Author's Accepted Manuscript
Optimizing the transfer of [18F]fluoride from aqueous to organic solvents by electrodeposition using carbon electrodes Fabian Kügler, Daniel Roehrens, Milosch Stumpf, Christian Drerup, Johannes Ermert, Kurt Hamacher, Heinz H. Coenen
www.elsevier.com/locate/apradiso
PII: DOI: Reference:
S0969-8043(14)00158-4 http://dx.doi.org/10.1016/j.apradiso.2014.04.019 ARI6674
To appear in:
Applied Radiation and Isotopes
Received date: 13 December 2013 Revised date: 17 April 2014 Accepted date: 28 April 2014 Cite this article as: Fabian Kügler, Daniel Roehrens, Milosch Stumpf, Christian Drerup, Johannes Ermert, Kurt Hamacher, Heinz H. Coenen, Optimizing the transfer of [18F]fluoride from aqueous to organic solvents by electrodeposition using carbon electrodes, Applied Radiation and Isotopes, http://dx.doi.org/10.1016/j. apradiso.2014.04.019 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Optimizing the transfer of [18F]fluoride from aqueous to organic solvents by electrodeposition using carbon electrodes Fabian Kügler, Daniel Roehrens, Milosch Stumpf, Christian Drerup, Johannes Ermert, Kurt Hamacher, Heinz H. Coenen Institute of Neuroscience and Medicine, INM-5: Nuclear Chemistry, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany
Keywords: [18F]fluoride, electrodeposition, carbon electrodes, intercalation, micro fluidics Abstract The effect of varying structural modifications of carbon anodes, ranging from thin layers of crystalline boron-doped diamond up to highly graphitic bulk materials, was systematically examined for the possibility of electrochemical fixation and desorption of no-carrier-added [18F]fluoride from an aqueous solution. Pyrolysed carbon, i.e. “glassy carbon” (Sigradur®G), proved as the most efficient material for deposition and release. An overall radiochemical yield of about 60 % was achieved when using this for fixation and DMSO/ionic additive as organic solution for the release of [18F]fluoride.
1. Introduction Transfer of n.c.a. [18F]fluoride from water to an organic solvent almost exclusively marks the first essential step for every radiofluorination in order to achieve an activated anion for nucleophilic substitution. The electrodeposition of radioactive [18F]fluoride on carbon electrodes from aqueous media has been studied as one possible method for more than two decades (Alexoff et al., 1989; Hamacher et al., 2002; Reischl et al. 2002, Rensch et al. 2009, Saiki et al., 2010) and was readily employed as an alternative to the generally used, more classical approaches to remove water for the production of radiopharmaceuticals (Saito et al., 2004; Saito et al., 2007; Hamacher et al., 2006). The attractiveness of the electrochemical method for isolation of n.c.a. [18F]fluoride in comparison is due to i) ease recovery of highly enriched [18O]water, ii) technical simplification of its drying and transfer into appropriate organic solvents, and iii) of its concentration into small volume, useful for minimizing synthesizer apparatuses down to microfluidic devices.
2
The azeotropic distillation has some disadvantages compared to an electrochemical separation, because it is more time consuming and requires additional technical equipment in a remote-controlled synthesizer like gas flow and pressure controllers. Rapid azeotropic drying is technically even more challenging to be integrated in a microfluidic system (Rensch et al., 2013). The alternative approach of water removal by a solid phase drying method on a strong anion-exchange resin (Wessmann et al., 2012), however, also usually requires 200 µL to 480 µL elution volumes for sufficient [18F]fluoride recovery. Thus, in spite of the many efforts , there is still an unsolved challenge for transferring n.c.a. [18F]fluoride from (several) milliliters of target water into microliter volumes of organic solvent. Here, the electrochemical method enables simplification of the hardware architecture which was already verified in automated syntheses for routine production of e.g. n.c.a. [18F]altanserin (Hamacher et al., 2006), [18F]FDG (Saiki et al., 2010) and [18F]flumazenil (Wong et al., 2012). The other above mentioned advantage of the electrochemical method for transferring the radionuclide into anhydrous solvents is the efficient recovery of highly enriched [18O]water. This is of special interest since the enriched material is expensive and availability sometimes limited. So far performed studies (Hamacher et al., 2006, Saiki et al., 2010) attempted quantitative anodic deposition of the [18F]fluoride primarily using glassy carbon electrodes at cell voltages ranging from 2 to 5 V and employing a platinum counter electrode. The deposited activity is subsequently released after removal of water into a dry organic solvent under a reverse potential with milder voltages. Typically very high degrees of anodic deposition of up to 90 % have been demonstrated in earlier studies, while the cathodic release proved to be the limiting factor for the overall recovery yield. So far, significant release rates only exhibit an efficiency of about 60 % which served as a primary motivation for the search of novel electrode materials. A further challenge was the observation that glassy carbon surfaces degrade under electrical re-polarisation which can be associated with the release of particulates (Sadeghi et al., 2010). The mechanistic details of deposition and release processes of [18F]fluoride using an electric field have not been elaborated in detail in earlier studies. Hamacher and coworkers postulated as model an electrostatic adsorption of [18F]fluoride on the anode surface which means that the [18F]fluoride is trapped and held by the electric field (Hamacher et al., 1995). Quite recently, Sadeghi and coworkers studied different metallic materials for trapping and releasing of [18F]fluoride in a micro-flow cell (Sadeghi et al., 2013). They found out that a brass anode at a temperature of 65 °C and an applied potential of +20 V gave the best results
3 of [18F]fluoride deposition. By performing X-ray photoelectron spectroscopy (XPS) studies on different anode surfaces after (non-radioactive) macroscopic fluoride trapping the authors hypothesized that the performance of fluoride fixation and desorption is related to surface oxides, depth of intercalation, and the nature of chemical bonds formed on the surface during the electrochemical process. The conclusions drawn involved less sharply defined parameters, such as the cell voltage, the geometry and reactor type (batch or flow), and an optimal setup has yet to be identified. The nature of the carbon anode material is assumed to be of foremost importance, and systematic studies are required. Aside from radiochemical applications, graphite fluorides as a class of intercalation compounds with varying stoichiometry are well documented compounds (Rudorff et al., 1947; Rudorff et al., 1959). First, they have been reported as an anodic by-product during fluorine production from an ionic source (Nakajima et al., 1988). Graphite fluorides are readily formed from aqueous sources using analogous conditions like in the radiochemical deposition studies. These structures have been characterized as metastable compounds which decompose in the presence of water and air (Takenaka et al., 1987; Noel et al., 1995; Noel et al., 1998). In this study, the comprehensive mechanistic and structural information known for intercalation of stable [19F]fluoride was applied with the examination of the electrodeposition of [18F]fluoride on carbon-electrode surfaces in aqueous media. Despite several publications on single materials, to the best of our knowledge no comparative study exists up to now in which a wide range of carbon materials is compared and evaluated for their ability for electrochemical absorption of [18F]fluoride ions. Since the influence of the electrode material will determine overall yields and transfer-process efficiency, a comparative examination under identical conditions is essential for the development of an optimized electro deposition set-up. Therefore, a systematic approach was used here to compare the yields of fixation on electrodes from graphite, glassy carbon (low and high temperature modification), amorphous diamond-like carbon (DLC) thin films, and polycrystalline boron doped diamond (BDD) in a planar electrochemical flow cell reactor.
