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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 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 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 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 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 ‘’ 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 , The increasing use of generator-produced radionuclides solvent 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 ‘’ 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 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 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 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 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 from long lived Sr [1]. The technology reported as early as 1903 by the French scientist M.A. Hol- was further extended to other parent/daughter systems such lard [48, 49], who utilized this approach for the separation of 188 188 99 99m as W/ Re, Mo/ Tc etc. [2-4, 42-45]. This article re- nickel from zinc using amalgamated zinc as anode and plati- views the prospect of using electrochemistry as a separation num as cathode. Subsequently, a host of papers were pub- method in radionuclide generator technology and essential lished on the electrochemical separation of other metal ions. features of the electrochemical generator systems developed. An exhaustive summary of the important electrochemical Electrochemical Separation is an Attractive Strategy for Development Current Radiopharmaceuticals, 2012, Vol. 5, No. 3 273

Potentiostat The development of radionuclide generators based on electrochemistry represents a novel area of research that re- D.C. Inert Gas Power Bubbling quires an intimate knowledge of electrochemistry and radio- chemistry. Considerable research efforts are therefore re- V quired to assess the potential of this approach to yield valu- able results in the evolution of radionuclide generator tech-

Vent nology. The process of depositing daughter radionuclide on an inert electrode from an aqueous electrolyte must be de- SCE Reference Electrode veloped and validated through a series of practical studies, Platinum Plate experiments and demonstrations. Additional efforts are Platinum Plate needed regarding recovery of daughter radionuclide from the Parent-daughter Electrolyte electrode since this process is quite different from conven- Argon Gas Cylinder tional separation techniques. The use of electrochemical Magnetic Stirrer separation presents an attractive alternative to the conven- tional column chromatography since it eliminates the sorp- Fig. (2). Schematic diagram of the electrochemical set up used in tion capacity restriction and allows the use of LSA parent radionuclide generators. radioisotope to avail daughter radionuclide with very high radioactive concentration and radionuclidic purity. separations is provided in the classic textbook by Lingane [48]. Electrochemistry is also widely applied during the The electrochemical separation process using metallic preparation of targets and processing from production of electrodes precludes the possibility of radiolytic damage radioisotopes in accelerators [50-55]. The use of electro- often encountered in column generators and exhibits consis- chemistry in the production and isolation of carrier-free ra- tently good performance over a prolonged time period. The dioisotopes has been reviewed by Garrison and Hamilton electrochemical set up and the peripheral equipment re- [56]. However, no reports have been describing the use of quirement is simple and relatively inexpensive. The sche- electrochemistry in parent-daughter separation technology matic diagram of a typical electrochemical set up used in except the two early publications in the 1950s by Lange et radionuclide generator systems is shown in Fig. (2). Addi- al. [57] and Hamaguchi et al. [58], where electrochemistry tionally, multiple electrolyses are possible from the same was used for the separation of 90Y from 90Sr. The isolation of 99 primary feed solution without much chemical manipulation milligram quantities of long-lived technetium-99g ( Tc) which makes the process user-friendly and economical. This using electrochemical route was reported in 1960 [59]. How- technology thus leads to generation of minimum amounts of ever, for unknown reasons, the application of electrochemi- radioactive wastes in each batch, thereby simplifying the cal techniques for the development of radionuclide genera- issues associated with radioactive waste management. Fur- tors remained dormant for over 50 years after the early pub- lications of Lange et al. [57] and Hamaguchi et al. [58]. The thermore, the separation process generally involves electro- first report on use of electrochemistry in the development of chemistry in aqueous medium using solid electrodes and is medically useful radionuclide generators was published by therefore easily amenable for automation. In essence, the the authors in 2008 which demonstrated the separation of 90Y electrochemical generators can be conveniently used for from 90Sr [1]. The technology was further utilized for the large-scale production of daughter radionuclides in remotely- preparation of a fully automated generator under the initia- operated lead shielded facilities in centralized radiopharma- tive of the International Atomic Energy Agency (IAEA) and cies. The radionuclide generator systems for which the elec- a commercial model “Kamadhenu” is available from Isotope trochemical separation approach has been utilized are sum- Technologies, Dresden [60]. marized in Table 1.

Table 1. The Radionuclide Generator Systems Developed by the Electrochemical Separation Approach

Generator System 90Sr/90Y 188W/188Re 99Mo/99mTc

Parent production 235U(n,f)90Sr 186W(n,)187W(n,)188W 98Mo(n,)99Mo

2+ + 2- - Electrochemical reactions Sr + 2e  Sr WO3 + 6H + 6e  W + 3 H2O MoO4 + 4H2O + 6e  Mo + 8OH Eº = -2.89 V Eº = -0.090 V Eº= 1.05 V

3+ - +  + Y + 3e  Y ReO4 + 8H + 7e  Re + 4 H2O TcO4 + 4H +3e  TcO2 + 2H2O Eº = -2.27 V Eº = +0.362 V Eº= +0.738 V

Daughter is selectively electrodeposited by careful control of applied potential

Daughter applications Radioimmunotherapy, radiation Radioimmunotherapy, radiation Diagnostic nuclear medicine proce- synovectomy, liver cancer therapy, synovectomy, bone pain palliation, dure using SPECT mould brachytherapy for treatment liver cancer therapy, prevention of of superficial skin cancers, etc. restonosis after angioplasty using 188Re liquid filled balloons, etc. 274 Current Radiopharmaceuticals, 2012, Vol. 5, No. 3 Chakravarty et al.

Fig. (3). Criterion for choosing the optimum electrode potential for selective electrodeposition of the daughter.

