RADIOISOTOPE RECOVERY

Abstract

The present invention relates to a method and an apparatus for separating and recovering a radioisotope from a solution. More particularly, certain embodiments of the invention relate to a method for recovering a radioisotope from a solution by electro-trapping and release using a microfluidic cell (10). The radioisotope may subsequently be used in the preparation of radiopharmaceuticals.

Claims

1. A method for separating and recovering a radioisotope from an aqueous solution comprising the radioisotope, the method comprising: using a microfluidic device comprising a chamber; flowing the aqueous solution to the chamber, the chamber comprising a first electrode and a second electrode; generating a first electric field between the first and second electrodes, thereby trapping the radioisotope on the first electrode; flowing an organic-based solution to the chamber comprising the first and the second electrodes; and generating a second electric field between the first and the second electrodes; wherein the second electric field has an opposing polarity to the first electric field, thereby releasing the radioactive isotope from the first electrode into the organic-based solution; and wherein the first electrode is formed from a carbon rod or section thereof.

2. The method of claim 1, further comprising one or more of the features selected from: flowing the aqueous solution at a flow rate of at least 0.1 mL/min; flowing the organic-based solution at a flow rate of at least 0.05 mL/min; applying a voltage of no greater than 30 V across the first and second electrodes to generate the first electric field; and applying a voltage of no greater than 10 V across the first and second electrodes to generate the second electric field.

3-5. (canceled)

6. The method of claim 1, wherein the chamber has a volume of no greater than approximately 50 L.

7. The method of claim 1, wherein the first electrode has a flat surface comprising a plurality of recesses and/or the first electrode has a polished surface layer.

8. (canceled)

9. The method of claim 1, wherein the distance between the first and second electrodes is no greater than 0.5 mm.

10. The method of claim 1, wherein the radioisotope is trapped on the first electrode with an efficiency of at least 94% and the radioisotope is released from the first electrode with an efficiency of at least 96%.

11. (canceled)

12. The method of claim 1, further comprising removing the aqueous solution from the chamber prior to flowing the organic-based solution to the chamber.

13. The method of claim 1, further comprising washing the chamber after trapping the radioisotope on the first electrode and before flowing the organic-based solution to the chamber.

14-15. (canceled)

16. The method of claim 1, further comprising heating the chamber and/or the organic based solution to a temperature of from 50 to 100 C. prior to generating the second electric field.

17. The method of claim 1, further comprising reacting the radioisotope released from the first electrode with a precursor to provide a radiopharmaceutical or an intermediate in the synthesis of a radiopharmaceutical.

18. The method of claim 17, further comprising transferring the organic-based solution containing the released radioisotope to a reactor in which the radioisotope is reacted with the precursor.

19. The method of claim 17, wherein the organic-based solution comprises the precursor such that the radioisotope reacts with the precursor in the chamber upon release of the radioisotope from the first electrode.

20. (canceled)

21. An apparatus for separating and recovering a radioactive isotope from an aqueous solution comprising the radioactive isotope, the apparatus comprising: an inlet; an outlet; and a chamber in fluid communication with the inlet and the outlet to form a fluid pathway, the chamber comprising a first electrode and a second electrode; wherein: the first electrode is formed from a carbon rod; the chamber has a volume capacity of no greater than about 50 L; the distance between the first electrode and the second electrode is no greater than 0.5 mm; and the apparatus optionally comprises a heater.

22. The apparatus of claim 21, wherein the surface area of the first electrode which comes into contact with the flow of aqueous solution is at least 20 mm.sup.2.

23. The apparatus of claim 21, wherein the first electrode has a flat surface comprising a plurality of recesses and/or the first electrode has a polished surface layer.

24. (canceled)

25. The apparatus of claim 21, wherein the apparatus is configured to receive fluid at a flow rate of at least 0.1 mL/min.