2. Materials and methods All BDD and DLC thin layer electrodes were prepared by the Fraunhofer Institute for Surface Engineering and Thin Films (IST, Braunschweig, Germany), employing specialized chemical vapor deposition (CVD) methods on tungsten substrates (Matthée et al., 1997; Fryda et al., 2003). Bulk glassy carbon electrodes of Sigradur®G and Sigradur®K quality were
4 purchased from HTW GmbH (Thierhaupten, Germany) and bulk graphite electrodes from NGS Naturgraphit GmbH (Leinburg, Germany). The perfluorinated-elastomer seal (FPM 75) was delivered by Zrunek Gummiwaren GmbH (Vienna, Austria). The fluid transport was realized by a dosing diaphragm pump RO5-3, delivered by Fink Chem+Tec OHG (Bad Dürrheim, Germany). Radioactivity in the cell was monitored with a Geiger counter (Ø 13.5 mm; 90 mm) from Genitron Instruments GmbH (Frankfurt, Germany). Radioactive solutions were quantified with an ionization chamber (Curiementor 2 from PTW, Freiburg, Germany). The temperature of the electrodes was measured and regulated by the Quick-Control QC-PCOS 22G device, purchased from Quick-Ohm GmbH (Wuppertal, Germany). The electrical potential control was realized by a Keithley Series 2400 SourceMeter delivered by Keithley Instruments, Inc. (Cleveland, Ohio, USA). All solvents and chemicals were purchased from Fluka (Buchs, Switzerland) and used without further purification. Ion-chromatography was performed on a Metrohm 882 Compact IC plus with a Metrosep A Supp 5 - 150/4.0 column (Deutsche METROHM GmbH & Co. KG,
70794 Filderstadt) using an aqueous buffer
solution of 3.2 mM Na2CO3 and 1 mM NaHCO3. 2.1
Electrode material
Different carbon materials were used as electrode within an electric potential ranging from 0 to 5 V. Besides graphite, glassy carbon (Sigradur®) exhibits the highest ratio of graphitic structural elements among the selected materials. It is composed of 100 % sp2-configured carbon without surface dangling bonds (Dekanski et al., 2001). Both modifications of bulk material of glassy carbon, low temperature Sigradur®K and high temperature Sigradur®G, were examined. In order to analyze electrode surfaces with a higher fraction of sp3 hybridized carbon thin layers of diamond-like carbon on tungsten backings were employed as working electrodes in the electrochemical cell (Schäfer et al., 2006, Petrikowski et al., 2013). As amorphous carbon material it displays higher sp3 carbon content while most of its structure still consists of unsaturated carbon. It may be regarded as an intermediate form between highly graphitic modifications and crystalline diamond. Finally, polycrystalline boron doped diamond electrodes were used as material for anodic fixation. Doping levels of boron were varied between approximately 500 ppm to 4000 ppm in order to test a wide range of electrical conductivity which may affect the deposition process. Additionally, the morphology and crystallographic properties of the diamond films were varied by applying three different types of diamond deposition processes leading to microcrystalline, nanocrystalline and (110)-texturized films. Under polycrystalline growth
5 conditions the randomly oriented diamond crystals grow in average to sizes from about 0.5 to 4 µm by increasing the film thickness from 2 to 8 microns. The corresponding layer roughness increases from Ra = 100 nm to Ra = 500 nm (Ra = average roughness), respectively. For obtaining smooth electrode surface samples, corresponding growth conditions were chosen in order to prepare nanocrystalline diamond films with particle sizes well below 50 nm. In this case the surface roughness corresponds mainly to the initial roughness of the backing-material. Finally, 110-textured diamond layers were grown exhibiting a pronounced preferential crystallographic orientation. For each BDD modification, different layer thicknesses were prepared. With this set of electrodes, a wide spectrum of chemical, crystallographic, morphological and electrical surface modifications was covered. A list of the employed electrode materials is given in Table 1.
Table 1 2.1.
Preparation of [18F]fluoride
N.c.a. [18F]fluoride was produced via the 18O(p,n)18F nuclear reaction by bombardment of isotopically enriched [18O]water (> 96%) purchased from Rotem Industrial Park (Israel) in a titanium-target (Qaim et al., 1993) with 17 MeV protons at the JSW cyclotron BC 1710 (INM-5, Forschungszentrum Jülich, Germany). 2.2.
Electrochemical flow cell
The electrochemical cell consists of a planar two electrode arrangement. Anode and cathode are fitted together as an aluminum stack with a 0.5 mm thick electrically isolating elastomer gasket located in between the planar electrodes. A cut-out in the middle of the seal with a length of 62 mm and a width of 10 mm defines the size of the cell chamber. A schematic view of the complete cell is shown in Figure 1. In comparison, Sadeghi et al. (2013) use for their studies an electrochemical flow-cell in shape of a serpentine channel pattern a fluid path of 46 mL volume cut into a polymer film, which is clamped between two rigid electrodes. Rensch et al. (2009) use a 20 µL microfluidic reactor with a glassy carbon anode. Both set-ups were optimized with regard to performing radiofluorination in microfluidic systems. The focus in the study here, however, was to test the suitability of different carbon electrodes for electrochemical separation of [18F]fluoride, rather than to perform radiofluorination experiments. Thus, the area of the electrode was of
6 less importance and much larger which also resulted from the methods of their production, especially for the BDD and DLC material. Figure 1 2.3.
Experimental procedure of electrodeposition of [18F]fluoride with different electrodes
An automated module was developed for the fixation and desorption of about 50-150 MBq n.c.a. [18F]fluoride. A flow chart of the module for the deposition and release process is given in Fig. 2. For each experiment a 2 mL aliquot of an aqueous [18F]fluoride solution was used. Preconditioning Before starting with the deposition experiments the electrochemical cell was preconditioned by passing a volume of about 5 mL H2O (sterile water, B.Braun, Melsungen, Germany) at 2 mL/min through the cell chamber while applying a constant cell voltage of 5 V in an anodic polarization configuration, referring to the carbon working electrode. Through this, potential impurities on the surface of electrodes were removed (Engstrom et al., 1984). Furthermore, the synthesis of diamond layers by chemical vapor deposition lead to a surface which is terminated with hydrogen atoms and is hydrophobic and p-type conducting (Albin et al., 1990). The preconditioning procedure converts the layer to an oxygen-terminated diamond surface which improves the hydrophilic and insulating properties of the layer.
Figure 2 Fixation process The aqueous [18F]fluoride solution was transported directly through the cell at a constant flow rate of 0.2 mL/min under a previously set constant cell voltage, and the
18
F-depleted
water was collected. After the deposition step, the cell was purged by a flow of helium in order to transport the residual water into the collection vial. The amount of the deposited [18F]fluoride was determined by subtracting the decay corrected activity of the eluted from that of the starting solution, quantitatively determined with an ionization chamber. Additionally, the process was monitored by a cylindrical radiation detector in a fixed geometry at 1 cm distance directly above the planar cell in order to continuously record the level/ amount of radioactivity during the process. Release process
7 After the deposition step the cell voltage was set to 0 V and the cell chamber was conditioned with 1-2 mL of dry organic solvent used for the release of [18F]fluoride. Subsequently, a reversed electric potential of -2.5 V was applied where the carbon working electrode acted as cathode. A solution of either an additive (3 mmol) in 3 mL of dry dimethyl sulfoxide (DMSO), 3 mL of pure DMSO, or 3 mL of water was then pumped through the cell with a constant flow of 0.2 mL/min. The eluted radioactive solution was collected and analyzed as described above for the fixation step. 3. Results and Discussion 3.1. Fixation of [18F]fluoride on carbon electrodes Both modifications of glassy carbon (Sigradur®G and Sigradur®K) showed nearly quantitative fixation of [18F]fluoride of 96 ± 3 % (n = 3) over a range of 3 to 5 V when using BDD as cathode material. The use of tungsten as cathode, however, yielded a lower fixation of [18F]fluoride on Sigradur®G (Figure 3). For comparison, with pure graphite a quantitative fixation was already reached at 4 V. The adsorption pattern of the graphitic bulk electrodes showed a strong increase from the baseline at a characteristic cell voltage which is indicative for an electrochemical nature of the adsorption mechanism. Fluoride is incorporated into the graphite matrix which requires a characteristic electrode potential and a charge transfer (electrical current flow) in order to facilitate a transport of ions through the phase barrier. Figure 3 2
In spite of the higher sp content of DLC electrodes compared to the BDD electrodes it is obviously not high enough. This is probably why they display only low to moderate fixation and thus appear not suitable for the separation process. Additionally, all DLC layers were immediately affected by very strong and rapid degradation of the surface, even using relatively moderate cell voltages of below 4 V. Upon closer microscopic inspection, the degraded surfaces exhibited large areas of cracks and holes and a significant part of the layer turned black which indicated formation of graphite. Although these unintentionally carbonized surfaces surprisingly exhibited an improved adsorption behavior (see Chapter 3.3), yet they cannot repeatedly be employed in a process of technical relevance. All crystalline BDD electrodes tested were completely ineffective with regard to [18F]fluoride trapping from aqueous solutions (Figure 4). For cell voltages between 0 and 5 V only a loss of activity on the level of the background was recorded which can be attributed to residual liquid on the surface of electrodes. Even at much higher cell voltages of 20 V this picture did not change; due to the strong electrolysis of water under such conditions no stable
8 process conditions could be achieved. Additionally, for some electrodes even degradation and carbonization of the surface was observed at cell voltages of more than 4 V after different time periods. Especially the thin layers of 2 µm were prone to this effect. High current densities led to an increased application of energy that caused a carbonization process. The metastable diamond layers were partially converted to graphite layers which is the thermodynamically more stable form of carbon. This process was accompanied by an increase of current of more than one order of magnitude. As discussed for the DLC layers, the resulting higher graphitic content of carbonized electrodes led again to an increased fixation of [18F]fluoride. Figure 4 The results plotted in Figure 5 demonstrate that BDD layers are not suitable as anode material for a technical separation process. In general, comparing the materials of electrodes, a significant trend is recognizable which shows a dependence of the rate of [18F]fluoride fixation on the graphitic content of the electrodes. The lowest [18F]fluoride fixation was observed on different kinds of BDD electrodes. The fixation rates increased when using DLC electrodes and the best results were obtained with glassy carbon electrodes and graphite. This means that not only the electronic but also the structural configuration of carbon is a determining factor for the separation of [18F]fluoride out of aqueous media (Figure 3). These findings are in agreement with previous studies reporting anodic fluoride intercalation in graphitic electrodes (Noel et al., 1995). On the other hand, BDD electrodes can be used as cathode which then serve as anode during the release process of [18F]fluoride. The advantage leis in their inertness against trapping of [18F]fluoride and their electrochemical stability. Figure 5 2
The fact that only electrodes with a sp content are able to trap [18F]fluoride underlines the proposed mechanism of an intercalation complex which must be formed in order to trap the [18F]fluoride (Figure 6). This is in agreement with a quite recently published study (Sadeghi et al., 2013) which postulated the same mechanism for the electrochemical separation of [18F]fluoride using different metal electrodes. Therefore, the previously proposed electrostatic adsorption model (Hamacher et al., 1995) has to be strongly questioned Figure 6 3.2. Release of [18F]fluoride
9 For the release of [18F]fluoride, different solvents and the addition of ionic additives at - 2.5V were tested (cf. Figure 7). Results from research on lithium-ion batteries exhibited that for the release of fluoride from an intercalation complex of the type CFX an adequate cation M+ supports the first step of reductive ‘deintercalation’ (Takenaka et al., 1987; Watanabe et al., 1988). The whole process was described according to the following equation: CFn + n · M + n · e- → MnCFn → C + n · MF Thus, ionic additives like sodium chloride or sodium dodecylsulfonate should facilitate the release and were tested of their influence on the desorption of the intercalated [18F]fluoride. For all additives it is required that they are stable within the electric potentials applied.