PRINCIPLE OF ELECTROCHEMICAL SEPARA- such as the design of the electrochemical cell, choice of elec- TION OF THE DAUGHTER RADIONUCLIDE FROM trodes, choice of electrolyte, electrolyte pH, electrodeposi- THE PARENT tion time, etc. are also responsible for effective and efficient separation of the daughter radionuclide with purity suitable The electrochemical separation of daughter radionuclide for radiopharmaceutical application. These factors also play from its long-lived parent is primarily based on the differ- a crucial role in sustained and reproducible performance of ence in their formal electrode potential in a particular elec- the generator in all the batches over its shelf-life (usable life trolyte solution. This process therefore requires careful con- time of the generator). Hence, careful optimization of these trol of the applied potential so that either the daughter or the parameters is necessary prior to the preparation of the radi- parent is selectively deposited on a metallic electrode. The onuclide generators using electrochemical approach. preference is for the deposition of daughter radionuclide so that after the electrolysis it can be stripped back in minimum volume of desired solution in order to avail it with maximum Applied Potential radioactive concentration. Further, by electrodepositing the In order to achieve selective electrodeposition of the daughter radionuclide the primary electrolyte solution con- daughter radionuclide from the parent/daughter , the taining the parent remains unaffected and it can be used for applied potential should be more negative than the formal subsequent electrolysis after allowing sufficient time for the reduction potential of the daughter but should be less growth of the daughter, with minimum chemical manipula- negative than the formal reduction potential of the parent ion tion. Though electrolysis can generally be performed under in that particular medium. This condition is applicable only both galvanostatic (constant current) as well as potentiostatic if the formal electrode potential of the parent ion is more (constant potential) conditions, for radiochemical separations negative than the formal electrode potential of the daughter the preferred approach is to carry out the electrolysis under ion, or in other words, the parent ion is more difficult to re- constant potential condition so that the co-deposition of the duce compared to the daughter ion. The criterion for choos- extraneous radionuclides and other elements can be avoided and the desired radionuclide will be available with high radi- ing the optimum electrode potential for selective electrode- onuclidic and chemical purity. position of the daughter is illustrated in Fig. (3), by consider- ing examples of the 90Sr/90Y, 188W/188Re and 99Mo/99mTc generator systems. If the reverse is true, the parent radioiso- PARAMETERS TO BE OPTIMIZED FOR DEVELOP- tope must be selectively electrodeposited instead of the ING AN ELECTROCHEMICAL GENERATOR daughter required for electrochemical separation which The applied potential is the major driving force for the might not be a desirable feature. Therefore, the optimum selective electrodeposition of a particular radionuclide from applied potential should be determined on a case-to-case parent/daughter mixture. Besides this, several other factors basis. Electrochemical Separation is an Attractive Strategy for Development Current Radiopharmaceuticals, 2012, Vol. 5, No. 3 275

+ _ POWER SUPPLY For determination of the optimum potential, cyclic volt- Argon Vent gas ammograms (CV) of the parent and daughter solutions purging should be generally recorded under the same electrolytic Water outlet conditions using an appropriate working electrode. However, if the electrolysis is carried out under highly acidic condi- Platinum Mercury anode cathode tions (pH <2) and a platinum electrode is used as the work- Water inlet ing electrode, the CV might exhibit erroneous results at a potential <0 V owing to intense hydrogen evolution which Clamp stand Platinum cathode Stop might mask the reduction peaks corresponding to the metal cock ions. Under such conditions, the electrodeposition yields of

Collection both the parent and daughter radionuclides should be evalu- beaker ated at different applied potentials and the optimum potential should be judiciously selected based on this data.

Choice of the Electrolyte Fig. (4). Schematic diagram of the water-jacketed electrochemical The medium in which the electrolysis is performed plays cell for maintaining the temperature of the electrolyte. a crucial role in the electrochemical separation of the daugh- ter radionuclide from the parent radionuclide. Generally, the electrolysis, the pH of the electrolyte tends to increase due to + formal electrode potential of a particular ion in a given elec- loss of H ions in the form of hydrogen gas. Therefore, a trolytic medium is governed by its tendency to form com- suitable buffer must be added to the electrolyte to annul the plexes in that medium. The electrolyte must be carefully change in pH. However, the chosen buffer should not inter- chosen so that there is a substantial difference in the formal fere in the electrochemical process. electrode potential of the two ions to achieve their electro- chemical separation. Occasionally, it may be essential to Choice of Electrode dissolve a suitable complexing agent in the electrolyte solu- Generally, for electrochemical separation in a radionu- tion to ease the selective electroreduction of a particular ion clide generator the electrode material should be inert so that [61]. Additionally, the potential applied for electrodeposition it does not add chemical impurities to the daughter product. should be within the ‘electrochemical potential window’ of Ideally, the electrode material should not react in the electro- the electrolyte so that the electrolyte itself does not undergo lyte medium and should resist oxidation/reduction during the electrolytic degradation during the course of electrolysis course of electrolysis. Moreover, it should be able to with- [48,62]. stand the intense radiation during multiple electrolyses over A variety of organic electrolytes and room temperature a prolonged period of time. Generally, gold and platinum ionic liquids (RTILs) in which electrolysis can be carried out electrodes are preferred for such applications due to their over a wide range of potential are now commercially avail- high conductance, good electrochemical and chemical inert- able [63,64]. However, such solvents with organic frame- ness, excellent radiation stability and ease of fabrication into works are generally not suitable for use in radionuclide gen- any dimension due to malleability of these metals. Such elec- erators, as the electrolyte itself might undergo radiolysis in trodes can easily be cleaned and polished prior to subsequent the presence of intense radiation, which in turn might affect electrolysis. the separation efficacy of the electrochemical process. The radiolytic products may be constituted as chemical impuri- Temperature of the Electrolyte ties with the daughter product and affect the subsequent ra- diolabeling experiments. Moreover, owing to radiolytic The temperature of the electrolyte bath is usually main- damage, multiple electrolyses using the same primary elec- tained well below its boiling point during the course of elec- trolyte would give non-reproducible results. trolysis. Generally, in aqueous medium the optimum tem- perature range is between 25-60 ºC. Sometimes it may be The use of an aqueous electrolyte is thus preferred for necessary to carry out the electrolysis in a water jacketed electrochemical separation of the daughter radionuclide from glass cell, as shown in Fig. (4), having provision for circula- the parent using this radionuclide generator technology. Al- tion of cold water in order to maintain the temperature of the though, evolution of hydrogen gas by the electrolysis of wa- electrolyte [43]. If the electrolysis is carried out at tempera- ter in aqueous medium reduces the current efficiency of the ture near the boiling point, rapid of the electro- electrodeposition process, the chances of radiolytic damage lyte might lead to deposition of solute residue (carrying par- are minimal. Prior to electrolysis, the radiolytic products of ent radionuclide) along with the electrodeposition of daugh- water can easily be removed by warming the electrolyte for ter radionuclide on the surface of the electrode. Hence, the sometime with constant purging of an inert gas. Moreover, separated daughter product might contain radionuclidic im- due to evolution of hydrogen gas at the cathode, a non- purities in the form of parent radionuclide and further purifi- adherent deposit of the daughter radionuclide is formed on cation would be required prior to its utilization for the prepa- the surface of cathode which can easily be stripped off for ration of radiopharmaceuticals. subsequent use. Time of Electrolysis The pH of the aqueous electrolyte also plays an important role in the electrodeposition process as it influences the vigor The time for which the electrolysis is carried out must be of hydrogen evolution. Generally, during the course of the carefully optimized in order to achieve the electrochemical 276 Current Radiopharmaceuticals, 2012, Vol. 5, No. 3 Chakravarty et al. separation within a reasonable time-frame. This is especially The ohmic overpotential (o) is the product of the resis- important while dealing with short-lived daughter products. tance (R) of the cell in ohms and the current (I) in amperes This can be achieved by studying the electrodeposition yield and is called the IR drop of the cell. The IR drop can be re- at different time intervals. If electrolysis is carried out for duced by increasing the ionic strength of the electrolyte solu- time periods longer than necessary, the possibility of co- tion [62]. Generally, in electrochemical separation inert sol- deposition of extraneous radionuclides and other elements utes like KCl or NH4NO3 (as supporting electrolyte) which might increase. Additionally, if electrolysis is carried out for do not participate in the electrochemical reaction are added a long time period, the cathodic deposit in the presence of to the primary electrolyte solution to increase the conduc- electric current might convert into a phase which may be tance of the cell. The IR drop can also be reduced by using a strongly adherent to the electrode surface and hence may be ‘three-electrode assembly’ comprising a counter electrode difficult to leach out from the electrode for subsequent use (anode), working electrode (cathode) and a reference elec- [2,42]. However, if electrolysis is carried out for time less trode [62]. The current passes between the working electrode than what is necessary the electrodeposition yield of the and the counter electrode. Generally, saturated calomel elec- daughter radionuclide will be low. Hence, the optimum time trode (SCE) or Ag/AgCl electrode is used as the reference period should be carefully evaluated and chosen prior to ac- electrode. With this arrangement, only a very small current tual electrochemical separation runs. The optimum time pe- passes between the working electrode and the reference elec- riod need not necessarily be the time needed for the highest trode and minimizes the IR drop. Besides, the use of the yield as minimization of the deposition of the parent during ‘three-electrode system’ has an additional advantage over the electrolysis is also important to ensure higher radionuclidic conventional ‘constant applied potential’ method using a purity for the isolated daughter radionuclide. two-electrode assembly. Though the ‘constant potential method’ using two electrodes is quite selective, it may some- THE CONSIDEREATIONS IN SETTING UP THE times require an inordinately long electrolysis time [48,62]. ELECTROCHEMICAL ASSEMBLY FOR RADIONU- Therefore, the most direct and satisfactory method of pre- CLIDE GENERATORS cisely controlling the potential of a working electrode, and thus achieving a high degree of selectivity is to apply con- A simple and robust electrochemical assembly, as shown stant potential to the working electrode (cathode) against a in Fig. (2) would be required for the development of a radi- onuclide generators providing in-house availability of daugh- standard reference electrode. However, wherever applicable, ter radionuclides with purity adequate for clinical applica- the use of the two-electrode system is desirable and can also tions. The electrochemical cell is generally an open end be used for radiochemical separations, since it is compara- quartz cylinder of appropriate dimensions, fitted with an tively simpler and involves an inexpensive electrochemical acrylic or teflon cap. The positive and negative electrodes set-up. generally consist of platinum plates of high purity (>99%). Concentration over potential (c) occurs because of the The electrodes are fitted through holes in the cap and main- finite rate of from the solution to the electrode tained at distance as close as possible (generally ~5 mm) surface [62]. With sustained electrolysis, the concentration at from each other. Reducing the distance between the elec- the electrode surface differs from that in the bulk of the solu- trodes decreases the internal resistance of the cell, thereby tion and the electrode potential differs from its value with no increasing the current efficiency of the electrochemical proc- current flow. In order to have a steady current in the cell ess. In order to avoid short-circuiting, care must be taken to during the course of electrolysis, the interfacial region must ensure that the electrodes do not touch each other. After ad- be continuously replenished with reactant from the bulk of dition of the appropriate electrolyte to the electrochemical the solution. During electrolysis, the concentration polariza- cell, the electrodes are connected to a potentiostat (constant tion can be decreased by ‘forced convection’, such as stirring potential power supply) and the electrolysis is carried out by the electrolyte or using rotating electrodes [62]. Therefore, a applying the desired potential (Fig. 2). provision for stirring the electrolyte solution using a mag- An electrode through which a finite current is passing has netic stirrer is provided in the electrochemical assembly (Fig. a potential different from the zero-current or equilibrium 2) to reduce the effects of concentration polarization during value [62]. This difference is called the ‘overpotential’ value the course of the electrolysis. (). Basically,  is the difference in potential when the elec- The third component is referred to as the activation over- trode is at equilibrium and when it is sustaining a net anodic potential (a) which is associated with rate-determining elec- or cathodic reaction: tron-transfer process and is not much dependent on the ex-