26. The apparatus of claim 21, wherein the second electrode is made of platinum.

27. The apparatus of claim 21, wherein the first electrode has a hardness of at least 2.0 on the Mohs scale.

28. The apparatus of claim 21, wherein the chamber has a volume capacity of no greater than about 30 L.

29. (canceled)

30. The apparatus of claim 21, wherein the apparatus is a microfluidic cell.

Description

[0145] Embodiments of the invention will now be described by way of example only and with reference to the accompanying Figures in which:

[0146] FIG. 1 is an exploded view of a microfluidic cell in accordance with an embodiment of the present invention;

[0147] FIG. 2 is a perspective view of the microfluidic cell of FIG. 1;

[0148] FIG. 3 is an exploded view of a microfluidic cell in accordance with another embodiment of the present invention;

[0149] FIG. 4a is a schematic side view of a microfluidic cell in accordance with a further embodiment of the present invention;

[0150] FIG. 4b is an exploded view of the microfluidic cell of FIG. 4a;

[0151] FIG. 5 is a schematic diagram of a microfluidic system comprising the microfluidic cell of FIG. 4; and

[0152] FIG. 6a depicts a top view of a microfluidic system comprising a RIM and RPM as described herein which comprises a heat reduction means; and

[0153] FIG. 6b illustrates the temperature difference observed between the directly heated area of the RPM and the chamber of the RIM as measured with an infrared thermometer;

[0154] FIG. 7A-C illustrate the microfluidic system of FIG. 6 secured in a holder.

[0155] With reference to FIG. 1, a microfluidic cell 10 comprises upper 12 and lower 14 rectangular glass plates, which have been machined to the desired size and shape. It will be appreciated that in alternative embodiments, the plates may be formed from other materials such as quartz or polymer. In the centre of the lower plate 14 there is a circular cut-out 16 which extends through the entire depth of the plate 14, and which receives a carbon disk (10 mm diameter) that forms the working electrode 18. The working electrode 18 is cut to size and polished. A first lead 20 connects the working electrode 18 to an electrical circuit (not shown). The working electrode 18 is secured in place by a first cylindrical glass liner 22 which is sized to fit into the cut-out 16 of the lower plate 14. The glass liner 22 may be a stock component, or it may be machined to the required shape and size.

[0156] The upper plate 12 has a circular cut-out 24 in a position corresponding to that of the cut-out 16 in the lower plate 14. The upper plate further comprises two holes 26, one either side of the cut-out 24, each of which is fluidly connected to the cut-out 26 via a channel 28. One of the holes 26a provides an inlet to allow fluids into the cell 10, while the other 26b provides an outlet. A circular platinum counter electrode 30 (10 mm diameter) is received in the cut-out 24 in the upper plate 12. The counter electrode 30 is connected to the circuit by a second lead 32. The counter electrode 30 is secured in place by a second cylindrical glass liner 34 which is sized to fit into the cut-out 24 in the upper plate 12. The glass liner 34 may be a stock component, or it may be machined to the required shape and size.

[0157] FIG. 2 shows the cell 10 of FIG. 1 with the components assembled. To assemble the cell, the upper and lower plates 12, 14 are aligned before being thermally bonded together. Once the plates 12, 14 are bonded the counter electrode 30 is placed within the cut-out 24 in the upper plate 12. The electrode lead 32 is inserted and a sealant is applied to the interior surface of the cut-out 24 before inserting the second glass liner 34. The sealant is allowed to set before the process is repeated for securing the working electrode 18 in the cut-out 16 in the lower plate 14.

[0158] Once assembled, the upper and lower plates 12, 14 together with the first and second glass liners 22, 34 define a chamber which houses the working electrode 18 and the counter electrode 30 in a face-to-face arrangement. The gap between the electrodes is 250 m, and the volume of the chamber is 19.6 L. Fluids can be flowed through the chamber via the inlet and outlet 26a, 26b.

[0159] FIG. 3 shows an alternative embodiment of a microfluidic cell 110 comprising upper 112 and lower 114 glass plates which are substantially square. The lower plate 114 comprises a cavity 116 which provides a chamber for electro-trapping and release. The cavity 116 can be any depth or shape. In the embodiment shown, the cavity 116 is key-shaped, i.e. it comprises a circular portion 116a and an elongate portion 116b extending from the circular portion 116a. A sputter coated metallic layer formed on a surface of the cavity 116 provides the counter electrode 130. Two holes 126 extend through the lower plate 114 into the cavity 116, providing an inlet 126a and an outlet 126b for fluids.