Figure 7 The release efficiencies of the high temperature modification of glassy carbon (Sigradur®G) amounted to 60 ± 10 % (n = 4) in water in presence of sodium chloride and to 59 ± 5 % (n = 6) in DMSO in presence of sodium dodecylsulfonate as ionic additives, respectively. About 58 ±5 % (n = 2) of the [18F]fluoride could be released in DMSO in presence of the important anion activator Kryptofix© 2.2.2/potassium carbonate. A raise of the temperature to 60 °C only led to a minor increased liberation of [18F]fluoride. Therefore, heating is not required which simplifies the process engineering. The use of tetrabutylammonium bicarbonate led to a liberation of [18F]fluoride with 55 ± 5 % (n = 6) in acetonitrile at RT. Thus, it could be found that the release of [18F]fluoride is considerably improved in the presence of an ionic additive. In water, a release of [18F]fluoride of 42 ± 5 % (n = 2) was found which is probably due to the presence of protons destabilizing the fluoridecarbon intercalation compounds. In contrast, graphite electrodes (not shown in Fig. 7) and the low temperature modification Sigradur®K electrodes showed extremely poor [18F]fluoride release. Graphite electrodes showed a strong tendency to co-intercalate solvent molecules probably because of their porosity (Novák et al., 1997). Sigradur®K possibly shows similar effects. Thus, graphite as well as Sigradur®K are not suitable electrode materials for the separation of [18F]fluoride from the target water. These results altogether are a further affirmation of intercalation as the determinant process of the electrodeposition of [18F]fluoride when using carbon electrode material.
10
3.3. Sensitivity and degradation of electrode materials The high sensitivity of thin electrode layers with respect to degradation in contrast to bulk electrode materials causes difficulties when using such devices. The surfaces are mechanically sensitive to pressure and friction. Moreover, the particularly high electric energy transferred may result in chemical reactions. As discussed above (Chap. 3.1.) diamond and diamond-like coatings tend to change to thermodynamically more stable modifications at high voltages. This is of special relevance to thin BDD- und all DLC-layers. Possibly the high sp2 content of the latter facilitates more rapid conversion of the whole layer. Figure 8 In both cases resulting structures are porous and may scale off easily. Vapor locks arising in the porous material are due to electrolysis and can lead to an extensive flaking of material up to an exposure of the metal basis; especially when the layers are inhomogeneous. Due to resulting macroscopic defects electrodes were often not usable anymore after short applications during the performed studies. Especially reproducibility cannot be guaranteed above electric potentials of 2.5 V. Some BDD anode materials are pictured in Figure 8 after use for a short time. Graphite and glassy carbon electrodes, however, were subject to aging processes as well. As mentioned above (Chap. 3.2.) the mechanism of intercalation includes microscopic layer stripping effects which can influence the quality of electrodes. Extensive cleaning is thus necessary after each application and effects on surface roughness cause ablation of graphite and glassy carbon electrodes. Theoretically, it is possible that ablated carbon particles released due to surface degradation may influence subsequent nucleophilic 18F-fluorination. Moreover, carbon oxidation products, acetate and formate, were found with up to 6 ppm by ion chromatography analysis in the [18F]fluoride solution after separation by the Sigradur®G electrode. However, the synthesis of [18F]altanserin was not strongly influenced by these impurities as shown in a previous study (Hamacher et al., 2006).
4. Conclusion The best results for electrochemical trapping and release of [18F]fluoride were achieved with the glassy carbon electrodes of the type Sigradur®G. They are superior to pure graphite electrodes which are susceptible to water incorporation because of their physical properties and small pore size. Optimal results with glassy carbon at room temperature were achieved at
11 a cell voltage of 5 V for the fixation step and -2 to -4 V for the release step. No effect of the flow rate of water and organic liquids could be found. In contrast, BDD and DLC electrodes do not prove suitable for trapping and release of 18
[ F]fluoride. They only show little rates of [18F]fluoride fixation which probably can be attributed to a small loss of residual fluid on the surface of electrodes. Moreover, they degrade rapidly when applying voltages higher than 5 V. Inert BDD electrodes, however, appear better suitable as counter electrodes in order to maximize the potential window in water and to minimize competing fluoride losses on the counter electrode. This is especially valid for the release step with the reversed polarization. The used electrode combination of a Sigradur®G anode with a BDD cathode has the advantage of releasing [18F]fluoride at room temperature in comparable moderate yields as reported in a previous study (Saiki et al., 2010) where, however, conditions of elevated temperature were needed. The results obtained here clearly confirm an intercalation mechanism, as also proposed in previous studies with macroscopic amounts of fluoride, as determinant parameter for the [18F]fluoride fixation on graphitic carbon surfaces as well as its release from those. During preparation of this manuscript Sadeghi et al. (2013) published a study where they examined different metallic materials for trapping and releasing of [18F]fluoride. They found the same mechanism of intercalation when using brass-platinum electrodes (Sadeghi et al., 2013). In contrast to glassy carbon electrodes the brass electrode does not suffer from erosion and is thus reusable and faster while operating at increased voltages.
Acknowledgments The authors like to thank Mr. Karl-Heinz Riedel (INM-5, FZJ) and the Ferchau GmbH for construction and building the electrochemical cell. Our gratitude also goes to Drs. Markus Höfer and Lothar Schäfer from Fraunhofer IST (Braunschweig) for providing chemical deposition of diamond electrodes. This research project was supported by the VDI Technologiezentrum GmbH within a support program of the BMBF, Bundesministerium für Bildung und Forschung (MediWing, MoBi-Chip, FKZ 13N10272).
References Albin, S., Watkins, L., 1990. Electrical properties of hydrogenated diamond. Appl. Phys. Lett. 56, 1454-1456.