 = (E)reaction - (E)equilibrium ternal factors during the course of electrolysis [62]. When electrolysis is carried out in aqueous solutions, as where (E)reaction is the potential of the electrode on passing in the case of the electrochemical generators, two possible current through it and (E)equilibrium is the equilibrium potential. The overpotential  is required to overcome the hindrance in background processes always occur which are the evolution the overall electrode reaction. Generally, it comprises of of hydrogen at the cathode and evolution of oxygen at the anode [48,62]: three components namely, ohmic overpotential o, concen- tration overpotential c and activation overpotential a. Thus, the total overpotential (T) is the sum of all these Evolution of Hydrogen components: + 2H + 2e  H2 (acidic medium) - T = o + c + a 2H2O + 2e  H2 + 2OH (basic medium) Electrochemical Separation is an Attractive Strategy for Development Current Radiopharmaceuticals, 2012, Vol. 5, No. 3 277

Evolution of Oxygen potentials periodically for certain duration of time. Subse- quently, the electrode is again washed with deionized water, 2H O O + 4H+ + 4e (acidic medium) 2  2 followed by washing with acetone. - 4OH  O2 + 2H2O+ 4e (basic medium) Therefore, a small outlet is provided in the cap of the DEVELOPMENT OF RADIONUCLIDE GENERA- electrochemical cell (Fig. 2) for venting the gases evolved. If TORS there is no provision for removing these gases, the mixture of hydrogen and oxygen might form an explosive mixture. A brief review of the electrochemical approaches used Moreover, the presence of oxygen gas in the electrolytic cell for development of radionuclide generators is presented be- may interfere in the reduction of the daughter radionuclide. low and detailed descriptions have been published [1-4]. The electrolyte solution might also contain other dissolved 90 90 gases such as carbon dioxide which may react with the spe- Sr/ Y Generator cies deposited on the surface of the electrode and give unde- Yttrium-90 (90Y) is a therapeutic radioisotope of enor- sirable results [65]. To expedite the removal of the dissolved mous interest and radiopharmaceuticals based on 90Y are gases from the electrolyte, a provision of passing an inert gas widely used for the treatment of cancer as well as in radia- (such as argon) through a glass tube dipping into the electro- tion synoviorthesis [67-76]. The broad interest in the use of lyte is provided (Fig. 2). The passage of the inert gas not 90Y in therapeutic nuclear medicine is due to its suitable nu- only removes the dissolved gases but also agitates the elec-  clear characteristics (t = 64.1 h,  max 2.28 MeV, no - trolyte solution in order to reduce the concentration polariza- emission) [77] and M (+3) coordination chemistry suitable tion. for complexation with various ligands and biomolecules. A In order to minimize the radiation exposure to working radionuclide generator system based on the secular equilib- 90 90 personnel, the electrochemical cell (Fig. 2) needs to be rium of strontium-90 ( Sr) decaying to Y is a convenient 90 housed within a shielded plant or inside a fume-hood with method for the production of high specific activity Y [78- adequate local shielding. It is advisable to reuse the reaction 80]. Unlike other therapeutic radionuclides, there is an un- 90 90 vessel (electrolytic cell) to contain the parent radionuclide limited potential for availing Y, since Sr is one of the major fission products and the annual world production of after each separation which will help in maintaining an in- 90 ventory control of the parent radionuclide. In order to re- Sr in nuclear reactors amounts to several hundred megacu- cover the daughter radionuclide after the electrolysis, the ries [81]. 90 deposit on the cathode can be transferred to a vessel having a Owing to the long half-life of Sr (t = 28.8 y), the tech- suitable solution to dissolve the daughter. If this is not easily nology required for fabrication of 90Sr/90Y generators is con- achievable, the electrode is transferred into a new electrolytic siderably different from the column chromatographic separa- cell containing requisite volume of the solution of interest tions used for other commercially available generators such and the deposit is electrochemically dissolved (oxidized) by as the 99Mo/99mTc and 188W/188Re generator systems [78]. reversing the polarity of the electrode and applying a high The 90Sr parent cannot be maintained on the column matrix applied potential for a short period of time. The solution of any longer than necessary, because of denaturation of the the daughter radionuclide obtained can then be used for sub- sorbent resulting from energy deposition of the high energy sequent applications. These issues are discussed in more – particles from decay of 90Sr and 90Y. Such decomposition 90 detail in the examples which follow. of the adsorbent often results in lower Y yields and break- through of 90Sr in the eluate [78]. The availability of 90Y with It is generally believed that platinum and gold are truly very low levels of 90Sr contamination is essential for thera- inert metals and do not undergo oxidation when used as elec- peutic applications, since 90Sr localizes in the skeleton and, trodes in prolonged bulk electrolysis. However, thermody- owing to its long half-life, has a very low maximum permis- namic metal-metal oxide potentials indicate that oxidation of sible body burden of 74 kBq (2 μCi) over patient lifetime these metals can certainly occur under electrochemical con- [82]. The presence of 90Sr in bones can induce primary bone ditions [48, 62, 66]. Moreover, when electrolysis is carried cancer, cancer of nearby tissues and leukemia. Because of out using platinum electrodes at potential values sufficiently + the potential dangers involved in handling and possible spill cathodic than that required for reduction of H ions (E0 = 0 of 90Sr, in-house reloading of generator columns cannot be V), hydrogen gas is evolved and the platinum electrode ad- recommended and can only be performed in specialized sorbs the evolved hydrogen [48, 62]. However, gold does not . This is also essential from the security perspec- sorb hydrogen to any appreciable extent [62]. The oxidation tive of 90Sr in hospital radiopharmacies in order to prevent its of the electrodes and sorption of hydrogen gas passivates the misuse in the public domain. Therefore, it is necessary that electrode surface after a typical batch of electrolysis. If the the 90Sr/90Y generator supplied to radiopharmacies must be a electrodes are not cleaned after each batch, the electrodeposi- closed system with strict maintenance of the inventory of tion yield decreases substantially from subsequent batches. 