Electrochemical Separation: Promises, Opportunities, and Challenges

Feb 20, 2014 - This review provides a comprehensive summary of the role of the electrochemical separation process to develop next-generation radionucl...
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Electrochemical Separation: Promises, Opportunities, and Challenges To Develop Next-Generation Radionuclide Generators To Meet Clinical Demands Ashutosh Dash* and Rubel Chakravarty Isotope Applications and Radiopharmaceuticals Division, Bhabha Atomic Research Centre (BARC), Mumbai 400 085, India S Supporting Information *

ABSTRACT: This review provides a comprehensive summary of the role of the electrochemical separation process to develop next-generation radionuclide generators to meet future research and clinical demands. This innovative technology paradigm, straddling the disciplines of electrochemistry and separation science, is poised to serve as a springboard to spur new breakthroughs and bring evolutionary progress in radionuclide generator technology. Without doubt, the major impetus for the advancement in radionuclide generator technology stems from nuclear medicine requirements, as a means of obtaining shortlived radionuclides on demand for the formulation of a gamut of diagnostic and therapeutic radiopharmaceuticals. The tremendous prospects associated with the use of electrochemical radionuclide generators in nuclear medicine dictate that a holistic consideration should given to all governing factors that determine their success. The purpose of this paper is to present a concise and comprehensive review of the latest research and development activities in the utility of electrochemical separation process in development of radionuclide generators that have already established footholds of acceptance in nuclear medicine and are expected to change the future landscape of radionuclide generator technology. This review provides a summary of the principle, factors that govern the electrochemical separation, desirable characteristics of the generator systems developed with typical examples, critical assessment of recent developments, contemporary status, key challenges, and apertures to the near future.

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INTRODUCTION The role of radionuclide generators in providing short-lived radionuclides for the formulation of a wide variety of diagnostic and therapeutic radiopharmaceuticals in nuclear medicine needs hardly to be reiterated.1−5 Widespread applications of radionuclide generators have not only accelerated the progress of nuclear medicine practice but also offered numerous opportunities in other related disciplines including oncology and interventional specialties.6−21 The scope of using radionuclide generators is enticing because it would ensure costeffective availability of no-carrier-added (NCA) radionuclides on demand and also obviate the need for on-site accelerators or reactor production facilities. A large number of the nuclear medicine procedures performed in many parts of the world would not have been possible without the availability of radionuclide generators.1,5,6,22 Growth in the field of radionuclide generators has been phenomenal and paralleled the complementary development of targeting agents for therapy and positron emission tomography (PET).11,22−24 Whereas a radionuclide generator “lives” at the interface between many disciplines, its dependence on separation science is arguably the strongest. The evolution and continued success of radionuclide generators in nuclear medicine, since their inception, has been, in large part, due to technological advancements in separation science. The incredible prospects associated with the use of radionuclide generators in nuclear medicine along with the challenge of providing daughter radionuclides of requisite quality have led to a considerable amount of fascinating research and innovative strategies. In light of the explicit need to obtain the daughter radionuclide in an ionic form having © 2014 American Chemical Society

acceptable radionuclidic and radiochemical purity, essentially every conceivable separation strategy has been exploited. Among the various separation technologies harnessed for the development of radionuclide generators, column chromatography technology has dominated the field significantly due to operational simplicity and user friendliness.1,12,25 Although the use of column chromatography technology has been productive and drawn widespread acceptance, the limited adsorption capacity of the adsorbents emerged as a major impediment, which requires the use of high specific activity parent radionuclide owing to the explicit need to obtain high radioactive concentration (RAC) or specific volume of the daughter radionuclide amenable for the preparation of a broad panoply of radiopharmaceuticals.1 To adsorb the required amount of parent activity in a generator, the use of low specific activity parent radionuclide necessitates a large amount of adsorbent, which not only increases the size of the column but in turn also requires a large volume of eluent for the elution of the daughter radionuclide.1 The low RAC of daughter radionuclide imposes the need for its concentration prior to the formulation of radiopharmaceuticals.1 Additionally, the utility of column chromatography technology is limited when applied to systems containing alpha- or beta-emitting radionuclides due to susceptibility of the chromatographic support to radiation damage.11,17 Radiolytic damage inflicted by these Received: Revised: Accepted: Published: 3766