12 Alexoff, D., Schlyer, D.J., Wolf, A.P., 1989. Recovery of [18F]fluoride from [18O]water in an electrochemical cell. Appl. Radiat. Isot. 40, 1-6. Dekanski, A., Stevanović, J., Stevanović, R., Nikolić, B.Z., Jovanović, V.M., 2001. Glassy carbon electrodes: I. Characterization and electrochemical activation. Carbon 39, 11951205. Engstrom, R.C., Strasser, V.A., 1984. Characterization of electrochemically pretreated glassy carbon electrodes. Anal. Chem. 56, 136-141. Fryda, M., Matthée, Th., Mulcahy, S., Hampel, A., Schäfer, L., Tröster, I., 2003. Fabrication and application of Diachem® electrodes. Diam. Rel. Mat. 12, 1950-1956. Hamacher, K., Blessing, G., 1995, Process for separating carrier free radionuclides from target liquids, its use and arrangement therefor, Patent WO 95/18668. Hamacher, K., Hirschfelder, T., Coenen, H.H., 2002. Electrochemical cell for separation of [18F]fluoride from irradiated O-18 water and subsequent no carrier added nucleophilic fluorination. Appl. Radiat. Isot. 56, 519–523. Hamacher, K., Coenen, H.H., 2006. No-carrier-added nucleophilic 18F-labelling in an electrochemical cell exemplified by the routine production of [18F]altanserin. Appl. Radiat. Isot. 64, 9, 989-994. Matthée, Th., Schäfer, L., Schmidt, A., Klages, C.-P., 1997. Insulating diamond coatings on tungsten electrodes. Diam. Rel. Mat. 6, 293-297. Nakajima, T., Ogawa, T., Watanabe, N., 1988. Graphite anode reaction in the KF2HF melt. J. Fluor. Chem. 40, 407-417. Noel, M., Santhanam, R., Flora, F., 1995. Comparison of fluoride intercalation/deintercalation processes on graphite electrodes in aqueous and aqueous methanolic HF media. J. Power Sources 56, 125-131. Noel, M., Santhanam, R., 1998. Electrochemistry of graphite intercalation compounds, J. Power Sources 72, 53-65. Novák, P., Scheifele, W., Winter, M., Haas, O., 1997. Graphite electrodes with tailored porosity for rechargeable ion-transfer batteries. J. Power Sources 68, 267-270. Petrikowski, K., Fenker, M., Gäbler, J., Hagemann, A., Pleger, S., Schäfer, L., 2013. Study of CrNx and NbC interlayers for HFCVD diamond deposition onto WC–Co substrates. Diamond and Related Materials 33, 38-44. Qaim, S.M., Clark, J.C., Crouzel, C., Guillaume, M., Helmecke, H.J., Nebeling, B., Pike, V.W., Stöcklin, G., 1993, in Radiopharmaceuticals for PET, Stöcklin, G. and Pike, V.W. (Eds.), Kluwer Academic Publishers, Dordrecht, pp. 15 – 26.
13 Reischl, G., Ehrlichmann, W., Machulla, H.J., 2002. Electrochemical transfer of [18F] fluoride from [18O]water into organic solvents ready for labeling reactions. J. Radioanal. Nucl. Chem. 254, 29-31. Rensch, C., Boeld, C., Bachmann, B., Riese, S., Reischl, G., Ehrlichmann, W., Heumesser, N., Baller, M., Samper, V., 2009. Microfluidic radiosynthesis: Electrochemical phase transfer for drying [18F]fluoride. J. Labelled Compds Radiopharm. 52, S8. Rensch, C., Jackson, A., Lindner, S., Salvamoser, R., Samper, V., Riese, S., Bartenstein, P., Wängler, C., Wängler, B., 2013. Microfluidics: A groundbreaking technology for PET tracer production? Molecules 18, 7930-7956. Rüdorff, W., 1947. Salzartige Verbindungen des Graphits mit Flußsäure. Anorg. Allg. Chem. 254, 319-328. Rüdorff, W., 1959. Graphite Intercalation Compounds. Adv. Inorg. Chem. Radiochem. 1, 223266. Sadeghi, S., Ly, J., Deng, Y., Van Dam, R.M., 2010. A robust platinum-based electrochemical micro flow cell for drying of [18F]fluoride for PET tracer synthesis. In: Proceedings of the 14th International Conference on Miniatur- ized Systems for Chemistry and Life Sciences. Presented at the MicroTAS 2010, Groningen, The Netherlands, pp. 318–320. Sadeghi, S., Liang, V., Cheung, S., Woo, S., Wu, C., Ly, J., Deng, Y., Eddings, M., van Dam, R.M., 2013. Reusable electrochemical cell for rapid separation of [18F]fluoride from [18O]water for flow-through synthesis of 18F-labeled tracers. Appl. Radiat. Isot. 75, 85-94. Saito, F., Hyodo, T., Nagashima, Y., Iwaki, M., Goto, A., Inoue, T., Oka, T., Takahashi, N., 2004. Application of an Electro-Chemical Procedure to the Production of 18FPharmaceuticals. In: 17th International Conference on Cyclotrons and Their Applications, p.15. Saito, F., Nagashima, Y., Goto, A., Iwaki, M., Takahashi, N., Oka, T., Inoue, T., Hyodo, T., 2007. Electrochemical transfer of 18F from 18O water to aprotic polar solvent. Appl. Radiat. Isot. 65, 5, 524-527. Saiki, H., Iwata, R., Nakanishi, H., Wong, R., Ishikawa, Y., Furumoto, S., Yamahara, R., Sakamoto, K., Ozeki, E., 2010. Electrochemical concentration of no-carrier-added [18F]fluoride from [18O]water in a disposable microfluidic cell for radiosynthesis of
18
F-
labeled radiopharmaceuticals. Appl. Radiat. Isot. 68, 9, 1703-1708. Schäfer, L., Höfer, M., Kröger, R., 2006. The versatility of hot-filament activated chemical vapor deposition. Thin Solid Films 515, 1017-1024.
14 Takenaka, H., Kawaguchi, M., Lerner, M., Bartlett, N., 1987. Synthesis and Characterization of Graphite Fluorides by Electrochemical Fluorination in Aqueous and Anhydrous Hydrogen Fluoride. J. Chem. Soc. Chem. Commun. 19, 1431-1432. Wessmann, S.H., Henriksen, G., Wester, H.J., 2012. Cryptate mediated nucleophilic
18
F-
fluorination without azeotropic drying. Nukl. Med. 51, 1-8. Wong, R., Iwata, R., Saiki, H., Furumoto, S., Ishikawa, Y., Ozeki, E., 2012. Reactivity of electrochemically concentrated anhydrous [18F]fluoride for microfluidic radiosynthesis of 18
F-labeled compounds. Appl. Radiat. Isot. 70, 193-199.
Table 1. Boron-doped diamond (BDD) and diamond-like carbon (DLC) selected as electrodes.
Layer thickness Qualitative (boron)-doping- [µm] level BDD-1 microcrystalline high 2 BDD-2 microcrystalline middle 10 BDD-3 microcrystalline low 8 BDD-4 microcrystalline low 2 BDD-5 110-texturized low 15.3 BDD-6 110-texturized high 13.5 BDD-7 microcrystalline low 7.9 BDD-8 nanocrystalline low 8.0 BDD-9 nanocrystalline high > 10 BDD-10 nanocrystalline high > 10 BDD-11 nanocrystalline low > 10 BDD-12 nanocrystalline low > 10 BDD-13 microcrystalline high 15 DLC-1 DLC > 10 DLC-2 DLC WC* > 10 DLC-3 DLC > 10 DLC-4 DLC WC* > 10 DLC-5 DLC > 10 *Doped with tungsten carbide (WC = tungsten carbide) No.
Carbon-crystaltype
Configuration in fixation step anode cathode anode anode anode anode cathode anode anode anode anode anode anode anode anode anode anode anode
15
Figure 1. Cell design for the on-line fixation of n.c.a. [18F]fluoride. The volume of the chamber between the two electrodes amounts to about 330 µL.
Figure 2. Scheme of the device for electrodeposition of [18F]fluoride in a flow cell.
16
Figure 3.
Dependence of [18F]fluoride deposition on cell voltage using graphite or glassy carbon anode
and BDD or tungsten (W) cathode, respectively.
Figure 4. Dependence of [18F]fluoride deposition on cell voltage using DLC anodes.
17
Figure 5. Dependence of [18F]fluoride deposition on cell voltage using BDD anodes.
Figure 6. Proposed mechanism based on suggestion of Noel et al. (1998).
18
Figure 7. [18F]Fluoride release from Sigradur®K (SK) and Sigradur®G (SG) electrodes under different conditions. *n=2; **n=4; ***n=6. Release efficiency is based on the deposited amount.
19
Figure 8. Some BDD and DLC surfaces after the electrochemical process cycle. The active layer in contact with the solution is significantly degraded as is visible due to a strong color change. Some areas have turned partially black due to carbonization. A: BDD-10 after single application with local carbonization in the reaction area; B/C: BDD-3 and BDD-4 after single application and long-time conditioning with complete separation of the nano crystalline layer along the fluid channel; D/E: BDD-1 and BDD-9 after multiple applications and voltages above 3 V with complete surface destruction; F: BDD-8 after a single application. Enlargement of the reaction area showing separation of the nano crystalline layer.
Research Highlights •
Pyrolysed carbon proved as most efficient carbon material for electrodeposition of [18F]fluoride.
•
Transfer of 60 % [18F]fluoride into dry organic solvents.
•
An intercalation mechanism was found for the electrodeposition of [18F]fluoride.