90Sr. Several procedures have been recommended in the literature for cleaning the noble-metal electrodes [48, 62]. Generally, The Need for Electrochemical Separation of 90Y from the electrode is dipped in strong nitric acid solution over- 90Sr night and then washed several times with deionized water. In order to hasten and ensure completion of the cleaning proc- Over the past three decades, several separation technolo- 90 90 ess it is preferable to use electrical pretreatment by immers- gies were reported for the development of Sr/ Y genera- ing the electrode in a clean electrolyte solution (containing tors [79, 80, 83-99]. Most of these separation techniques no electroactive species) and applying positive and negative involve multiple steps employing conventional separation 278 Current Radiopharmaceuticals, 2012, Vol. 5, No. 3 Chakravarty et al. approaches such as solvent extraction, ion exchange or ex- time required for a complete run was about 3–4 h and the traction chromatography either alone or in combination. overall yield of 90Y achieved was >90%. However, none of these procedures are amenable for regular Over a period of 3 years, the above experiments were re- use in a hospital radiopharmacy or in a central radiophar- 90 peated >50 times with 1.85 GBq (50 mCi) of Sr, using the macy. With the commercial availability of an electrochemi- same feed solution in order to ascertain the consistency in cal 90Sr/90Y generator (named Kamadhenu), its routine use in the performance of the generator and the results were quite a central radiopharmacy can be visualized [60]. reproducible in all the batches. The pH of the solution was When the electrochemical separation of 90Y3+ from 90Sr2+ checked and adjusted, if needed, prior to each run. The ace- by Lange et al. [57] and by Hamaguchi et al. [58] was re- tone used for washing the electrodes was the only source of ported as early as 1957-58, the term ‘generator’ was yet to be radioactive waste in the entire process and it was found that used. Surprisingly electrochemistry was never exploited for the total liquid waste generated in one typical operation con- the preparation of a generator system until the authors first tained < 1 MBq of 90Sr. reported the development of a 90Sr/90Y generator in 2008 [37]. However, Reischl et al. [65] and Yoo et al. [100] used Quality Control of 90Y electrochemistry for the separation of 86Y, a PET radionu- The extremely high toxicity of 90Sr limits its levels in the clide, from milligram quantities of a proton irradiated stron- 90 tium target. Y product and also necessitates its absolute quantification before patient administration of 90Y-based radiopharmaceuti- 90 2+ 2+ 90 cal. Sr is analogous to Ca and accumulates in bone. The Principle of Electrochemical Separation of Y from 90 Because of this bone-seeking nature and the very long half- Sr life of 28.8 y, the maximum permissible body burden The separation of Y from a mixture of Sr and Y is based (MPBB) for 90Sr is as low as 74 kBq (2 μCi) [78,82]. This on the selective electrodeposition of Y on a platinum elec- value translates to a limit of 74 kBq of 90Sr in 37 GBq of 90Y, trode, attributed to the difference in standard electrode poten- assuming that a patient may be administered with a maxi- 90 tial of Sr2+ and Y3+ ions in acidic media. The electrochemical mum of 37 GBq of Y over an entire life time. These limits necessitate that 90Y should be carefully analyzed to ensure reactions involved and their standard reduction potentials are 90 as follows [66]: that the levels of Sr are well below the limits of 74 kBq per 37 GBq of 90Y. In the case of the 90Sr/90Y pair, both the par- 2+ Sr + 2e  Sr Eº = -2.89 V ent and daughter are pure - emitters and no -emissions are 3+ available to permit -analysis. Additionally, -spectra of Y + 3e  Y Eº = -2.27 V these two radioisotopes overlap to a large extent [79]. There- fore, - counting has to be performed unambiguously for Though the difference in the standard electrode potentials 90 90 of Sr2+ and Y3+ ions is relatively small, Y3+ could be selec- analysis of trace level of Sr present in Y. tively electrodeposited on the cathode by control of the ap- Trace levels of 90Sr in 90Y availed from the electrochemi- plied potential. cal generator could not be quantified by the authors adopting conventional approaches such as half-life determination, - The Methodology for the Electrochemical Separation of spectrometric analysis adding 85-89Sr as tracer, paper chroma- 90 90 Y from Sr tographic analysis etc. [101]. Therefore, a novel extraction (EPC) technique was developed for The electrochemical separation process involved two the quality control of 90Y [102]. The procedure is based on electrolysis cycles - the first cycle for separation and the sec- the selective retention of 90Y by 2-ethyl-hexyl-2-ethyl-hexyl- ond cycle for purification of 90Y [1]. The electrochemical phosphonic acid, a chelate impregnated at the point of appli- set-up used was similar to the one shown in Fig. (2). In the 90 90 cation of the paper chromatography strip. Estimation of the first cycle, Sr in the form of Sr(NO3)2 was added to the amount of 90Sr by this method, in several batches gave the electrolysis cell and used as the primary electrolyte. Elec- value as 30.2±15.2 kBq (817±411 nCi) of 90Sr per 37 GBq (1 trolysis was performed for 90 min potentiostatically at 2.5 Ci) of 90Y, corresponding to (0.817±0.411 ppm) of 90Sr V with respect to SCE. After the electrolysis, the electrodes which was well within the acceptable limits. were removed from the electrolysis cell without switching off the power supply. This was essential since the carrier- Advantages of the Electrochemical 90Sr/90Y Generator free 90Y was deposited on the cathode in extremely small quantities (ng-μg levels) and was thinly spread over the elec- The electrochemical method offers several advantages over the conventional approaches reported for 90Sr/90Y gen- trode surface which would be quickly dissolved by the acidic 90 electrolyte solution in the absence of the potential. erators. The same Sr feed solution can be used for elec- trolysis without further modification, except pH adjustment, The electrode was transferred to another electrolysis cell which is a significant advantage. Therefore, such generators containing nitric acid solution and the polarity of the elec- are expected to be safer than the presently reported systems trode was reversed and electrolysis was carried out under the which require regular handling of the 90Sr inventory. The 90 same conditions. During this process, Y was leached from entire separation procedure employs simple electrochemistry the platinum plate and was deposited onto another platinum and is amenable for automation. The electrodes used are re- 90 electrode. At the end of electrolysis, the deposited Y on the usable after proper cleaning. Minimal amounts of chemicals 90 cathode was dissolved in acetate buffer. The deposited Y are used for the whole process, and hence there is very little could also be dissolved into chloride or nitrate form. The possibility of additional introduction of metal contamination. Electrochemical Separation is an Attractive Strategy for Development Current Radiopharmaceuticals, 2012, Vol. 5, No. 3 279