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high LET nuclides can lead to a decrease in daughter radionuclide yields, increased parent radionuclide breakthrough, and decreased flow through the chromatographic column. Whereas postelution concentration (PEC) or purification procedures26−36 have tangible benefits to render the daughter radionuclide useful for radiopharmaceutical applications, the scope of using alternative separation strategies where this step can be avoided is a credible proposition. The development of alternative separation strategies represents an important challenge and can only be overcome by technical breakthroughs in areas of separation science. Over the past few decades, the evolution of a number of alternative separation strategies has revolutionized the development of radionuclide generators.12,19−21 Among the available alternative separation strategies that have evolved, the prospects of using electrochemical separation technique in the development of radionuclide generators seemed to be an intuitive proposition and holds significant promise.4,37 Electrochemical separation strategy exploits the difference between the standard reduction potentials of the parent and daughter radionuclides, to separate the daughter radionuclide of interest under the influence of controlled applied potential. This approach stands at the threshold of an exciting leap forward in generator technology and is poised to change its landscape in the future. This elegant separation strategy neither requires high specific activity parent radionuclide nor is susceptible to radiation damage inflicted by high LET radiation and can be used to overcome limitations of column chromatography-based separation technique. Herein, we attempt to present a concise and comprehensive review on the latest research and development activities on electrochemical separation strategy, which is expected to pave the way for developing state-of-the-art radionuclide generators adaptable to existing and foreseeable clinical demands. In the following sections, the electrochemical separation principle, different types of electrochemical radionuclide generators developed to date, current status, and future perspectives are discussed. Conspicuous harnessing of the electrochemical separation strategy will not only reinvigorate the radionuclide generator technology but can foster the sustainability of this novel concept.

Figure 1. Schematic diagram of the electrochemical radionuclide generator setup.

yield, selection of an appropriate radiochemical separation process is not only a necessity but also a determinant for the success of radionuclide generators. Several requirements need to be fulfilled for effective separation of daughter radionuclide, and in general the process should be fast and reproducible and provide daughter radionuclides of required purity in high radiochemical yield. There is a steadily expanding list of separation procedures, each with different characteristics, which are currently being used or can potentially be used for radionuclide generator technology. An overview of the principle, utility, and relative strengths and weaknesses of the above radiochemical separation processes with respect to 99 Mo/99mTc generators are elaborated in a recent review that, in principle, can be extended to all other radionuclide generator systems.12 Regardless of the separation strategy adopted, the process of obtaining daughter radionuclides should remain simple and flexible. Once the activity of the daughter is recovered from the mixture, the daughter activity begins to grow again until its activity level reaches a maximum and is in equilibrium with the parent radionuclide. The growth and separation of the daughter radionuclide can be continued as long as there are useful activity levels of the parent radionuclide available. The radionuclide generator provides the scope of separating daughter radionuclides any time before equilibrium is reached, and the activity levels of the daughter recovered will depend on the time elapsed since the last separation. Table S1 in the Supporting Information summarizes the characteristics of several key radionuclide generator systems that are being routinely used and could be useful to provide daughter radionuclides for a variety of research and clinical applications.6

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RADIONUCLIDE GENERATOR Before a discussion of electrochemical radionuclide generators in detail, it is pertinent to throw some light on the basics of radionuclide generators, parent−daughter nuclear equilibrium, and the intimate relationship that exists between them. This will be beneficial for the readers to understand the role of electrochemical separation in the development of radionuclide generators. A radionuclidic generator is a self-contained system (Figure 1) housing an equilibrium mixture of a parent−daughter radionuclide pair and designed to provide the daughter radionuclide formed by the decay of a parent radionuclide, which is free from the parent.6,7,20,21 The parent−daughter nuclear relationships offer the possibility to separate the shortlived daughter at suitable time intervals. Overviews of the principle, criteria for the selection of parent−daughter pairs, radioactive equilibrium, and the growth and equilibrium of the daughter radionuclide with the parent radionuclide have been elaborately discussed in recent reviews.6,7,20,21 In light of the explicit need to separate the daughter radionuclide free from the parent radionuclide with suitable 3767