Optimizing the transfer of [18F]fluoride from aqueous to organic solvents by electrodeposition using carbon electrodes Fabian Kügler, Daniel Roehrens, Milosch Stumpf, Christian Drerup, Johannes Ermert, Kurt Hamacher, Heinz H. Coenen
www.elsevier.com/locate/apradiso
PII: DOI: Reference:
S0969-8043(14)00158-4 http://dx.doi.org/10.1016/j.apradiso.2014.04.019 ARI6674
To appear in:
Applied Radiation and Isotopes
Received date: 13 December 2013 Revised date: 17 April 2014 Accepted date: 28 April 2014 Cite this article as: Fabian Kügler, Daniel Roehrens, Milosch Stumpf, Christian Drerup, Johannes Ermert, Kurt Hamacher, Heinz H. Coenen, Optimizing the transfer of [18F]fluoride from aqueous to organic solvents by electrodeposition using carbon electrodes, Applied Radiation and Isotopes, http://dx.doi.org/10.1016/j. apradiso.2014.04.019 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Optimizing the transfer of [18F]fluoride from aqueous to organic solvents by electrodeposition using carbon electrodes Fabian Kügler, Daniel Roehrens, Milosch Stumpf, Christian Drerup, Johannes Ermert, Kurt Hamacher, Heinz H. Coenen Institute of Neuroscience and Medicine, INM-5: Nuclear Chemistry, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany
Keywords: [18F]fluoride, electrodeposition, carbon electrodes, intercalation, micro fluidics Abstract The effect of varying structural modifications of carbon anodes, ranging from thin layers of crystalline boron-doped diamond up to highly graphitic bulk materials, was systematically examined for the possibility of electrochemical fixation and desorption of no-carrier-added [18F]fluoride from an aqueous solution. Pyrolysed carbon, i.e. “glassy carbon” (Sigradur®G), proved as the most efficient material for deposition and release. An overall radiochemical yield of about 60 % was achieved when using this for fixation and DMSO/ionic additive as organic solution for the release of [18F]fluoride.
1. Introduction Transfer of n.c.a. [18F]fluoride from water to an organic solvent almost exclusively marks the first essential step for every radiofluorination in order to achieve an activated anion for nucleophilic substitution. The electrodeposition of radioactive [18F]fluoride on carbon electrodes from aqueous media has been studied as one possible method for more than two decades (Alexoff et al., 1989; Hamacher et al., 2002; Reischl et al. 2002, Rensch et al. 2009, Saiki et al., 2010) and was readily employed as an alternative to the generally used, more classical approaches to remove water for the production of radiopharmaceuticals (Saito et al., 2004; Saito et al., 2007; Hamacher et al., 2006). The attractiveness of the electrochemical method for isolation of n.c.a. [18F]fluoride in comparison is due to i) ease recovery of highly enriched [18O]water, ii) technical simplification of its drying and transfer into appropriate organic solvents, and iii) of its concentration into small volume, useful for minimizing synthesizer apparatuses down to microfluidic devices.
2
The azeotropic distillation has some disadvantages compared to an electrochemical separation, because it is more time consuming and requires additional technical equipment in a remote-controlled synthesizer like gas flow and pressure controllers. Rapid azeotropic drying is technically even more challenging to be integrated in a microfluidic system (Rensch et al., 2013). The alternative approach of water removal by a solid phase drying method on a strong anion-exchange resin (Wessmann et al., 2012), however, also usually requires 200 µL to 480 µL elution volumes for sufficient [18F]fluoride recovery. Thus, in spite of the many efforts , there is still an unsolved challenge for transferring n.c.a. [18F]fluoride from (several) milliliters of target water into microliter volumes of organic solvent. Here, the electrochemical method enables simplification of the hardware architecture which was already verified in automated syntheses for routine production of e.g. n.c.a. [18F]altanserin (Hamacher et al., 2006), [18F]FDG (Saiki et al., 2010) and [18F]flumazenil (Wong et al., 2012). The other above mentioned advantage of the electrochemical method for transferring the radionuclide into anhydrous solvents is the efficient recovery of highly enriched [18O]water. This is of special interest since the enriched material is expensive and availability sometimes limited. So far performed studies (Hamacher et al., 2006, Saiki et al., 2010) attempted quantitative anodic deposition of the [18F]fluoride primarily using glassy carbon electrodes at cell voltages ranging from 2 to 5 V and employing a platinum counter electrode. The deposited activity is subsequently released after removal of water into a dry organic solvent under a reverse potential with milder voltages. Typically very high degrees of anodic deposition of up to 90 % have been demonstrated in earlier studies, while the cathodic release proved to be the limiting factor for the overall recovery yield. So far, significant release rates only exhibit an efficiency of about 60 % which served as a primary motivation for the search of novel electrode materials. A further challenge was the observation that glassy carbon surfaces degrade under electrical re-polarisation which can be associated with the release of particulates (Sadeghi et al., 2010). The mechanistic details of deposition and release processes of [18F]fluoride using an electric field have not been elaborated in detail in earlier studies. Hamacher and coworkers postulated as model an electrostatic adsorption of [18F]fluoride on the anode surface which means that the [18F]fluoride is trapped and held by the electric field (Hamacher et al., 1995). Quite recently, Sadeghi and coworkers studied different metallic materials for trapping and releasing of [18F]fluoride in a micro-flow cell (Sadeghi et al., 2013). They found out that a brass anode at a temperature of 65 °C and an applied potential of +20 V gave the best results
3 of [18F]fluoride deposition. By performing X-ray photoelectron spectroscopy (XPS) studies on different anode surfaces after (non-radioactive) macroscopic fluoride trapping the authors hypothesized that the performance of fluoride fixation and desorption is related to surface oxides, depth of intercalation, and the nature of chemical bonds formed on the surface during the electrochemical process. The conclusions drawn involved less sharply defined parameters, such as the cell voltage, the geometry and reactor type (batch or flow), and an optimal setup has yet to be identified. The nature of the carbon anode material is assumed to be of foremost importance, and systematic studies are required. Aside from radiochemical applications, graphite fluorides as a class of intercalation compounds with varying stoichiometry are well documented compounds (Rudorff et al., 1947; Rudorff et al., 1959). First, they have been reported as an anodic by-product during fluorine production from an ionic source (Nakajima et al., 1988). Graphite fluorides are readily formed from aqueous sources using analogous conditions like in the radiochemical deposition studies. These structures have been characterized as metastable compounds which decompose in the presence of water and air (Takenaka et al., 1987; Noel et al., 1995; Noel et al., 1998). In this study, the comprehensive mechanistic and structural information known for intercalation of stable [19F]fluoride was applied with the examination of the electrodeposition of [18F]fluoride on carbon-electrode surfaces in aqueous media. Despite several publications on single materials, to the best of our knowledge no comparative study exists up to now in which a wide range of carbon materials is compared and evaluated for their ability for electrochemical absorption of [18F]fluoride ions. Since the influence of the electrode material will determine overall yields and transfer-process efficiency, a comparative examination under identical conditions is essential for the development of an optimized electro deposition set-up. Therefore, a systematic approach was used here to compare the yields of fixation on electrodes from graphite, glassy carbon (low and high temperature modification), amorphous diamond-like carbon (DLC) thin films, and polycrystalline boron doped diamond (BDD) in a planar electrochemical flow cell reactor.
