell is as described above. The second separation element is in fluid communication with an outlet 3450 provided in the electrochemical cell.

(66) The chip also comprises a fifth intersecting channel 3230 which intersects the first microchannel at a junction between the sixth valve element 3140 and the seventh valve element 3145. An inlet port 3240 referred to as a sixth inlet port, is provided in fluid communication with the fifth intersecting channel upstream from the junction.

(67) The fifth intersecting channel 3230 is in flow communication with a first separation element 3400 provided in the further detection zone 3520. The first separation element is a monolithic body. The first separation element is as described above.

(68) The first separation element 3400 is in fluid communication with a further microchannel 3440 which flows into an electrochemical cell 3410. The electrochemical comprises a working electrode, a reference electrode and a counter electrode as described above. The chip may further comprise an outlet 3460 downstream from the electrodes of the electrochemical cell.

(69) FIG. 9 illustrates a chip 6000 according to certain embodiments of the invention. The chip comprises a separable component 6010 which comprises two monolithic bodies 6020 and 6030 as described herein. The chip also incorporates an electrochemical cell 6040 which in the illustrated embodiment is a screen printed electrode. The electrode may be slid into a recess in the chip.

(70) The chip also comprises a Raman chamber 6060. A pin valve membrane 6050 is provided to control flow of a sample to the Raman chamber. The chip comprises a plurality of inlets and outlets as described herein. Furthermore, the chip is provided with a plurality of detection channels. Fibres, for example, the fibres 6070 and 6080 are positioned adjacent to an end of a respective detection channel for spectroscopic analysis of a solution, e.g. a portion of a sample, which is provided in the detection channel.

(71) In another embodiment, a microfluidic based system (FIG. 7) has been developed for [.sup.18F]FDG synthesis in which a microfluidic electrochemical cell is used for the separation of [.sup.18F]fluoride from [.sup.18O]water, a serpentine channel microreactor for the radiolabeling reaction and C18-column for performing hydrolysis of trapped ACY-FDG. The C18-column may be a reverse phase monolithic body comprised in a monolithic module. This system is advantageous because it eliminates evaporation steps for solvent-exchange in both processes of labeling reaction and hydrolysis reaction. The elimination of evaporation process offers an opportunity to realize dose-on-demand production in an integrated system. Under optimal parameters [.sup.18F]fluoride activity of 94-99% (initial activity up to 30 mCi) can be efficiently trapped within 1-2 min and over 96% of trapped [.sup.18F]fluoride can be released into either MeCN-water (4%) or DMF-water (4%) containing K222-KHCO.sub.3 within 5-6 min. Using this released solution for fluorination of mannose triflate, 100% ACY-FDG can be obtained within 1.2 min at 100° C. After basic hydrolysis (2 min) at room temperature 98.3% FDG can be achieved without further purification.

(72) The first embodiment of FIG. 8 b) illustrates a cross section of a double coated monolithic body where the outer coating is made up of the plastic holder or mould into which silicone was poured and subsequently moulded around the monolithic body.

(73) The second embodiment of FIG. 8 c) illustrates a double coated monolithic body where the outer coating is made itself by injection moulding. The outer coating may first be prepared by injection moulding and the silicone subsequently injected into it around the monolithic body. Alternatively the silicone coating is applied first by injection moulding and the outer layer subsequently applied by injection moulding. The outer coating may have various cross section shapes as shown.