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PRINCIPLE OF ELECTROCHEMICAL SEPARATION The electrochemical separation process exploits the differences in the standard reduction potential of metal ions to separate the metal ion of interest under the influence of an applied potential. A mixture of metal ions having adequate difference in their formal potentials values in an electrolytic medium can be mutually separated by selective electrodeposition of one metal on an electrode surface under the application of the applied potential. With regard to the application of an electrochemical separation process for preparation of radionuclide generator, it requires careful control of the applied potential to achieve selective electrodeposition of daughter radionuclide on a metallic electrode. In this process, the potential of the working electrode is maintained constant (or within a narrow range) by regulation of the voltage applied to the cell in such a way to permit the quantitative deposition (by reduction) of the daughter radionuclide on an electrode surface, from a suitable electrolyte solution containing parent−daughter mixture. The parent radionuclide is generally more difficult to reduce in that electrolytic medium. The electrodeposited daughter radionuclide then can be conveniently recovered in a small volume of solution of interest, and the electrode can be reused for subsequent deposition of the daughter radionuclide. The key to success in the electrochemical technique is to select an appropriate electrobath and to identify how this approach can be successfully applied to separate the daughter radionuclide from a solution containing parent−daughter radionuclides within a reasonable period of time (1−2 h). Advantages of Electrochemical Separation Strategy in Preparation of Radionuclide Generators. The clectrochemical separation strategy possesses the following advantages. • The electrochemical route offers the scope of utilizing parent radionuclide of any specific activity. Because the electrode selectively deposits NCA daughter radionuclide, the parent nuclide specific activity is essentially irrelevant. • The process is basically an oxidation−reduction reaction in which the electron brings about separation without the use of external chemical reagents. The process is consistent with the principles of “green chemistry”. • Recovery of valuable parent isotopes after electrolysis is quantitative, which not only offers the scope of storing the parents for regrowth of daughter radionuclides for subsequent recovery but also provide a means of recycling as targets. • The capacity is not limited by the amount of adsorbent or extractants. • The method is versatile and flexible and can be scaled up or down per demand and supply. • The electrochemical route provides the scope for using high LET nuclides owing to the absence of radiolytic damage often encountered in column chromatography generators. As the daughter radionuclide is selectively electrodeposited on a metallic electrode, radiolytic damage is precluded. • The process offers a means of availing daughter radionuclide of high radioactive concentration. Electrodepositing only the minute mass of the daughter radionuclide on the electrode surface enables one to recover the daughter radionuclide in a small volume of solution that may be conveniently diluted to the appropriate dose for clinical use. • The daughter radionuclide obtained by this method is of better quality than that obtained from a column generator

owing to the absence of impurities generated as a result of radiolytic damage of the adsorbent.11 • Separation efficiency and product purity remain unchanged on repeated separation. • The generation of radioactive waste is very low. • The electrochemical generator has a long shelf life compared to other generators, with periodic addition/ replacement of parent radionuclide. • The off-the-shelf availability of electrolytic cells and peripheral equipment offers the scope of developing generators. • The process is amenable to automation. Limitations of the Electrochemical Separation Strategy in Preparation of Radionuclide Generators. Despite its excellent attributes, the applicability of the electrochemical separation process in the preparation of radionuclide generators has certain limitations, which are outlined below. • Skilled manpower well versed in both electrochemistry and radiochemistry is required, which might not be easily found in a hospital radiopharmacy. • The operating protocol must be strictly followed owing to the sensitive nature of electrochemical process. • The process is applicable to those systems where there is significant difference between the formal electrode potential of parent and daughter radionuclides. The greater the difference, the higher is the success probability. • The process is not applicable for those systems where the parent or daughter radionuclide ion forms an alloy with the electrode material upon electrodeposition. • After electrodeposition, the daughter radionuclide should be loosely adhered on the electrode surface, so that it can be easily recovered in the desired medium with minimum chemical modifications. • An automated module and a dedicated shielded facility are required for the production of clinically useful amounts of daughter radioactivity. Despite these limitations, the electrochemical separation procedure not only holds promise as an innovative approach but has the potential to revolutionize radionuclide generator technology. This separation strategy has the potential to harbor boundless possibilities and bring innovation in radionuclide generator technology. The interest in electrochemical separation will vary according to the parent−daughter radionuclide pair considered.

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FACTORS INFLUENCING ELECTROCHEMICAL SEPARATION Realization of electrochemical separation process for the development of radionuclide generator technology is not a trivial process and poses formidable scientific and technical challenges. Any electrochemical separation strategy needs to be evaluated thoroughly to assess its prospects of success. The inherent determinant for the success of an electrochemical separation process resides in the identification of the experimental parameters that influence the separation process and their optimization to ensure selective deposition of daughter radionuclide onto an electrode. A more holistic understanding of the experimental factors that governs the electrochemical separation process will not only drive the innovation forward but also empower future developments. Experimental parameters expected to influence the success of electrochemical separation are discussed in the following text. Applied Potential. The success of an electrochemical separation strategy depends on the difference in the formal 3768