2. Materials and methods All BDD and DLC thin layer electrodes were prepared by the Fraunhofer Institute for Surface Engineering and Thin Films (IST, Braunschweig, Germany), employing specialized chemical vapor deposition (CVD) methods on tungsten substrates (Matthée et al., 1997; Fryda et al., 2003). Bulk glassy carbon electrodes of Sigradur®G and Sigradur®K quality were
4 purchased from HTW GmbH (Thierhaupten, Germany) and bulk graphite electrodes from NGS Naturgraphit GmbH (Leinburg, Germany). The perfluorinated-elastomer seal (FPM 75) was delivered by Zrunek Gummiwaren GmbH (Vienna, Austria). The fluid transport was realized by a dosing diaphragm pump RO5-3, delivered by Fink Chem+Tec OHG (Bad Dürrheim, Germany). Radioactivity in the cell was monitored with a Geiger counter (Ø 13.5 mm; 90 mm) from Genitron Instruments GmbH (Frankfurt, Germany). Radioactive solutions were quantified with an ionization chamber (Curiementor 2 from PTW, Freiburg, Germany). The temperature of the electrodes was measured and regulated by the Quick-Control QC-PCOS 22G device, purchased from Quick-Ohm GmbH (Wuppertal, Germany). The electrical potential control was realized by a Keithley Series 2400 SourceMeter delivered by Keithley Instruments, Inc. (Cleveland, Ohio, USA). All solvents and chemicals were purchased from Fluka (Buchs, Switzerland) and used without further purification. Ion-chromatography was performed on a Metrohm 882 Compact IC plus with a Metrosep A Supp 5 - 150/4.0 column (Deutsche METROHM GmbH & Co. KG,
70794 Filderstadt) using an aqueous buffer
solution of 3.2 mM Na2CO3 and 1 mM NaHCO3. 2.1
Electrode material
Different carbon materials were used as electrode within an electric potential ranging from 0 to 5 V. Besides graphite, glassy carbon (Sigradur®) exhibits the highest ratio of graphitic structural elements among the selected materials. It is composed of 100 % sp2-configured carbon without surface dangling bonds (Dekanski et al., 2001). Both modifications of bulk material of glassy carbon, low temperature Sigradur®K and high temperature Sigradur®G, were examined. In order to analyze electrode surfaces with a higher fraction of sp3 hybridized carbon thin layers of diamond-like carbon on tungsten backings were employed as working electrodes in the electrochemical cell (Schäfer et al., 2006, Petrikowski et al., 2013). As amorphous carbon material it displays higher sp3 carbon content while most of its structure still consists of unsaturated carbon. It may be regarded as an intermediate form between highly graphitic modifications and crystalline diamond. Finally, polycrystalline boron doped diamond electrodes were used as material for anodic fixation. Doping levels of boron were varied between approximately 500 ppm to 4000 ppm in order to test a wide range of electrical conductivity which may affect the deposition process. Additionally, the morphology and crystallographic properties of the diamond films were varied by applying three different types of diamond deposition processes leading to microcrystalline, nanocrystalline and (110)-texturized films. Under polycrystalline growth
5 conditions the randomly oriented diamond crystals grow in average to sizes from about 0.5 to 4 µm by increasing the film thickness from 2 to 8 microns. The corresponding layer roughness increases from Ra = 100 nm to Ra = 500 nm (Ra = average roughness), respectively. For obtaining smooth electrode surface samples, corresponding growth conditions were chosen in order to prepare nanocrystalline diamond films with particle sizes well below 50 nm. In this case the surface roughness corresponds mainly to the initial roughness of the backing-material. Finally, 110-textured diamond layers were grown exhibiting a pronounced preferential crystallographic orientation. For each BDD modification, different layer thicknesses were prepared. With this set of electrodes, a wide spectrum of chemical, crystallographic, morphological and electrical surface modifications was covered. A list of the employed electrode materials is given in Table 1.
Table 1 2.1.
Preparation of [18F]fluoride
N.c.a. [18F]fluoride was produced via the 18O(p,n)18F nuclear reaction by bombardment of isotopically enriched [18O]water (> 96%) purchased from Rotem Industrial Park (Israel) in a titanium-target (Qaim et al., 1993) with 17 MeV protons at the JSW cyclotron BC 1710 (INM-5, Forschungszentrum Jülich, Germany). 2.2.
Electrochemical flow cell
The electrochemical cell consists of a planar two electrode arrangement. Anode and cathode are fitted together as an aluminum stack with a 0.5 mm thick electrically isolating elastomer gasket located in between the planar electrodes. A cut-out in the middle of the seal with a length of 62 mm and a width of 10 mm defines the size of the cell chamber. A schematic view of the complete cell is shown in Figure 1. In comparison, Sadeghi et al. (2013) use for their studies an electrochemical flow-cell in shape of a serpentine channel pattern a fluid path of 46 mL volume cut into a polymer film, which is clamped between two rigid electrodes. Rensch et al. (2009) use a 20 µL microfluidic reactor with a glassy carbon anode. Both set-ups were optimized with regard to performing radiofluorination in microfluidic systems. The focus in the study here, however, was to test the suitability of different carbon electrodes for electrochemical separation of [18F]fluoride, rather than to perform radiofluorination experiments. Thus, the area of the electrode was of
6 less importance and much larger which also resulted from the methods of their production, especially for the BDD and DLC material. Figure 1 2.3.
Experimental procedure of electrodeposition of [18F]fluoride with different electrodes
An automated module was developed for the fixation and desorption of about 50-150 MBq n.c.a. [18F]fluoride. A flow chart of the module for the deposition and release process is given in Fig. 2. For each experiment a 2 mL aliquot of an aqueous [18F]fluoride solution was used. Preconditioning Before starting with the deposition experiments the electrochemical cell was preconditioned by passing a volume of about 5 mL H2O (sterile water, B.Braun, Melsungen, Germany) at 2 mL/min through the cell chamber while applying a constant cell voltage of 5 V in an anodic polarization configuration, referring to the carbon working electrode. Through this, potential impurities on the surface of electrodes were removed (Engstrom et al., 1984). Furthermore, the synthesis of diamond layers by chemical vapor deposition lead to a surface which is terminated with hydrogen atoms and is hydrophobic and p-type conducting (Albin et al., 1990). The preconditioning procedure converts the layer to an oxygen-terminated diamond surface which improves the hydrophilic and insulating properties of the layer.
Figure 2 Fixation process The aqueous [18F]fluoride solution was transported directly through the cell at a constant flow rate of 0.2 mL/min under a previously set constant cell voltage, and the
18
F-depleted
water was collected. After the deposition step, the cell was purged by a flow of helium in order to transport the residual water into the collection vial. The amount of the deposited [18F]fluoride was determined by subtracting the decay corrected activity of the eluted from that of the starting solution, quantitatively determined with an ionization chamber. Additionally, the process was monitored by a cylindrical radiation detector in a fixed geometry at 1 cm distance directly above the planar cell in order to continuously record the level/ amount of radioactivity during the process. Release process
7 After the deposition step the cell voltage was set to 0 V and the cell chamber was conditioned with 1-2 mL of dry organic solvent used for the release of [18F]fluoride. Subsequently, a reversed electric potential of -2.5 V was applied where the carbon working electrode acted as cathode. A solution of either an additive (3 mmol) in 3 mL of dry dimethyl sulfoxide (DMSO), 3 mL of pure DMSO, or 3 mL of water was then pumped through the cell with a constant flow of 0.2 mL/min. The eluted radioactive solution was collected and analyzed as described above for the fixation step. 3. Results and Discussion 3.1. Fixation of [18F]fluoride on carbon electrodes Both modifications of glassy carbon (Sigradur®G and Sigradur®K) showed nearly quantitative fixation of [18F]fluoride of 96 ± 3 % (n = 3) over a range of 3 to 5 V when using BDD as cathode material. The use of tungsten as cathode, however, yielded a lower fixation of [18F]fluoride on Sigradur®G (Figure 3). For comparison, with pure graphite a quantitative fixation was already reached at 4 V. The adsorption pattern of the graphitic bulk electrodes showed a strong increase from the baseline at a characteristic cell voltage which is indicative for an electrochemical nature of the adsorption mechanism. Fluoride is incorporated into the graphite matrix which requires a characteristic electrode potential and a charge transfer (electrical current flow) in order to facilitate a transport of ions through the phase barrier. Figure 3 2
In spite of the higher sp content of DLC electrodes compared to the BDD electrodes it is obviously not high enough. This is probably why they display only low to moderate fixation and thus appear not suitable for the separation process. Additionally, all DLC layers were immediately affected by very strong and rapid degradation of the surface, even using relatively moderate cell voltages of below 4 V. Upon closer microscopic inspection, the degraded surfaces exhibited large areas of cracks and holes and a significant part of the layer turned black which indicated formation of graphite. Although these unintentionally carbonized surfaces surprisingly exhibited an improved adsorption behavior (see Chapter 3.3), yet they cannot repeatedly be employed in a process of technical relevance. All crystalline BDD electrodes tested were completely ineffective with regard to [18F]fluoride trapping from aqueous solutions (Figure 4). For cell voltages between 0 and 5 V only a loss of activity on the level of the background was recorded which can be attributed to residual liquid on the surface of electrodes. Even at much higher cell voltages of 20 V this picture did not change; due to the strong electrolysis of water under such conditions no stable
8 process conditions could be achieved. Additionally, for some electrodes even degradation and carbonization of the surface was observed at cell voltages of more than 4 V after different time periods. Especially the thin layers of 2 µm were prone to this effect. High current densities led to an increased application of energy that caused a carbonization process. The metastable diamond layers were partially converted to graphite layers which is the thermodynamically more stable form of carbon. This process was accompanied by an increase of current of more than one order of magnitude. As discussed for the DLC layers, the resulting higher graphitic content of carbonized electrodes led again to an increased fixation of [18F]fluoride. Figure 4 The results plotted in Figure 5 demonstrate that BDD layers are not suitable as anode material for a technical separation process. In general, comparing the materials of electrodes, a significant trend is recognizable which shows a dependence of the rate of [18F]fluoride fixation on the graphitic content of the electrodes. The lowest [18F]fluoride fixation was observed on different kinds of BDD electrodes. The fixation rates increased when using DLC electrodes and the best results were obtained with glassy carbon electrodes and graphite. This means that not only the electronic but also the structural configuration of carbon is a determining factor for the separation of [18F]fluoride out of aqueous media (Figure 3). These findings are in agreement with previous studies reporting anodic fluoride intercalation in graphitic electrodes (Noel et al., 1995). On the other hand, BDD electrodes can be used as cathode which then serve as anode during the release process of [18F]fluoride. The advantage leis in their inertness against trapping of [18F]fluoride and their electrochemical stability. Figure 5 2
The fact that only electrodes with a sp content are able to trap [18F]fluoride underlines the proposed mechanism of an intercalation complex which must be formed in order to trap the [18F]fluoride (Figure 6). This is in agreement with a quite recently published study (Sadeghi et al., 2013) which postulated the same mechanism for the electrochemical separation of [18F]fluoride using different metal electrodes. Therefore, the previously proposed electrostatic adsorption model (Hamacher et al., 1995) has to be strongly questioned Figure 6 3.2. Release of [18F]fluoride
9 For the release of [18F]fluoride, different solvents and the addition of ionic additives at - 2.5V were tested (cf. Figure 7). Results from research on lithium-ion batteries exhibited that for the release of fluoride from an intercalation complex of the type CFX an adequate cation M+ supports the first step of reductive ‘deintercalation’ (Takenaka et al., 1987; Watanabe et al., 1988). The whole process was described according to the following equation: CFn + n · M + n · e- → MnCFn → C + n · MF Thus, ionic additives like sodium chloride or sodium dodecylsulfonate should facilitate the release and were tested of their influence on the desorption of the intercalated [18F]fluoride. For all additives it is required that they are stable within the electric potentials applied.