188W, relatively long irradiation periods are required even for the production of 188W of modest specific activity. Conse- quently, 188W from high-flux reactors ( ~1015 n cm-2 s-1) such as the HFIR in Oak Ridge National , USA; SM Reactor in Dimitrovgrad, Russian Federation or the BR3 Reactor in Belgium can alone be used to produce 188W/188Re generators to obtain NCA 188Re. The specific activity of 188W, produced in high-flux reactors, ranges from 150-190 GBq g-1 of W [116].

The Need for Electrochemical Separation of 188Re from 188W The commercially available 188W/188Re generators adopt the column chromatographic approach wherein 188W is re- 188 90 90 tained on an alumina column and Re is eluted with 0.9% Fig. (5). A fully automated Sr/ Y generator (Kamadhenu) com- NaCl solution [117-120]. Owing to the reported limited sorp- mercially available from Isotope Technologies Dresden, Germany tion capacity of alumina (50 mg W/g) [117], 188Re availed (Photograph courtesy of J. Comor.). from these generators loaded with <55.5 GBq (1.5 Ci) of 90 188W is of low radioactivity concentration, even while using The chances of radiolytic degradation are minimal. Y was 188 obtained in acetate buffer medium (pH ~5) with appreciably W produced in high-flux reactors. Often post-elution con- 188 high radioactive concentration and was therefore directly centration of the Re eluate is required prior to preparation suitable for radiolabeling biomolecules without any further of radiopharmaceuticals [116,121-124]. Recently, numerous chemical modifications. The waste generated is expected to high-capacity sorbents like PZC, PTC, TiP, nano-zirconia, contain only trace levels of 90Sr and therefore can be easily synthetic alumina and nano-alumina have been reported for the preparation of chromatographic 188W/188Re generators monitored, classified and disposed as per regulatory re- 188 quirements. There is almost no solid waste from the entire using W produced in high-flux reactors [27-37,40]. How- process. A 90Sr/90Y generator of 37 GBq (1 Ci) 90Sr capacity, ever, further studies using these high-capacity sorbents for 188 188 can yield 16.6–18.5 GBq (450–500 mCi) of 90Y twice a the preparation of a clinical-scale (~37 GBq) W/ Re 188 week, with insignificant loss of 90Sr activity except by natu- generator using low-specific activity W produced in me- 14 -2 -1 ral decay. Supplementing the activity by adding about 10% dium-flux reactors ( ~10 n cm s ) have not been re- (3.7 GBq or 100 mCi) of 90Sr once in every 4–5 years will be ported. In spite of the long shelf-life of these generators, the adequate to keep the 90Y supply constant. Since 90Y can be dependence on only three high-flux reactors for the produc- 188 188 ‘milked’ from this 90Sr/90Y generator virtually for an indefi- tion and global supply of W escalates the cost of Re, 188 nite period of time, it was named as ‘90Y-Kamadhenu’, based reducing the cost-effectiveness of Re-based radiopharma- on the mythical cow ‘Kamadhenu’, which yields unlimited ceuticals for clinical use. supply of milk. There are >50 operational reactors in the world having 14 -2 -1 A fully automated electrochemical module was devel- fluxes >1  10 n cm s [125], which is adequate for the 188 oped by Dr. Josef Comor and the module (Fig. 5) is com- production of medium to low-specific-activity W. In order mercially available from M/s Isotope Technologies Dresden to minimize the dependence on the very few high flux reac- 188 (ITD), Germany. The automated module is already in opera- tors and utilize the low specific activity W for providing 188 tion at some centers. Re suitable for preparation of radiopharmaceuticals, an electrochemical approach for the separation of 188Re from 188 188W/188Re Generator W was developed. The feasibility of this separation method, both in terms of yield and the purity of the 188Re for There is a great deal of interest in the use of rhenium-188 radiopharmaceuticals applications was continuously evalu- 188 ( Re) for therapeutic applications due to its reasonable half- ated and demonstrated over a period of 6 months [2]. life (t = 16.9 h), high-energy beta radiation (Emax = 2.118 MeV), low abundance (15.8%) of 155 keV photons and con- 188 188 188 Principle of Electrochemical Separation of Re from venient availability from the W/ Re generator in no- 188W 188 carrier-added (NCA) form [77,103]. Currently, Re is used 188 188 188 for various medical applications including radioimmunother- Separation of Re from a W/ Re mixture was based 188 apy, radionuclide synovectomy, bone pain palliation, liver on selective electrodeposition of Re on a platinum cath- cancer therapy and use of liquid-filled balloons for preven- ode. This is based on the difference in standard reduction tion of restonosis after angioplasty and stent placement [104- electrode potential of tungsten and rhenium ions in acidic 113]. solutions. + The major impediment in the widespread utilization of WO3 + 6H + 6e  W + 3 H2O Eº = -0.090 V [66] this radioisotope for clinical applications is that its tungsten- - + 188 ReO4 + 8H + 7e  Re + 4 H2O Eº = +0.362 V [66] 188 ( W) precursor (t = 69 d) can only be produced by double neutron capture with low neutron absorption cross- Though the standard electrode potential of W is close to 186 187 187 188 sections [ W(n,) W (=37.9±0.6 b); W(n,) W zero, it cannot be electrodeposited from its aqueous solu- (=64±10 b)] [114,115]. Owing to a rather long half-life of tions. This is because of the low hydrogen over-voltage and 280 Current Radiopharmaceuticals, 2012, Vol. 5, No. 3 Chakravarty et al.