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the explicit need to quantitatively recover the daughter radionuclide from the electrode surface and to render the electrode amenable for subsequent electrolysis, a weak adhesion between the deposit and the electrode surface is critical for its success in radionuclide generator. Prior to electrolysis, it is essential to warm the electrolyte with constant purging of an inert gas to ensure that it is free from radiolytic gaseous products. pH of the Electrolyte. The pH of the aqueous electrolyte is one of the critical characteristics that need to be optimized for successful and reproducible electrodeposition of daughter radionuclides. Generally, during the course of the electrolysis, the pH of the electrolyte tends to increase due to loss of H+ ions in the form of hydrogen gas. It might be essential to use a suitable buffer for maintaining the pH of the electrolyte during the course of electrolysis. However, it must be ensured the chosen buffer does not interfere in the electrochemical process. Choice of Electrode. Spurred by the perceived need to recover the daughter radionuclide free from trace metal ions, the scope of using electrodes made from inert metal seemed sagacious. A useful attribute of the inert material electrode is its ability to retain its chemical characteristics on repeated exposure to electrolyte medium for a prolonged period of time. The process of identifying and selecting an appropriate electrode material primarily resides in its ability to resist oxidation/reduction and withstand the intense radiation during the course of multiple electrolyses over an extended period of time. Among the various materials available and investigated, gold and platinum electrodes are the most preferred materials owing to their high conductance, proven chemical inertness, excellent radiation stability, and ease of fabrication into desired shapes and sizes. Temperature of the Electrolyte. The effect of temperature of the electrolyte bath on the electrodeposition of daughter radionuclide needs to be evaluated on a case-by-case basis. The temperature of the electrolyte bath is usually maintained well below its boiling point during the course of electrolysis. Sometimes it may be necessary to carry out the electrolysis in a water-jacketed glass cell, having provision for circulation of cold water to maintain the temperature of the electrolyte.43 Time of Electrolysis. To preclude the decay loss of daughter radionuclide and the deposition of extraneous impurities, the electrolysis time needs to be optimized judiciously. Additionally, if electrolysis is carried out for a long time period, the cathodic deposit in the presence of electric current might convert into a phase that may be strongly adherent to the electrode surface and hence may be difficult to leach out from the electrode for subsequent use.34,44 Although electrochemical separation is a discipline requiring manpower well versed in both electrochemistry and radiochemistry and a number of experimental parameters need to be optimized, the reward at the end of the road is sufficient to justify the effort. The parameters influencing the separation of the daughter from the parent in the electrochemical radionuclide generator systems studied to date, the electrochemical reactions involved, and the final chemical form in which the daughter radionuclide is separated are summarized in Table S2 in the Supporting Information.

electrode potentials of the parent and daughter ions and on the application of a suitable potential (voltage). Successful outcomes are best achieved when the formal electrode potential of the parent ion is more negative than the formal electrode potential of the daughter ion or, in other words, the parent ion is more difficult to reduce compared to the daughter ion. To achieve selective electrodeposition of the daughter radionuclide from the parent−daughter mixture, the applied potential should be more negative than the formal reduction potential of the daughter ion and at the same time more positive compared to the formal reduction potential of the parent ion in that particular medium. Electrolyte. The electrochemical separation strategy requires an electrolyte in which the parent−daughter radionuclide is dissolved and remains electroactive. The concentration of the electrolyte solution depends on the specific activity of the parent radioisotope. In principle, there is no restriction on the maximum concentration of the electrolyte solution because the daughter radioisotope that is electrodeposited is always in NCA form (micromolar concentration even for Ci level of activity), irrespective of the specific activity of the parent radioisotope. However, it must be ensured that the parent radioactivity should always be completely soluble in the requisite volume of electrolyte which can be contained in the electrolysis cell and no salting-out effect should ever be observed during the period of utility of the generator. Among the different factors contributing to the success of an electrochemical separation strategy, the medium in which the electrolysis is performed plays a crucial role in determining the outcome. Generally, the formal electrode potential of a particular ion in a given electrolytic medium is governed by its tendency to form complexes in that medium. With a view to achieve selective electrodeposition of daughter radionuclide, it is of utmost importance to choose an appropriate electrolyte capable of maintaining a substantial difference in the formal electrode potential of the two ions. In an effort to ease the selective electroreduction of a particular ion, the scope of using a suitable complexing agent in the electrolyte solution has been seen as an intuitive strategy.38 To maintain the applied potential within the “electrochemical potential window”, it is of paramount importance to prevent the electrolytic degradation of the electrolyte during the course of electrolysis.39,40 Over the years, we have witnessed an intense activity and tremendous progress toward the use of a variety of organic electrolytes and room temperature ionic liquids (RTILs) owing to their ability to offer wide electrochemical windows and high conductivities. Although the use of such electrolytes constitutes a successful paradigm of performing electrolysis over a wide range of potential,41,42 the organic framework of such solvents emerged as the primary impediment that continues to thwart efforts for their use in radionuclide generators owing to susceptibility of the electrolyte to radiolysis in the presence of intense radiation. The radiolytic products not only affect the separation efficacy of the electrochemical process but also render the electrolyte unsuitable for subsequent electrolysis. In view of this premise, assessing the potential of an aqueous electrolyte is not only an interesting prospect but may be viewed as a necessity for the development of radionuclide generator technology. Whereas the use of aqueous electrolyte leads to the evolution of hydrogen gas as a result of electrolysis of water and also reduces the current efficiency of the process, the ability to produce a nonadherent deposit of the daughter radionuclide represents an advantageous attribute. In view of 3769