[0160] The microfluidic cell 110 further comprises a disk-shaped working electrode 118 formed from a carbon rod. The working electrode 118 is greater in diameter than the circular portion 116a of the cavity 116 in the lower plate 114 which forms the chamber. The working electrode 118 is housed within a circular recess 124 in the upper plate 112. The upper plate 112 further comprises a first hole 132 in the approximate centre of the plate which extends into the recess 124, enabling electrical connection of the working electrode 118. A second hole 134 in the upper plate 112 is provided in a position corresponding to the elongate portion 116b of the cavity 116 in the lower plate 114, thereby enabling electrical connection with the counter electrode 130.

[0161] To assemble the cell 110, the upper plate 112, lower plate 114 and working electrode 118 are loosely assembled and the plates 112, 114 aligned before the plates 112, 114 are thermally bonded together. The electrical contacts (not shown) are then secured in the holes 132, 134 in the upper plate 112 using a sealant

[0162] With reference to FIGS. 1-3, an embodiment of a method of radioisotope recovery (solvent exchange) by electro-trapping and release using a microfluidic cell in accordance with the present invention will now be described. The method first comprises flowing .sup.18O-enriched water containing .sup.18F into the chamber of the microfluidic cell 10, 110 via the inlet 26a, 126a. An electric field is generated between the electrodes 18, 118, 30, 130 by applying a voltage across the electrodes such that the negatively charged .sup.18F ions are attracted to the working electrode 18, 118, causing them to be trapped on the working electrode 18, 118. Waste H.sub.2.sup.18O is removed from the cell 10, 110 via the outlet 26b, 126b. The chamber is then washed by flowing acetonitrile through the chamber. An organic-based solution comprising K222 and K.sub.2CO.sub.3 in acetonitrile (and optionally 4% H.sub.2O) is introduced into the chamber via the inlet 26a, 126a. The polarity of the electric field is then reversed, causing the .sup.18F ions to be released from the working electrode 18, 118 into the organic-based solution. The organic-based solution containing the released .sup.18F ions can then be removed from the chamber via the outlet 26b, 126b, and transferred to a separate reactor where the .sup.18F ions are reacted with a precursor to generate a radiotracer. Alternatively, the precursor may be provided in the organic-based solution so that the nucleophilic substitution reaction between the precursor and the .sup.18F ions occurs within the chamber.

[0163] Turning to FIG. 4a, in a further embodiment a microfluidic cell 210 comprises a rectangular upper plate 212, an opposing lower plate 214 of the same size and shape as the upper plate 212, and a silicon spacer 216 disposed between the upper and lower plates 212, 214. The plates 212, 214 are machined to the required size and shape. The upper and lower plates 212, 214 and the silicon spacer 216 are held together within a clamp 217. A cut-out is formed in the centre of silicon spacer 216, thus defining a channel which constitutes a reaction chamber 215. A rectangular working electrode 218 formed from a section of carbon rod is positioned against the upper plate 212 and forms a ceiling of the reaction chamber 215. The working electrode 218 is polished prior to assembly of the cell 210. A platinum foil counter electrode 230 is positioned on the lower plate 214, facing the working electrode 218, forming a floor of the reaction chamber 215. The electrodes are held in place by the force of the clamp 217 and are sealed using sealant. Leads connect the working and counter electrodes 218, 230 to a circuit. Two holes 226 are formed in the upper plate which provide an inlet 226a and an outlet 226b to allow fluids to flow through the chamber 215 via capillary tubing. FIG. 4b shows an exploded view of the microfluidic cell 210.

[0164] FIG. 5 shows a microfluidic system 240 for the preparation of a radiotracer. In the embodiment shown, the system is set up for the synthesis of [.sup.18F]-FDG, but it will be appreciated that the system could be used to prepare any desired radiopharmaceutical. The system eliminates evaporation steps for solvent exchange, and enables dose-on-demand production of radiotracers in an integrated system.

[0165] The system 240 comprises the microfluidic cell 210 for solvent exchange of .sup.18F by electro-trapping and release. The microfluidic cell 210 is supplied with fluids from a set of four syringes, a first syringe 242 containing a source of .sup.18F, a second syringe 244 containing acetonitrile for washing, a third syringe 246 containing an organic-based solvent and a fourth syringe 248 containing water. A line 250 connects the syringes 242, 244, 246, 248 to the inlet 226a of the microfluidic cell 210. The flow of fluids into the cell 210 is controlled by a first valve 252 positioned at a point at which the line 250 diverges between a first branch 254 leading to the first syringe 242 and a second branch 256 leading to the second 244, third 246 and fourth 248 syringes.