Figure 7 The release efficiencies of the high temperature modification of glassy carbon (Sigradur®G) amounted to 60 ± 10 % (n = 4) in water in presence of sodium chloride and to 59 ± 5 % (n = 6) in DMSO in presence of sodium dodecylsulfonate as ionic additives, respectively. About 58 ±5 % (n = 2) of the [18F]fluoride could be released in DMSO in presence of the important anion activator Kryptofix© 2.2.2/potassium carbonate. A raise of the temperature to 60 °C only led to a minor increased liberation of [18F]fluoride. Therefore, heating is not required which simplifies the process engineering. The use of tetrabutylammonium bicarbonate led to a liberation of [18F]fluoride with 55 ± 5 % (n = 6) in acetonitrile at RT. Thus, it could be found that the release of [18F]fluoride is considerably improved in the presence of an ionic additive. In water, a release of [18F]fluoride of 42 ± 5 % (n = 2) was found which is probably due to the presence of protons destabilizing the fluoridecarbon intercalation compounds. In contrast, graphite electrodes (not shown in Fig. 7) and the low temperature modification Sigradur®K electrodes showed extremely poor [18F]fluoride release. Graphite electrodes showed a strong tendency to co-intercalate solvent molecules probably because of their porosity (Novák et al., 1997). Sigradur®K possibly shows similar effects. Thus, graphite as well as Sigradur®K are not suitable electrode materials for the separation of [18F]fluoride from the target water. These results altogether are a further affirmation of intercalation as the determinant process of the electrodeposition of [18F]fluoride when using carbon electrode material.
10
3.3. Sensitivity and degradation of electrode materials The high sensitivity of thin electrode layers with respect to degradation in contrast to bulk electrode materials causes difficulties when using such devices. The surfaces are mechanically sensitive to pressure and friction. Moreover, the particularly high electric energy transferred may result in chemical reactions. As discussed above (Chap. 3.1.) diamond and diamond-like coatings tend to change to thermodynamically more stable modifications at high voltages. This is of special relevance to thin BDD- und all DLC-layers. Possibly the high sp2 content of the latter facilitates more rapid conversion of the whole layer. Figure 8 In both cases resulting structures are porous and may scale off easily. Vapor locks arising in the porous material are due to electrolysis and can lead to an extensive flaking of material up to an exposure of the metal basis; especially when the layers are inhomogeneous. Due to resulting macroscopic defects electrodes were often not usable anymore after short applications during the performed studies. Especially reproducibility cannot be guaranteed above electric potentials of 2.5 V. Some BDD anode materials are pictured in Figure 8 after use for a short time. Graphite and glassy carbon electrodes, however, were subject to aging processes as well. As mentioned above (Chap. 3.2.) the mechanism of intercalation includes microscopic layer stripping effects which can influence the quality of electrodes. Extensive cleaning is thus necessary after each application and effects on surface roughness cause ablation of graphite and glassy carbon electrodes. Theoretically, it is possible that ablated carbon particles released due to surface degradation may influence subsequent nucleophilic 18F-fluorination. Moreover, carbon oxidation products, acetate and formate, were found with up to 6 ppm by ion chromatography analysis in the [18F]fluoride solution after separation by the Sigradur®G electrode. However, the synthesis of [18F]altanserin was not strongly influenced by these impurities as shown in a previous study (Hamacher et al., 2006).
4. Conclusion The best results for electrochemical trapping and release of [18F]fluoride were achieved with the glassy carbon electrodes of the type Sigradur®G. They are superior to pure graphite electrodes which are susceptible to water incorporation because of their physical properties and small pore size. Optimal results with glassy carbon at room temperature were achieved at
11 a cell voltage of 5 V for the fixation step and -2 to -4 V for the release step. No effect of the flow rate of water and organic liquids could be found. In contrast, BDD and DLC electrodes do not prove suitable for trapping and release of 18
[ F]fluoride. They only show little rates of [18F]fluoride fixation which probably can be attributed to a small loss of residual fluid on the surface of electrodes. Moreover, they degrade rapidly when applying voltages higher than 5 V. Inert BDD electrodes, however, appear better suitable as counter electrodes in order to maximize the potential window in water and to minimize competing fluoride losses on the counter electrode. This is especially valid for the release step with the reversed polarization. The used electrode combination of a Sigradur®G anode with a BDD cathode has the advantage of releasing [18F]fluoride at room temperature in comparable moderate yields as reported in a previous study (Saiki et al., 2010) where, however, conditions of elevated temperature were needed. The results obtained here clearly confirm an intercalation mechanism, as also proposed in previous studies with macroscopic amounts of fluoride, as determinant parameter for the [18F]fluoride fixation on graphitic carbon surfaces as well as its release from those. During preparation of this manuscript Sadeghi et al. (2013) published a study where they examined different metallic materials for trapping and releasing of [18F]fluoride. They found the same mechanism of intercalation when using brass-platinum electrodes (Sadeghi et al., 2013). In contrast to glassy carbon electrodes the brass electrode does not suffer from erosion and is thus reusable and faster while operating at increased voltages.
Acknowledgments The authors like to thank Mr. Karl-Heinz Riedel (INM-5, FZJ) and the Ferchau GmbH for construction and building the electrochemical cell. Our gratitude also goes to Drs. Markus Höfer and Lothar Schäfer from Fraunhofer IST (Braunschweig) for providing chemical deposition of diamond electrodes. This research project was supported by the VDI Technologiezentrum GmbH within a support program of the BMBF, Bundesministerium für Bildung und Forschung (MediWing, MoBi-Chip, FKZ 13N10272).
References Albin, S., Watkins, L., 1990. Electrical properties of hydrogenated diamond. Appl. Phys. Lett. 56, 1454-1456.