100

80 Re (%)Re

188 60

40

20 (b)

Elution yield of 0 0 20 40 60 80 100 120 140 160 180 200

10 %)

-5 (a) 8

Re (10 6 188 4

2

0 W impurity in in impurity W

188 0 20 40 60 80 100 120 140 160 180 200 Time (days)

Fig. (6). Performance of the electrochemical 188W/188RE generator over a period of 6 months. high discharge potential of W ions in aqueous medium [126]. deposited in extremely small quantities (ng-μg levels) as a 0 However, electrodeposition of a very thin film of tungsten mixture of its oxide and metal form (72% ReO2 and 28% Re from an aqueous alkaline solution has been reported [126]. [127]). The 188Re deposit was then dissolved in 0.1 M HCl to Therefore, by careful choice of the appropriate acidic me- yield perrhenic acid, which was subsequently neutralized and dium, electrodeposition of W on the electrode can be inhib- passed through a small alumina column for removal of trace ited. On the other hand, Re can easily be electrodeposited amounts of 188W contamination (0.05-0.1%) associated with from aqueous solution and this phenomenon has been exten- 188Re. The overall yield of 188Re was always >70% and was sively studied [127]. The feasibility of electrodeposition of available in just 1 mL of solution. The performance of the Re from an aqueous acidic medium wherein the electrode- generator remained consistent in all the batches, over a pe- position of W could be precluded was exploited for the elec- riod of 6 months (Fig. 6). trochemical separation of 188Re from 188W. 188 When electrodeposition of 188Re was carried out in elec- Quality Control of Re trolytes comprised of common mineral acids like HCl, The presence of any 188W impurity in the recovered 188Re H2SO4, HNO3 etc., the electrodeposition yield was low, de- was determined by -spectrometric analysis of the decayed spite reasonable operation time. Moreover, there were sig- 188 -4 188 Re sample and was found to be <10 % in all the batches nificant levels of co-deposition of W. Therefore, electroly- 188 - (Fig. 6). The radiochemical purity of ReO4 was >99%. sis was carried out in oxalic acid medium since oxalate ions 188 - The level of Al ions in the Re eluate was determined by facilitate reduction of ReO4 ions through formation of a 1:1 188 complex [128]. The co-deposition of 188W was also insignifi- ICP-AES analysis of the decayed Re samples and was cant in this medium. <0.1 ppm and no other metallic ions were detected. Thus, the levels of radionuclidic, radiochemical and chemical impuri- 188 The Methodology for the Electrochemical Separation of ties in Re obtained from the generators were well within 188Re from 188W the acceptable limits prescribed in the pharmacopoeias [129].