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emanating from decay of the 90Sr as well as 90Y. Radiation degradation of the chromatographic matrix not only will decrease the performance in terms of product yield over time but also often results in 90Sr breakthrough in the eluate.46 The inadvertent presence of 90Sr in the generator-derived 90Y emerged as the major impediment for the preparation of radiopharmaceuticals owing to the radiotoxicity of 90Sr. Strontium-90 (t1/2 = 28.8 years) is known to be a bone seeker with a maximum permissible body burden (MPBB) of only 74 kBq (2 μCi).46,47 This translates to a limit of 74 kBq of 90Sr in 37 GBq of 90Y, assuming that a patient may be administered a maximum activity of 37 GBq of 90Y in his/her entire lifetime. A more prudent approach to promote the beneficial use of 90Y in therapy is to develop 90Sr/90Y generators based on alternative separation techniques. In the quest for an innovative approach, within the realm of separation technology, the scope of using an electrochemical separation technique seemed appropriate.48 In view of the necessity to achieve a satisfactory degree of separation of 90Y from 90Sr, resorting to two-step electrolysis was found to be effective.48 The two-step electrolysis enabled extraordinarily high decontamination factors to be achieved. Platinum seemed to be the best choice for the electrode and was hence adopted here. The first electrolysis was performed for 90 min in 90Sr(NO3)2 feed solution maintained at pH 2−3, applying a potential of −2.5 V (100−200 mA current) with respect to saturated calomel electrode. After the first electrolysis, the cathode was removed without switching off the voltage, washed with acetone, and transferred to a new electrolysis cell containing fresh electrolyte solution (0.003 M HNO3) and a new platinum electrode. The polarity of the electrodes was reversed, and the electrolysis process was repeated for another 45 min. The 90Sr(NO3)2 solution after the first electrolysis is stored for growth of 90Y and future recovery. The two-step electrolysis provides the scope for obtaining 90Y with acceptable radionuclidic purity. The 90Y deposited on the circular cathode after the second electrolysis was dissolved in acetate buffer to obtain 90Y acetate, suitable for radiolabeling. The noteworthy feature on the use of the electrochemical separation technique was to achieve a high overall yield (>90%) of 90Y. Owing to the stringent requirement of very high radionuclidic purity (90Sr/90Y activity ratio 1015 n cm−2 s−1. Due to the limited sorption capacity of alumina (∼50 mg W/ g), 188Re obtained from the alumina-based 188W/188Re generators is of low radioactive concentration and must be concentrated using a suitable postelution concentration technique to make it suitable for radiolabeling with 188 Re.22−24 The increasing clinical demand for 188Re has led to the development of automated systems for the concentration of 188Re eluate.69 However, the high cost involved in the operation of the complex automation systemsa further increases the production cost of 188Re and renders it cost-ineffective for routine therapeutic use. Development of 188W/188Re generators using low specific activity 188W produced from a moderate flux reactor amenable for routine clinical use is the cornerstone for the survival and strength of 188Re radiopharmacy. With a view to achieve this objective, several alternate sorbents such as hydroxyapatite, the hydrous oxides of zirconium, titanium, manganese, tin(IV), and cerium, silica gel, the AG 1-X12 and AG 50 W-X12 ionexchange resins, and activated charcoal, several sorbents with higher capacity for W such as gel−metal oxide composites, synthetic alumina, polymeric titanium oxychloride, and polymeric zirconium compound (PZC) have been studied to determine their suitability for the preparation of 188W/188Re generators.70−73 Despite many impressive advances, the promise of developing 188W/188Re generators using low specific activity 188W for routine clinical use remains elusive. Probably, the electrochemical approach is the only alternative to develop clinical scale 188W/188Re generators using medium to low specific activity 188W, which can be produced in medium-flux reactors.44 With the aim of realizing the selective electrodeposition of 188 Re from an aqueous 188W/188Re equilibrium mixture in an electrolysis cell, the selection of composition of the electrolyte has emerged as a crucial factor and a critical step to achieve satisfactory deposition of 188Re species onto working electrodes within a reasonable time. Within all of the unknowns and uncertainties related to the multistep complex process that govern the reduction of initial ReO4− species in aqueous solutions to Re metal, the scope of using an oxalate bath was found to be productive.44 Electrolysis was carried out in oxalic acid medium (pH 1−2) by applying a potential of 7 V for 45 min, using platinum electrodes. The presence of oxalate ions in the electrolyte helps in enhancing the reduction of ReO4− ions through formation of a 1:1 rhenium−oxalato complex.74 After the electrolysis, the cathode containing the 188Re deposit was removed and washed with acetone to remove loosely held 188 W. The deposit was dissolved in 0.1 M HCl to yield perrhennic acid, which was neutralized and passed through an alumina column for further purification. The overall decaycorrected yield of 188Re was >70%. The recovered 188Re had high radiochemical (>97%) and radionuclidic purity (>99.99%) and was suitable for radiolabeling various biomolecules. Repeated electrochemical separation of 188Re from the same stock solution of 188W could be demonstrated for a period of 6 months. The scope for using an electrochemical path for routine production of 188Re from low specific activity 188W is appealing