[0166] The system further comprises a microfluidic reactor 258 and a fifth syringe 260, which contains mannose triflate. A flow path 262 connects the fifth syringe 260 to the microfluidic reactor 258. A line 264 feeds fluids from the outlet 226b of the microfluidic cell 210 into the flow path 262. A second valve 266 is positioned at the junction of the line 264 with the flow path 262, and controls the flow of fluids into the microfluidic reactor 258.

[0167] The system additionally comprises a C.sub.18 deprotection column 268, a sixth syringe 270 containing water for elution and a seventh syringe 272 containing sodium hydroxide for hydrolysis. A flow path 274 supplies fluids from the sixth and seventh syringes 270, 272 to the deprotection column 268. A line 276 feeds fluids from the microfluidic reactor 258 into the flow path 274. A third valve 278 is positioned at the junction of the line 276 with the flow path 274, and thus controls the flow of fluids into the deprotection column 268.

[0168] Recovery of .sup.18F from an aqueous solution into an organic-based solution by electro trapping and release is carried out using the microfluidic cell 210, as described above. The organic-based solution containing the released .sup.18F ions leaves the microfluidic cell 210 via the outlet 226b, and is transferred to the microfluidic reactor 258 via the line 264. Mannose triflate is supplied to the microfluidic reactor 258 from the fifth syringe 260 via the flow path 262. Within the microfluidic reactor 258 the mannose triflate undergoes a nucleophilic substitution reaction with the .sup.18F ions, producing acetylated [.sup.18F]-FDG. The acetylated [.sup.18F]-FDG is then transferred to the deprotection column 268 via line 276 and flow path 274, where it undergoes hydrolysis in the presence of a sodium hydroxide solution to produce [.sup.18F]-FDG.

[0169] FIG. 6a shows a top view of a microfluidic system 300 for the preparation of a radiotracer. In certain embodiments, the system 300 is a combined RIM and RPM as described herein. In the embodiment shown, the system comprises a microfluidic cell 310 comprising a chamber 311 for solvent exchange of .sup.18F by electro-trapping and release. Adjacent to the microfluidic cell is valve 330. The system further comprises a microfluidic reactor 320. Area 321 of the microfluidic reactor is heated directly by means of a heater (not shown) positioned directly below area 321. Heat reduction means is provided in the form of a slot 340. The slot reduces heat transfer from the directly heated area (321) to the chamber of the microfluidic cell. FIG. 7A-C illustrates the microfluidic system of FIG. 6 which secured in a holder. The system may further comprise one or more valves which can control flow of solutions within and/or between each module.

[0170] FIG. 6b is a graphical representation of the temperature difference between area 321 and microfluidic cell 310 as measured by an infrared thermometer following direct heating of area 321.

Examples

[0171] Microfluidic cells similar to that shown in FIG. 4 were fabricated by clamping together two glass plates, a pair of electrodes (including a platinum counter electrode) and a silicon spacer comprising a channel. Details of the cell s are provided in Table 1.

[0172] The cells were tested with a low volume of .sup.18O-water comprising .sup.18F from an ABT cyclotron. Trapping and release efficiencies were probed at different voltages with variation of the flow rate. The results are shown in Tables 2 and 3. Efficiencies of up to 99% in trapping (Table 2) and up to 98% in release (Table 3) were observed.

TABLE-US-00001 TABLE 1 Cell design Working electrode Cell volume (L) 1 Graphite (15 4 mm) 30 2 Carbon disk (10 mm 32 diameter) 3 Carbon disk (10 mm 16 diameter) 4 Carbon 8 3 0.25 mm 6

TABLE-US-00002 TABLE 2 Trapping conditions Volume Cell .sup.18O-water Flow rate Trapping design (mL) (mL/min) Voltage (V) efficiency % 1 0.2 0.2 20 99 2 0.3 0.2 20 99 3 0.3 0.2 15-20 98 4 0.3 0.2 14-20 96-99