The electrochemical set up used was similar to the one Advantages of the Electrochemical 188W/188Re Generator used for the 90Sr/90Y generator as shown in Fig. (2). How- 188 188 ever, for the sake of convenience, the electrolysis was per- The electrochemical W/ Re generator system is inex- formed under constant applied potential mode using a ‘two- pensive, efficient, simple to operate and can be easily scaled electrode assembly’ unlike the ‘three electrode system’ used up to multi-curie levels. This method is an efficient new ap- 188 for the separation of 90Y from 90Sr. The equilibrium mixture proach for use of low-specific-activity W obtained from 188 188 of 188W/188Re as sodium (188W) tungstate was reconstituted the medium-high flux reactors for preparation of W/ Re 188 - in 0.1 M oxalic acid medium and used as the electrolyte. generators suitable for biomedical applications. The ReO4 Electrolysis was carried out by applying a constant potential is available from the generator with appreciably high radio- of 7 V for 60 min. As in the case of electrodeposition of 90Y, active concentration and purity and hence can directly be it was also essential here to remove the cathode after the used for the preparation of radiopharmaceuticals, such as 188 188 electrolysis while maintaining the potential, because 188Re is Re-HEDP, Re-DMSA etc. Additionally, the system Electrochemical Separation is an Attractive Strategy for Development Current Radiopharmaceuticals, 2012, Vol. 5, No. 3 281 produces very little radioactive waste and the entire process by irradiation of natural MoO3 target is much lower than that is amenable for automation. The adaptation of this technique of fission 99Mo (~104 Ci g-1) [141]. can extend the useful shelf-life of the 188W/188Re generator. Over the past 50 years, several versions [12-18] of the Another important feature is that, at the end of the generator 99 99m Mo/ Tc generator have been developed, the most com- life after a reasonable decay period, it would be possible to mon being the original alumina-based chromatographic gen- recover the unactivated enriched 186W target from the solu- erator system. The ease of operation, high elution efficiency, tion for fabrication of new targets for irradiation. high radionuclidic purity and high radioactive concentration 99m 99 99m of the Tc eluate are the attractive features of these genera- Mo/ Tc Generators tor systems. The capacity of alumina for adsorbing molyb- -1 The important role that technetium-99m (99mTc) has date ions is limited (2-20 mg Mo g of alumina) [14] neces- 99 played in shaping the field of diagnostic nuclear medicine sitating the use of fission Mo. However, the key challenge has been clearly established and remains undisputed [7,11]. in the use of this technique is the current and expected recur- 99 The early realization by investigators at Brookhaven Na- ring global shortage of fission Mo, attributable to the rea- 99m tional Laboratory (BNL) that 99mTc possesses ideal nuclear sons discussed above. Alternate approaches to obtain Tc 99 decay characteristics for organ imaging set forth a chain of from Mo include ‘batch’ solvent extraction, dry 99m 99 events that ensured the widespread acceptance of nuclear of Tc from (n,) MoO3 target and zirconium molybdate techniques in medical diagnosis [130, 131]. In spite of the gel based systems [12-18], all of which have their inherent greatly increased current availability of other radioisotopes, limitations. Recently, numerous high-capacity sorbents have 99mTc still remains the ‘work-horse’ of diagnostic nuclear been reported for the preparation of chromatographic 99 99m 99 medicine and is used in approximately 30 million procedures Mo/ Tc generator using (n,) Mo similar to the alumina- annually, comprising ~80% of all diagnostic nuclear based systems [24,26,33,37,41]. However, these latest de- medicine procedures worldwide [11]. The preeminence of velopments are still in their conceptual stage and their appli- 99mTc as a medically useful radioisotope is directly attribut- cability for the preparation of clinical-scale generators is yet able to the conception and development of the 99Mo/99mTc to be demonstrated. For these reasons, electrochemical sepa- 99m 99 generators in the late 1950s [11,130]. Without this develop- ration of Tc from Mo produced by the (n,) route is an- 99m ment, the ready availability of the short-lived Tc (t = 6 h) other attractive option which has been recently explored would not have become a reality. The relatively long half- [3,4]. 99 life of the parent molybdenum-99 ( Mo, t = 66 h) enables availability of this radionuclide for the in-house 99Mo/99mTc Principle of Electrochemical Separation of 99mTc from radionuclide generator production system for use at places 99Mo far away from the site of production. 99m 99 The separation of Tc from a mixture of Mo and The medical benefits of 99mTc are dependent on a reliable 99mTc is based on the selective electrodeposition of 99mTc on and continuous supply chain of 99Mo. More than 90% of the a platinum electrode by taking advantage of the difference in 99 2- - world’s supply of Mo is currently derived from the fission standard electrode potential of MoO4 and TcO4 ions in of highly enriched uranium (HEU) at primarily 5 nuclear alkaline media. The electrochemical reactions involved and reactors, which include the NRU at Chalk River in Canada, their standard reduction potentials are as follows [66]: HFR at Petten in Netherlands, BR-2 at Fleurus in Belgium, 2- - MoO4 + 4H2O + 6e  Mo + 8OH Eº= 1.05 V OSIRIS at Saclay in France and SAFARI-1 at Pelindaba in  + South Africa [132,133]. Most of these reactors are aged (42- TcO4 + 4H +3e  TcO2 + 2H2O Eº= +0.738 V 51 y), nearing the time of their decommissioning and need 99 5 The electrodeposition of long-lived Tc (t = 2.2  10 extensive routine maintenance [132,134], which is a serious y) has been well reported in the literature [59,142]. Similar concern for a reliable and consistent supply of 99Mo [132- to W, Mo metal cannot be electrodeposited from its aqueous 137]. A serious disruption in the supply of fission 99Mo re- solution [124] because of the low hydrogen overvoltage and sulted from a combination of many factors which adversely 2- affected patient services in many countries [133]. Addition- the high discharge overpotential of the MoO4 ions in aque- ally, nuclear non-proliferation and security concerns are re- ous medium. As an alternative, Mo coatings are electrode- posited almost exclusively from their molten salts [126]. stricting and will probably result in the eventual abolition of 99m the use of HEU, both as reactor fuel as well as targets for Because of these properties, Tc could be electrochemi- 99 99m producing fission products such as 99Mo [138]. cally separated from Mo in aqueous medium. Since Tc is continuously produced in the electrolyte as a result of the 99 The Need for Electrochemical Separation of 99mTc from radioactive decay of Mo, repeated electrodeposition is a 99m 99Mo feasible means to avail Tc from the same electrolyte solu- tion. A prudent approach to help alleviate the rather tenuous supply chain of 99Mo would be to reduce reliance on fission- 99 99 The Methodology for the Electrochemical Separation of produced Mo and implement the use of (n,) Mo which 99mTc from 99Mo can be produced in more than 100 operational nuclear reac- tors in the world [139,140]. This alternative approach needs The feasibility of developing 99Mo/99mTc generators up to to be further emphasized as a back-up measure and to sup- 29.6 GBq (800 mCi) level of activity has been recently plement 99mTc accessibility to meet the continually growing demonstrated [3,4]. The electrochemical set up used for this demand for 99mTc for nuclear medicine use. However, the process is similar to that used for the electrochemical separa- specific activity of (n,) 99Mo (~300-1000 mCi g-1) produced tion of 188Re from 188W. The 99Mo (specific activity 11-14 282 Current Radiopharmaceuticals, 2012, Vol. 5, No. 3 Chakravarty et al.

100

80 Tc (%)

99m 60

40

20

0 Elution yield of 10 01234567891011 %) -4 8

Tc (10 6 99m 4

2

0

Mo impurity in in Mo impurity 01234567891011 99 Time (days)

Fig. (7). Performance of the electrochemical 99Mo/99mTc generator over a period of 10 days.

GBq/g) solution in the form of sodium molybdate was added and chemical impurities in 99mTc obtained from the generator into the electrolysis cell and electrolysis was carried by ap- were well within the acceptable limits prescribed in the plying a constant potential of 5 V for 50 min. After the elec- Pharmacopoeias [129]. trolysis, the cathode (on the surface of which 99mTc was de- posited) was removed from the cell, while maintaining the Advantages of the Electrochemical 99Mo/99mTc Generator potential. The electrodeposited 99mTc was subsequently dis- The major advantage of the electrochemical technique is solved in 500 μL of saline (0.9% NaCl) solution by applying 99 a reverse potential (~20 V) for few seconds. In order to re- that there is no restriction on the specific activity of Mo 99 99m that can be used. Even while using medium- to low-specific move the trace levels of Mo that might be present in Tc, 99 99m 99m - activity (n,) Mo, Tc can be obtained with acceptable the TcO4 solution was passed through a small column 99m radioactive concentration and purity for clinical applications. containing 200 mg of alumina. The overall yield of Tc 99m was >80% and the performance of the 99Mo/99mTc generator The purity of Tc was comparable to that obtained from the standard alumina-column generators containing fission remained nearly consistent over a period of 10 days, which is 99 normally the shelf-life of a 99Mo/99mTc generator (Fig. 7). Mo. The separation process involves simple electrochemis- try and is therefore, amenable for automation. The adaptation 99m It was demonstrated that the electrodeposition of Tc of this technique extends the shelf-life life of a 99Mo/99mTc 2- was independent of the concentration of MoO4 ions present generator to a considerable extent and is therefore economi- 99 2- 99 99m in the electrolyte and MoO4 solutions of specific activity cal. The prospects of using the electrochemical Mo/ Tc as low as 1.85 GBq/g could be used for the preparation of generator system in a centralized radiopharmacy appear the generator. However, precaution had to be taken in main- highly promising. taining the inventory of 99Mo during the shelf-life of the 99Mo/99mTc generator. During the course of electrolysis, the FUTURE PROSPECTS OF ELECTROCHEMICAL pH of the Na 99MoO solution decreased slightly and it was 2 4 SEPARATION IN RADIONUCLIDE GENERATOR essential to adjust the pH of the electrolyte to ~13, after the TECHNOLOGY end of each electrolysis to make the solution ready for sub- sequent use. If the pH of the solution was not maintained at The demonstration of the feasibility of developing 90 90 188 188 99 99m ~13, black particles were observed in the electrolyte and the Sr/ Y, W/ Re and Mo/ Tc generators based on electrodeposition yield of 99mTc decreased substantially in electrochemical separation has opened up a new avenue for the subsequent electrolysis. The black particles might be the application of this approach for the development of other reduced species of molybdenum oxide, in which 99mTc was radionuclide generators and separation of carrier-free radioi- trapped and hence could not be electrodeposited. sotopes. However, it must be noted that electrochemical separation can be attempted for a parent/daughter system 99m only if a suitable electrolyte can be identified in which there Quality Control of Tc is a substantial difference in the formal electrode potential of The level of 99Mo impurity present in 99mTc as deter- the parent and daughter ions. The systems for which the mined by -spectrometry was <10-3% (Fig. 7). The radio- electrochemical separation may be attempted must be judi- 99m - chemical purity of TcO4 was determined by a paper ciously decided taking into consideration the time require- chromatographic technique and was found to be >99%. The ment for the electrolysis and the half-life of the daughter ICP-AES analysis of the decayed samples of 99mTc solutions radioisotope. This means that if this approach is attempted indicated <0.1 ppm of Al3+ ions, which was far below the for the 68Ge/68Ga generator, selective electrodeposition of 68 permissible level. The levels of radionuclidic, radiochemical Ga (t = 68 min) should be feasible within 5-10 min. How- Electrochemical Separation is an Attractive Strategy for Development Current Radiopharmaceuticals, 2012, Vol. 5, No. 3 283