because the process not only provides separation and concentration in one step but also offers the scope for quantitative recovery of enriched 186W for subsequent utilization. The success of the automated 90Sr/90Y generator system serves as a model, and the technological adaptation for making 188W/188Re generator system generator offer exciting possibilities. There is no doubt that soon efforts will be focused on the development of a fully automated electrochemical 188 W/188Re generator system, and its utility in radionuclide therapy will continue to move forward along a path that offers both greater diversity and higher flexibility. 99 Mo/99mTc Generators. The role of 99Mo/99mTc generator systems as the exclusive source for availing NCA 99mTc for single-photon imaging in diagnostic nuclear medicine needs hardly to be reiterated. Technetium-99m remained the “workhorse” of nuclear medicine for several decades and is expected to retain its status in the foreseeable future, notwithstanding the introduction of new diagnostic radiopharmaceuticals with other radionuclides.75−80 The99Mo/99mTc generator systems have not only played an important role in the evolution of nuclear medicine but also underpin its success. Diagnostic nuclear medicine would not have attained such a preeminent status but for this wonderful radionuclide having almost ideal nuclear properties for yielding functional images of the internal organs of the body.81−83 Every year, more than 30 million patient studies are performed worldwide using 99mTclabeled radiopharmaceuticals.75 The column chromatographic generator using a bed of acidic alumina has emerged as the most popular generator system the world over.12,78,79 Whereas the column chromatographic 99Mo/99mTc generator continues to reign as the procedure par excellence and has drawn widespread users’ acceptance, the limited capacity of alumina (up to 20 mg of Mo per g of alumina) for taking up molybdate ions necessitates the use of 99Mo of the highest specific activity, generally possible only in 99Mo produced through fission route. Current production capabilities of fission 99Mo are based on the use of highly enriched uranium (HEU) targets in limited numbers of aging research reactors.84 With the ready availability of relatively inexpensive fission 99Mo of required quality and quantity in the world market along with the mature production technology, the need for implementation of alternative 99 Mo/99mTc generator technologies was not felt until recently. A variety of factors, well described in the literature, resulted in the disruptions in fission 99Mo supplies on the world market during 2007−2009.84−90 The utilization of weapons-grade HEU for the production of fission 99Mo poses proliferation and terrorism risks owing to the possible acquisition of such materials by terrorists or rogue states to make nuclear weapons or improvised nuclear devices.91−93 The need for phasing out HEU together with the uncertainty in the continued use of a few aging reactors for the production of fission 99Mo necessitates the development of alternative 99Mo production strategies as well as 99 Mo/ 99m Tc generator technologies.12,84,88,94−98 In this context, a number of alternative 99Mo production strategies without the use of HEU, such as the aqueous homogeneous reactor (AHR) concept, target fuel isotope reactor (TFIR) concept, direct cyclotron production of 99m Tc, photofission of 238U, photon-induced transmutation of 100 Mo, and accelerator-driven subcritical assembly, have recently been pursued.84 However, most of these approaches are balanced on a fine line, with technical breakthroughs on the one hand and long-term economic viability on the other. 3772

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for electrochemical separation will provide technical solutions for the recovery and recycling of enriched 100Mo targets.

