Current Radiopharmaceuticals, 2012, 5, 271-287 271 Electrochemical Separation is an Attractive Strategy for Development of Radionuclide Generators for Medical Applications Rubel Chakravarty, Ashutosh Dash and M.R.A. Pillai* Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Mumbai – 400 085, India Abstract: Electrochemical separation techniques are not widely used in radionuclide generator technology and only a few studies have been reported [1-4]. Nevertheless, this strategy is useful when other parent-daughter separation techniques are not effective or not possible. Such situations are frequent when low specific activity (LSA) parent radionuclides are used for instance with adsorption chromatographic separations, which can result in lower concentration of the daughter radionuclide in the eluent. In addition, radiation instability of the column matrix in many cases can affect the performance of the generator when long lived parent radionuclides are used. Intricate knowledge of the chemistry involved in the elec- trochemical separation is crucial to develop a reproducible technology that ensures that the pure daughter radionuclide can be obtained in a reasonable time of operation. Crucial parameters to be critically optimized include the applied potential, choice of electrolyte, selection of electrodes, temperature of electrolyte bath and the time of electrolysis in order to ensure that the daughter radionuclide can be reproducibly recovered in high yields and high purity. The successful electrochemi- cal generator technologies which have been developed and are discussed in this paper include the 90Sr/90Y, 188W/188Re and 99Mo/99mTc generators. Electrochemical separation not only acts as a separation technique but also is an effective concen- tration methodology which yields high radioactive concentrations of the daughter products. The lower consumption of reagents and minimal generation of radioactive wastes using such electrochemical techniques are compatible with ‘green chemistry’ principles. Keywords: Electrochemical separation, No-carrier-added, Radionuclide generator, 99Mo/99mTc generator, 90Sr/90Y generator, 188W/188Re generator. INTRODUCTION in the production of radionuclides to be used as parent nu- clides in generators, development of sophisticated radio- The development of radionuclide generators over the past chemical separations and reliable technical designs of the five decades was primarily motivated by the increasing generator systems [5-7]. For example, over 30 million diag- gamut of applications of short-lived radionuclides and their nostic imaging studies are performed annually with 99mTc, compounds in nuclear medicine, oncology, interventional thanks to its convenient availability from different types of cardiology/radiology and related specialties [5-10]. The 99 99m Mo/ Tc generators [11]. The separation of the par- longer half-lives of parent radionuclides allow their transpor- ent/daughter pairs which more often belong to the adjacent tation to sites distant from the reactor or cyclotron-based group of elements is the most challenging aspect in the field parent production facilities for the on-site separation of of radionuclide generator research. Often the radiochemical daughter radionuclides which are otherwise not available. A separation is also complicated by the multiple par- radionuclide generator system consists of a convenient in- ent/daughter oxidation states and tendencies to form a vari- house production system comprising the parent/daughter pair ety of complexes with the chelating ligands that might be which is used on-demand to separate the daughter product in present in the eluent [8]. The requirement of the daughter a ready to use form. The successful routine use of a radionu- radionuclide in a form suitable for radiopharmaceutical ap- clide generator system depends on the efficiency of the ra- plications places stringent conditions on the separation tech- diochemical separation of the daughter radionuclide from the nique, production and handling of the generators. Hence, parent radionuclide which in turn depends on the extent of careful selection of the separation procedure capable of giv- difference in chemical properties of these two chemical spe- ing high yield of the daughter radionuclide in minimum vol- cies. Post separation, the daughter product should have high umes (high radioactive concentration) and highest purity is radionuclidic, radiochemical and chemical purity together important. Preferably, the daughter activity should be ob- with adequate radioactive concentration to ensure its subse- tained in a chemical form that is amenable for direct use in quent intended use. The daughter product is isolated in ‘no- the preparation of radiopharmaceuticals and