82 ever, for very short lived radioisotopes like Rb (t = 1.27 separation step but also is an effective concentration proce- min), which can be availed from 82Sr/82Rb generator, this dure as the daughter radionuclide is isolated in solid form approach is not feasible. adhering to the electrode which can be dissolved in a very small volume of the desired solvent. This represents a par- Although the electrochemical separation procedure has 99 99m 188 188 numerous advantages, the adaptation of this approach in the ticular advantage for Mo/ Tc and W/ Re generators where low radioactive concentration of the final product routine radiopharmacy setting associated with a hospital alone is the problem while using low-specific-activity parent would require increasing the personnel resources unless the radionuclides and using the existing separation techniques, systems are fully automated. Electrochemical generator sys- thereby needing additional concentration steps. tems, to start with, would be expected to be suitable for large-scale production and supply of radionuclides from a The electrochemical technique is attractive by virtue of centralized radiopharmacy. its simplicity, rapidity, reproducibility and the use of a minimum amount of reagents. The process is generally car- ried out at room temperature utilizing electrons to effect spe- ELECTROCHEMICAL SEPARATION AND PURIFI- cific electroreduction reactions to achieve the separation. CATION OF OTHER MEDICALLY USEFUL RA- Crucially, this strategy avoids generation of radioactive DIOISOTOPES wastes and is hence consistent with the principles of ‘green Although, major emphasis of this review is on the utiliza- chemistry’. Due to the above advantages, the interest in de- tion of electrochemical separation for radionuclide genera- velopment of radionuclide generators using an electrochemi- tors, its attractive features have also been exploited for the cal approach is expected to catch up and such generators radiochemical separation, purification and pre-concentration would eventually find acceptance in the nuclear medicine of other medically useful radioisotopes. Mirzadeh et al. have community. described an electrodeposition process for isolation of NCA 64/67 Owing to the complexities in the production of fission Cu from Zn target irradiated in a cyclotron [143,144]. 99Mo as well as nuclear non-proliferation and security con- Recently, there has been widespread interest in the isolation cerns associated with the use of HEU as target for producing of NCA 86Y from bulk amounts of proton irradiated Sr target 99 99 99m 86 fission Mo, an electrochemical Mo/ Tc generator using by selective electrodeposition of Y on a platinum electrode low-specific-activity (n,) produced 99Mo would be of con- [53,65,100]. Chakravarty el al. have used an electroamalga- siderable value for ensuring the availability of 99mTc for mation approach for the isolation and purification of NCA 177 clinical studies. Such a shift can bring many more reactors in Lu from neutron irradiated Yb2O3 [43]. This process was the World to contribute to the availability of LSA 99Mo and further extended for removal of 2-3% of 177Lu impurity from 99m 175 thereby enhance the availability of Tc for clinical studies. neutron irradiated Yb in order to render it suitable for A fully integrated electrochemical separation system for therapeutic applications [44]. The selective electrodeposition 99Mo/99mTc is an achievable objective as the basic automa- of NCA grade radionuclides on an inert electrode followed tion technology developed for Kamadhenu (90Sr/90Y genera- by stripping in saline solution of desired volume has been tor) can be readily adapted to its making. The electrochemi- utilized for the post-elution concentration and purification of cal generator technology is an open technology without any 99mTc and 188Re obtained from the conventional 99Mo/99mTc 188 188 intellectual property right (IPR) issues and hence can be used and W/ Re generators [42,45]. by entrepreneurs interested into getting into the business of making automated modules. Like FDG synthesis module CONCLUSIONS production, depending upon the demand, several manufac- turers could eventually control the market and provide cost- The ‘state-of-the-art’ electrochemical separation ap- effective automated modules. As done by the International proach was demonstrated as an innovative strategy for the Atomic Energy Agency (IAEA) by pooling resources of sev- development of clinically useful 90Sr/90Y, 188W/188Re and eral experts in the case of the development, validation and 99Mo/99mTc radionuclide generators. Compared with conven- automation of the 90Sr/90Y generator, the 99Mo/99mTc electro- tional chromatographic and solvent extraction methods, the chemical generator technology can also be brought to the electrochemical method provides higher yields as well as actual use by organizations such as IAEA, OECD Nuclear higher radioactive concentration of the daughter product, Energy Agency etc. which are working to combat the short- good reproducibility and acceptable product purity. The de- age of fission produced 99Mo and proliferation issues associ- velopment not only offers an alternative resource to meet the ated with the use of HEU targets for the production of 99Mo. growing demands in radionuclide generator technology but also is a first step towards application of electrochemical The electrochemical generator technology represents a new paradigm and hence regulatory approval for the process strategies for separation and concentration of other medically as well as finished products might be needed. However, this useful radionuclides. Though the technique was first devel- 90 90 should not be a problem as the equivalence of the product oped for the separation of Y from Sr, for which most of obtained from the electrochemical generator vis-à-vis the the reported separation techniques were either difficult or 90 approved products can be easily established. The electro- unable to give the level of decontamination needed from Sr to use it as a clinical product, its applicability in two more chemical approach is definitely not an answer for all medi- cally useful radionuclide generator systems, but is a viable important parent-daughter system was established. alternative to be considered when problems associated with The utility of the electrochemical technique for any parent-daughter radionuclide separation cannot be ad- 188W/188Re and 99Mo/99mTc generator systems is important as dressed by a simpler approach such as column chromatogra- the electrochemical separation procedure acts not only as a phy. 284 Current Radiopharmaceuticals, 2012, Vol. 5, No. 3 Chakravarty et al.

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Received: November 21, 2011 Revised: February 28, 2012 Accepted: March 28, 2012