Among several non-HEU reactor options considered, (n,γ)99Mo production is the least intricate route to access 99 Mo with negligible generation of radioactive waste and being proliferation resistant, inexpensive, and within the reach of most institutions having operating research reactors.12,84,97,98 This approach provides 99Mo with specific activity ranging from 7.4 to 130 GBq/g (0.2−3.5 Ci/g) depending upon the thermal neutron flux of the reactor undertaking irradiation. However, the relatively low specific activity [0.35−3.5 Ci g−1 (13−130 GBq g−1)] of (n,γ)99Mo is the major impediment for its utilization in the existing alumina-based generators. The scope of using (n,γ)99Mo is relatively more appealing because simple target dissolution capabilities will suffice. This capability is within the reach of most countries having operating research reactors and good geographic distribution around the world. Notably, this source of 99Mo is independent of existing supply chains and would provide redundancy and emergency backup. One important point to note is that irrespective of the specific activity of 99Mo used, the 99mTc is always NCA and has essentially the same specific activity. The principal challenge toward utilization of the neutron activation route for production of 99Mo was to tackle the extremely low specific activity of 99Mo produced, for which alternative separation techniques required to be developed for the preparation of 99 Mo/99mTc generators.12 An overview of the principle, utility, and relative strengths and weakness of the above are elaborated in a recent review.12 The success of electrochemical 90Sr/90Y and 188W/188Re generators not only served as the foundation but also paved the way for realizing the electrochemical separation of 99mTc from 99 Mo/99mTc mixture.99 This is primarily based on the selective electrodeposition of 99mTc on a platinum electrode by taking advantage of the difference in formal electrode potentials of MoO42− and TcO4− ions in alkaline media. The preferential electodeposition of 99mTc relies on applying a potential of 5 V in 0.1 M NaOH medium for 45 min. With a view to recover the 99m Tc deposit on the cathode, electrolysis was carried out in saline solution by reversing the polarity of the electrode and application of a high positive potential for a few seconds. In this process, the 99mTc deposit could be quantitatively brought into saline solution wherein 99mTc existed as 99mTcO4−. To ensure that the recovered 99mTc was free from trace contamination of 99 Mo, it was passed through a small column containing acidic alumina. Initially, the electrochemical separation process was demonstrated using 9.25 GBq (250 mCi) of 99Mo,99 which was further scaled up to 29.6 GBq (800 mCi) activity level.100 The overall yield of 99mTc was >90%, with >99.99% radionuclidic purity and >99% radiochemical purity. The performance of the generator remained consistent over a period of 2 weeks, which was comparable to the shelf life of the commercially available (fission 99Mo based) 99Mo/99mTc generators. The compatibility of the product in the preparation of 99mTc-labeled formulations was found to be satisfactory. Furthermore, it was demonstrated that the process was suitable for the separation of clinically useful 99mTc, even from very low specific activity (∼1.85 GBq/ mg) 99Mo.100 This state-of-the-art electrochemical separation technology is a major step in a vitally important direction, which also offers exciting opportunities to use 99Mo obtained from photon/ proton activation of enriched 100Mo or direct production of 99m Tc through accelerator route. The encompassing potential

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SUMMARY AND FUTURE PERSPECTIVES We have depicted here a fascinating world of electrochemical radionuclide generators wherein separation science and electrochemistry intersect. The interplay between these two broad research domains has not only unveiled bountiful possibilities but also seems poised to bring major breakthroughs in radionuclide generator technology, where the goals are attainable and the payoff of success would be substantial. In this review, we have showcased a few radionuclide generators for which the electrochemical separation technique has played a critical role in shaping the radionuclide generator technology adaptable for clinical use. Although application of the electrochemical separation process in the development of radionuclide generators is still in its infancy, its importance has been recognized in recent years and is expected to grow in the future. A review of the potential of electrochemical separation technique in the development of radionuclide generators indicates that the advances made so far are exciting, their utility is evolving, and there are no apparent barriers for their clinical adoption. It is necessary to add new exotic radionuclide generators to its reservoir to meet the research and clinical demands in the foreseeable future. With the appropriate selection of a parent− daughter radionuclide pair, it would be possible to envision a future in which the scale and scope of the electrochemical separation technique can be tailored to an individual situation to address the needs of the nuclear medicine community. The radionuclide generator has its roots in nuclear medicine, and its progress is inextricably linked to advancements in nuclear medicine. As nuclear medicine is moving to the forefront of modern medicine, demands for new radionuclides are emerging far more quickly than they did over the past decade. Because of the pace with which the field of nuclear medicine is evolving, radionuclide generator strategies need a vision for today and tomorrow. An examination of the radionuclide generator technologies indicates that in the lively debate between the column chromatography and solvent extraction techniques, the need for alternative separation techniques has often been overlooked. These alternative separation strategies deserve greater attention not only because a greater range of options will be needed but also for the adaptability to use high LET radionuclides or parent radionuclides produced from different sources with a wide range of specific activities. Although it might be true that the radionuclide generator systems based on alternative separation techniques in daily nuclear medicine practice to date have not lived up to their initial optimistic expectations, the outlook of the electrochemical radionuclide generator concept is bright given current trends in the evolution of centralized radiopharmacies concept. The existing modality of using radionuclide generators in nuclear medicine centers will diverge, making it likely that future supply in many countries will take place through centralized radiopharmacies set up to achieve cGMP compliance. Central radiopharmacies are manned with skilled staff, and hence generators based on electrochemical separation techniques, which need more manipulation, can be readily and unambiguously handled by trained people. Whereas the capital cost of an electrochemical generator is much higher than that of a conventional radionuclide generator 3773