suitable for hu- carrier-added’ (NCA) form with specific activity approach- man administration. ing the theoretical values. Various techniques, such as column chromatography, The increasing use of generator-produced radionuclides solvent extraction and sublimation have been traditionally for biomedical applications has fostered significant progress used for the preparation of radionuclide generators [12-17]. Conversion of the parent radionuclide into an insoluble ‘gel’ and its use as the column matrix from which the daughter *Address correspondence to this author at the Radiopharmaceuticals radionuclide can be eluted is yet another strategy that has Division, Bhabha Atomic Research Centre, Mumbai – 400 085, India; Tel: +91-22-25593676; Fax: +91-22-25505151; E-mail: [email protected] been reported [7,18-22]. The separation technique used in 1874-4729/12 $58.00+.00 © 2012 Bentham Science Publishers 272 Current Radiopharmaceuticals, 2012, Vol. 5, No. 3 Chakravarty et al. Power Supply (V) Electrolyte: Metallic salt in aqueous medium (Mn+ ) Cathode Anode (Working electrode) (Counter electrode) Electrolysis cell M n+ H 2 O "reduction" "oxidation" _ _ M n+ + ne M(0) M (0) M n+ + ne Evolution of hydrogen Evolution of oxygen + + 2H + 2e = H 2 (acidic medium) 2H 22 O = O + 4H + 4e (acidic medium) _ _ 2H 2 O + 2e = 2OH (basic medium) 4OH = O 2 + 2H 2 O + 4e (basic medium) Fig. (1). Schematic illustration of an electrochemical process in aqueous medium. radionuclide generators is usually selected based on techni- Although this discussion is by no means exhaustive, the in- cal, economic and logistical reasons, with emphasis on one tent is to provide a general overview of the electrochemical or another of these factors depending on the circumstances. separation approach, underlying the challenges involved and While the column chromatography generators (i.e. highlight the merits of this process for the development of 99Mo/99mTc, 90Sr/90Y and 188W/188Re etc.) are the most pre- radionuclide generators suitable for biomedical applications. ferred owing to their operational simplicity, often the limited radiation and chemical stability of the sorbent in certain cases [23,24] can be a major concern for their routine and/or ELECTROCHEMISTRY AS A TOOL IN RADIONU- long-term use. Such circumstances can lead to breakthrough CLIDE GENERATOR TECHNOLOGY of the longer lived parent radioisotope. In addition, chemical Electrochemistry is the branch of chemistry concerned impurities due to the dissolution of the column matrix and with the interrelation of electrical and chemical effects [46]. from degradation of the daughter may contaminate the The electrochemical process is basically an oxidation- daughter eluate, thereby rendering it unsuitable for clinical reduction reaction that takes place at the surface of conduc- use. Additionally, owing to the limited sorption capacity of tive electrodes in a chemical medium under the influence of many column matrices, the parent radioisotope must gener- an applied potential. The schematic illustration of an electro- ally be available with very high specific activity in order to chemical process in aqueous medium is provided in Fig. (1). minimize the size of the column bed so that the daughter Besides its numerous other applications, this method is activity can be eluted with appreciably high radioactive con- widely used in chemistry for the separation of metal ions as centration. Though the constraint on the specific activity of well as for developing analytical techniques for determina- the parent radioisotope can often be overcome to a great ex- tion of trace quantities of metal ions [47,48]. The major ad- tent by the use of solvent extraction [16], sublimation [17], vantage of using the electrochemical approach over other post-elution concentration [25] and ‘gel-based’ [18-22] tech- conventional methods is avoidance of addition of extraneous niques, these methods also have their inherent limitations reagents to the electrolyte solution which may complicate which may often restrict their applicability for clinical use subsequent studies. In electrolytic separations only hydrogen [12]. Recently, numerous high capacity sorbents have been ions are ordinarily introduced by the anode reaction by reported for the preparation of column chromatographic ra- amounts equivalent to the metal deposited at the cathode dionuclide generators which may show promise for wide- [48]. Therefore little additional treatment of the metal de- spread use [26-41]. posit would be required for the removal of any chemical im- The use of electrochemistry as a radionuclide generator purities. separation technique was first applied for the separation of The electrochemical separation of metal ions was first 90 90 clinical grade Y