12 Alexoff, D., Schlyer, D.J., Wolf, A.P., 1989. Recovery of [18F]fluoride from [18O]water in an electrochemical cell. Appl. Radiat. Isot. 40, 1-6. Dekanski, A., Stevanović, J., Stevanović, R., Nikolić, B.Z., Jovanović, V.M., 2001. Glassy carbon electrodes: I. Characterization and electrochemical activation. Carbon 39, 11951205. Engstrom, R.C., Strasser, V.A., 1984. Characterization of electrochemically pretreated glassy carbon electrodes. Anal. Chem. 56, 136-141. Fryda, M., Matthée, Th., Mulcahy, S., Hampel, A., Schäfer, L., Tröster, I., 2003. Fabrication and application of Diachem® electrodes. Diam. Rel. Mat. 12, 1950-1956. Hamacher, K., Blessing, G., 1995, Process for separating carrier free radionuclides from target liquids, its use and arrangement therefor, Patent WO 95/18668. Hamacher, K., Hirschfelder, T., Coenen, H.H., 2002. Electrochemical cell for separation of [18F]fluoride from irradiated O-18 water and subsequent no carrier added nucleophilic fluorination. Appl. Radiat. Isot. 56, 519–523. Hamacher, K., Coenen, H.H., 2006. No-carrier-added nucleophilic 18F-labelling in an electrochemical cell exemplified by the routine production of [18F]altanserin. Appl. Radiat. Isot. 64, 9, 989-994. Matthée, Th., Schäfer, L., Schmidt, A., Klages, C.-P., 1997. Insulating diamond coatings on tungsten electrodes. Diam. Rel. Mat. 6, 293-297. Nakajima, T., Ogawa, T., Watanabe, N., 1988. Graphite anode reaction in the KF2HF melt. J. Fluor. Chem. 40, 407-417. Noel, M., Santhanam, R., Flora, F., 1995. Comparison of fluoride intercalation/deintercalation processes on graphite electrodes in aqueous and aqueous methanolic HF media. J. Power Sources 56, 125-131. Noel, M., Santhanam, R., 1998. Electrochemistry of graphite intercalation compounds, J. Power Sources 72, 53-65. Novák, P., Scheifele, W., Winter, M., Haas, O., 1997. Graphite electrodes with tailored porosity for rechargeable ion-transfer batteries. J. Power Sources 68, 267-270. Petrikowski, K., Fenker, M., Gäbler, J., Hagemann, A., Pleger, S., Schäfer, L., 2013. Study of CrNx and NbC interlayers for HFCVD diamond deposition onto WC–Co substrates. Diamond and Related Materials 33, 38-44. Qaim, S.M., Clark, J.C., Crouzel, C., Guillaume, M., Helmecke, H.J., Nebeling, B., Pike, V.W., Stöcklin, G., 1993, in Radiopharmaceuticals for PET, Stöcklin, G. and Pike, V.W. (Eds.), Kluwer Academic Publishers, Dordrecht, pp. 15 – 26.
13 Reischl, G., Ehrlichmann, W., Machulla, H.J., 2002. Electrochemical transfer of [18F] fluoride from [18O]water into organic solvents ready for labeling reactions. J. Radioanal. Nucl. Chem. 254, 29-31. Rensch, C., Boeld, C., Bachmann, B., Riese, S., Reischl, G., Ehrlichmann, W., Heumesser, N., Baller, M., Samper, V., 2009. Microfluidic radiosynthesis: Electrochemical phase transfer for drying [18F]fluoride. J. Labelled Compds Radiopharm. 52, S8. Rensch, C., Jackson, A., Lindner, S., Salvamoser, R., Samper, V., Riese, S., Bartenstein, P., Wängler, C., Wängler, B., 2013. Microfluidics: A groundbreaking technology for PET tracer production? Molecules 18, 7930-7956. Rüdorff, W., 1947. Salzartige Verbindungen des Graphits mit Flußsäure. Anorg. Allg. Chem. 254, 319-328. Rüdorff, W., 1959. Graphite Intercalation Compounds. Adv. Inorg. Chem. Radiochem. 1, 223266. Sadeghi, S., Ly, J., Deng, Y., Van Dam, R.M., 2010. A robust platinum-based electrochemical micro flow cell for drying of [18F]fluoride for PET tracer synthesis. In: Proceedings of the 14th International Conference on Miniatur- ized Systems for Chemistry and Life Sciences. Presented at the MicroTAS 2010, Groningen, The Netherlands, pp. 318–320. Sadeghi, S., Liang, V., Cheung, S., Woo, S., Wu, C., Ly, J., Deng, Y., Eddings, M., van Dam, R.M., 2013. Reusable electrochemical cell for rapid separation of [18F]fluoride from [18O]water for flow-through synthesis of 18F-labeled tracers. Appl. Radiat. Isot. 75, 85-94. Saito, F., Hyodo, T., Nagashima, Y., Iwaki, M., Goto, A., Inoue, T., Oka, T., Takahashi, N., 2004. Application of an Electro-Chemical Procedure to the Production of 18FPharmaceuticals. In: 17th International Conference on Cyclotrons and Their Applications, p.15. Saito, F., Nagashima, Y., Goto, A., Iwaki, M., Takahashi, N., Oka, T., Inoue, T., Hyodo, T., 2007. Electrochemical transfer of 18F from 18O water to aprotic polar solvent. Appl. Radiat. Isot. 65, 5, 524-527. Saiki, H., Iwata, R., Nakanishi, H., Wong, R., Ishikawa, Y., Furumoto, S., Yamahara, R., Sakamoto, K., Ozeki, E., 2010. Electrochemical concentration of no-carrier-added [18F]fluoride from [18O]water in a disposable microfluidic cell for radiosynthesis of
18
F-
labeled radiopharmaceuticals. Appl. Radiat. Isot. 68, 9, 1703-1708. Schäfer, L., Höfer, M., Kröger, R., 2006. The versatility of hot-filament activated chemical vapor deposition. Thin Solid Films 515, 1017-1024.
14 Takenaka, H., Kawaguchi, M., Lerner, M., Bartlett, N., 1987. Synthesis and Characterization of Graphite Fluorides by Electrochemical Fluorination in Aqueous and Anhydrous Hydrogen Fluoride. J. Chem. Soc. Chem. Commun. 19, 1431-1432. Wessmann, S.H., Henriksen, G., Wester, H.J., 2012. Cryptate mediated nucleophilic
18
F-
fluorination without azeotropic drying. Nukl. Med. 51, 1-8. Wong, R., Iwata, R., Saiki, H., Furumoto, S., Ishikawa, Y., Ozeki, E., 2012. Reactivity of electrochemically concentrated anhydrous [18F]fluoride for microfluidic radiosynthesis of 18
F-labeled compounds. Appl. Radiat. Isot. 70, 193-199.
Table 1. Boron-doped diamond (BDD) and diamond-like carbon (DLC) selected as electrodes.
Layer thickness Qualitative (boron)-doping- [µm] level BDD-1 microcrystalline high 2 BDD-2 microcrystalline middle 10 BDD-3 microcrystalline low 8 BDD-4 microcrystalline low 2 BDD-5 110-texturized low 15.3 BDD-6 110-texturized high 13.5 BDD-7 microcrystalline low 7.9 BDD-8 nanocrystalline low 8.0 BDD-9 nanocrystalline high > 10 BDD-10 nanocrystalline high > 10 BDD-11 nanocrystalline low > 10 BDD-12 nanocrystalline low > 10 BDD-13 microcrystalline high 15 DLC-1 DLC > 10 DLC-2 DLC WC* > 10 DLC-3 DLC > 10 DLC-4 DLC WC* > 10 DLC-5 DLC > 10 *Doped with tungsten carbide (WC = tungsten carbide) No.
Carbon-crystaltype
Configuration in fixation step anode cathode anode anode anode anode cathode anode anode anode anode anode anode anode anode anode anode anode
15
Figure 1. Cell design for the on-line fixation of n.c.a. [18F]fluoride. The volume of the chamber between the two electrodes amounts to about 330 µL.
Figure 2. Scheme of the device for electrodeposition of [18F]fluoride in a flow cell.
16
Figure 3.
Dependence of [18F]fluoride deposition on cell voltage using graphite or glassy carbon anode
and BDD or tungsten (W) cathode, respectively.
Figure 4. Dependence of [18F]fluoride deposition on cell voltage using DLC anodes.
17
Figure 5. Dependence of [18F]fluoride deposition on cell voltage using BDD anodes.
Figure 6. Proposed mechanism based on suggestion of Noel et al. (1998).
18
Figure 7. [18F]Fluoride release from Sigradur®K (SK) and Sigradur®G (SG) electrodes under different conditions. *n=2; **n=4; ***n=6. Release efficiency is based on the deposited amount.
19
Figure 8. Some BDD and DLC surfaces after the electrochemical process cycle. The active layer in contact with the solution is significantly degraded as is visible due to a strong color change. Some areas have turned partially black due to carbonization. A: BDD-10 after single application with local carbonization in the reaction area; B/C: BDD-3 and BDD-4 after single application and long-time conditioning with complete separation of the nano crystalline layer along the fluid channel; D/E: BDD-1 and BDD-9 after multiple applications and voltages above 3 V with complete surface destruction; F: BDD-8 after a single application. Enlargement of the reaction area showing separation of the nano crystalline layer.
Research Highlights •
Pyrolysed carbon proved as most efficient carbon material for electrodeposition of [18F]fluoride.
•
Transfer of 60 % [18F]fluoride into dry organic solvents.
•
An intercalation mechanism was found for the electrodeposition of [18F]fluoride.