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radionuclides obtained from the generators have to meet strict specifications but also the separation processes and associated accessories must fulfill preset criteria. Nonetheless, to be effective in addressing the particular regulatory barriers, electrochemical radionuclide generator technologies must be customized to local legislative, regulatory, and institutional conditions for which a comprehensively designed and correctly implemented quality assurance system is of utmost importance. Change is needed to institute a paradigm shift toward adapting the electrochemical separation technique in radionuclide generator technology to address the needs of the nuclear medicine. Although this groundbreaking electrochemical radionuclide generator technology has passed many milestones and made considerable inroads, without doubt this is just the tip of the iceberg and further excitement in this field is awaiting. Clinical realization of this paradigm-changing concept requires effective harnessing of technology, inspired vision from scientists, and leading-edge engineering to produce functional radionuclide generators for nuclear medicine. It is the responsibility of all stakeholders, including research scientists, clinicians, radiopharmacists, hospitals, and industries, to share a common platform to harness the immense potential of electrochemical radionuclide generator technology to make it a mainstream device for clinical use.

based on column chromatography or solvent extraction concept, it is a one-time investment and the same system can be used repeatedly for several years. Only the electrolyte solution consisting of the parent−daughter mixture needs to be replenished after decay of the parent radioactivity to a level when it is no longer useful for generator application. In the evaluation of the cost of an electrochemical generator, it is customary to use “life cycle cost/benefit analysis”. The scope of using an electrochemical generator system is enticing as it is capable of providing measurable returns on the investments in the long run. Payback is substantial not only from the capital investment but also in the form of higher productivity and better quality of product. Minimal radioactive waste disposal problem is an added advantage, which will reduce the payback time and add an extra dimension to its value. This strategy constitutes an effective way of realizing a 90Sr/90Y generator amenable for use in hospital radiopharmacies where most of the conventional separation approaches have been proven ineffective. Also, the electrochemical separation approach represents a viable, cost-effective means of producing clinically useful 99mTc and 188Re even from their low specific activity precursors. From long-term perspectives, the electrochemical radionuclide generator approach is expected to be costeffective, realistic, implementable in a centralized radiopharmacy, and thus capable of providing pharmaceutical grade radionuclides in a seamless manner for routine use in nuclear medicine. The electrochemical generator technology is an open technology without any intellectual property rights (IPR) issues and provides the scope to commercial companies for reaping the rewards of this technological innovation. The future of electrochemical radionuclide generators is inextricably linked to the development of an automated system. The practical advantages of automation include reduction in radiation dose to operators, process robustness as well as product reproducibility, consistent performance of the generator system, traceability of the complete process, including documentation of all process parameters and functions, and better control of sterility and apyrogenicity of the generator-derived radionuclide. Automation is therefore an appealing vision for the ongoing efforts to create a foundation as well as advancement of electrochemical generator technology in nuclear medicine. Successful implementation of automation would not only ensure a sustained growth but also empower future developments. To advance automation, continuous interaction between users and manufacturers is warranted to define the requirements and, consequently, specifications. Operation steps of each generator need to be examined scrupulously, and automation has to be appropriately explored. It may be worth noting that efforts by commercial companies in devising an automated 90Sr/90Y generator have been fruitful and have drawn widespread praise as a step in the right direction to meet the demand for 90Y in nuclear medicine. The foreseeable integration of automation to other systems is perhaps not far from reality and well poised to take a major leap forward in closing the gap between requirements and capabilities. Radionuclides obtained from electrochemical radionuclide generators are considered to be approved pharmaceutical ingredients (APIs) as they are used as a starting material for the preparation of radiopharmaceuticals for human use and therefore subjected to regulatory approval with a view to ensure quality and safety. The emphasis on quality is most prominently manifested by the fact that not only the

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ASSOCIATED CONTENT

S Supporting Information *

Characteristics of different types of radionuclide generators. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*(A.D.) Phone: 91-22-25595372. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Research at the Bhabha Atomic Research Centre (BARC) is part of the ongoing activities of the Department of Atomic Energy, India, and is fully supported by government funding. We express our sincere thanks to Dr. M. R. A. Pillai, former Head, Radiopharmaceuticals Division, BARC, for his efforts to harness the utility of electrochemical separation strategy in the development of radionuclide generators in our laboratory. We are thankful to Dr. Gursharan Singh, Associate Director (I), Radiochemistry and Isotope Group, BARC, for his constant encouragement and support.

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REFERENCES

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dx.doi.org/10.1021/ie404369y | Ind. Eng. Chem. Res. 2014, 53, 3766−3777