TABLE-US-00003 TABLE 3 Release conditions Release Cell Volume Flow rate Voltage efficiency design Solvent (mL) (mL/min) (V) Temperature % 1 Water 0.2 0.1 1.6-3.8 r.t. 44-69 2 Water-K222 0.3 0.1 1.6-3.8 r.t. 94 2 K222-K.sub.2CO.sub.3 0.3 0.1 1.6-3.8 r.t. 85 MeCN-4% H.sub.2O 2 K222-K.sub.2CO.sub.3 0.3 0.1 1.6-4.1 r.t. 73 MeCN 3 K222-K.sub.2CO.sub.3 0.1 0.1 1.6-4.1 r.t. 76 MeCN-4% H.sub.2O 3 K222-K.sub.2CO.sub.3 0.1 0.1 1.6-4.1 80 C. 98 MeCN-4% H.sub.2O 4 K222-K.sub.2CO.sub.3 0.1 0.1 1.6-4.1 r.t. 82 MeCN-4% H.sub.2O 4 K222-K.sub.2CO.sub.3 0.1 0.1 1.6-4.1 80 C. 96-98 MeCN-4% H.sub.2O

[0173] In cell design 1 graphite was used as the anode (the working electrode). A trapping efficiency of 99% was achieved at 20 V within 1 minute but only 44-69% release efficiency could be obtained within 3 minutes. The low release efficiency was thought to be due to deformation of the graphite electrode. The cell was modified by replacing the graphite electrode with an electrode produced by cutting a small piece from a carbon rod (cell design 2, 3 and 3) and a significant improvement in the release efficiency was observed (Table 3). No significant difference in performance of cells 3 and 4 was observed over more than 40 runs, demonstrating excellent stability.

[0174] A system similar to that shown in FIG. 5 was fabricated and used to synthesise [.sup.18F]-FDG in accordance with the following method. 0.2-0.3 mL of .sup.18O-enriched H.sub.2O containing .sup.18F was passed through the cell at a flow rate of 0.2 mL/min under a constant electric potential (14-20 V) applied between the carbon and Pt electrodes. The cell was then washed by flushing with anhydrous MeCN (0.5 mL/min, 1 minute) while the voltage was disconnected. Next, 0.1 mL of organic-based solution containing K222 and KHCO.sub.3 in MeCNH.sub.2O (1-10%) was passed through the cell at flow rate of 0.1 mL/min under a reversed potential (2-4 V). The cell was heated to a pre-set temperature of 80 C. and the released solution was stored in a sample loop. The released solution containing .sup.18F, K222 and KHCO.sub.3 was 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. The mixture was then transferred to a microreactor (volume 0.05 mL) heated to 100 C. The reaction solution was mixed with H.sub.2O at a flow rate of 0.04 mL/min and then passed through a C18-monolith column for trapping the labelled precursor. The monolith was washed with water and dried with N.sub.2. 0.4 mL of 2 N NaOH solution was loaded into the monolith and hydrolysis was maintained at room temperature for 2 minutes. The product [.sup.18F]-FDG was eluted out with 1-5 mL of water.

[0175] Using this system, .sup.18F fluoride (initial activity up to 30 mCi) can be trapped with an efficiency of 94-99% and subsequently released with a release efficiency of 96-98%. Using the organic solution containing released .sup.18F fluoride for fluorination of mannose triflate, up to 100% acetylated [.sup.18F]-FDG. (ACY-[.sup.18F]-FDG) can be obtained. 100% ACY-[.sup.18F]-FDG can be obtained within 1.2 min at 100 C. After basic hydrolysis on the deprotection column (aptly a monolith) 98.3% [.sup.18F]-FDG was obtained. Optionally, the [.sup.18F]-FDG can be further purified by passing through cation-, anion-, silica- and C18-monoliths.

[0176] The use of microfluidic cells for processing of low volume of heavy water feed from the cyclotron offers an excellent method for solvent exchange to carry out nucleophilic substitution reactions with standard precursors. In addition to the excellent trap and release performance, the benefits of the invention include the use of a low voltage, re-use of electrodes and simple operation. The present invention thus offers significant potential in efficient dose-on-demand radiotracer production.

[0177] Throughout the description and claims of this specification, the words comprise and contain and variations of them mean including but not limited to and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[0178] Features, integers, characteristics or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of the features and/or steps are mutually exclusive. The invention is not restricted to any details of any foregoing embodiments. The invention extends to any novel one, or novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0179] The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.