Electrochemical Separation: Promises, Opportunities, and Challenges To Develop Next-Generation...

Electrochemical Separation: Promises, Opportunities, and ChallengesTo Develop Next-Generation Radionuclide Generators To MeetClinical DemandsAshutosh 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 developnext-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 newbreakthroughs and bring evolutionary progress in radionuclide generator technology. Without doubt, the major impetus for theadvancement in radionuclide generator technology stems from nuclear medicine requirements, as a means of obtaining short-lived radionuclides on demand for the formulation of a gamut of diagnostic and therapeutic radiopharmaceuticals. Thetremendous prospects associated with the use of electrochemical radionuclide generators in nuclear medicine dictate that aholistic consideration should given to all governing factors that determine their success. The purpose of this paper is to present aconcise and comprehensive review of the latest research and development activities in the utility of electrochemical separationprocess in development of radionuclide generators that have already established footholds of acceptance in nuclear medicine andare expected to change the future landscape of radionuclide generator technology. This review provides a summary of theprinciple, factors that govern the electrochemical separation, desirable characteristics of the generator systems developed withtypical examples, critical assessment of recent developments, contemporary status, key challenges, and apertures to the nearfuture.

■ INTRODUCTIONThe role of radionuclide generators in providing short-livedradionuclides for the formulation of a wide variety of diagnosticand therapeutic radiopharmaceuticals in nuclear medicineneeds hardly to be reiterated.1−5 Widespread applications ofradionuclide generators have not only accelerated the progressof nuclear medicine practice but also offered numerousopportunities in other related disciplines including oncologyand interventional specialties.6−21 The scope of using radio-nuclide generators is enticing because it would ensure cost-effective availability of no-carrier-added (NCA) radionuclideson demand and also obviate the need for on-site accelerators orreactor production facilities. A large number of the nuclearmedicine procedures performed in many parts of the worldwould not have been possible without the availability ofradionuclide generators.1,5,6,22 Growth in the field of radio-nuclide generators has been phenomenal and paralleled thecomplementary development of targeting agents for therapyand positron emission tomography (PET).11,22−24 Whereas aradionuclide generator “lives” at the interface between manydisciplines, its dependence on separation science is arguably thestrongest. The evolution and continued success of radionuclidegenerators in nuclear medicine, since their inception, has been,in large part, due to technological advancements in separationscience. The incredible prospects associated with the use ofradionuclide generators in nuclear medicine along with thechallenge of providing daughter radionuclides of requisitequality have led to a considerable amount of fascinatingresearch and innovative strategies. In light of the explicit needto obtain the daughter radionuclide in an ionic form having

acceptable radionuclidic and radiochemical purity, essentiallyevery conceivable separation strategy has been exploited.Among the various separation technologies harnessed for the

development of radionuclide generators, column chromatog-raphy technology has dominated the field significantly due tooperational simplicity and user friendliness.1,12,25 Although theuse of column chromatography technology has been productiveand drawn widespread acceptance, the limited adsorptioncapacity of the adsorbents emerged as a major impediment,which requires the use of high specific activity parentradionuclide owing to the explicit need to obtain highradioactive concentration (RAC) or specific volume of thedaughter radionuclide amenable for the preparation of a broadpanoply of radiopharmaceuticals.1 To adsorb the requiredamount of parent activity in a generator, the use of low specificactivity parent radionuclide necessitates a large amount ofadsorbent, which not only increases the size of the column butin turn also requires a large volume of eluent for the elution ofthe daughter radionuclide.1 The low RAC of daughterradionuclide imposes the need for its concentration prior tothe formulation of radiopharmaceuticals.1 Additionally, theutility of column chromatography technology is limited whenapplied to systems containing alpha- or beta-emitting radio-nuclides due to susceptibility of the chromatographic supportto radiation damage.11,17 Radiolytic damage inflicted by these

Received: December 24, 2013Revised: February 19, 2014Accepted: February 20, 2014Published: February 20, 2014

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high LET nuclides can lead to a decrease in daughterradionuclide yields, increased parent radionuclide break-through, and decreased flow through the chromatographiccolumn. Whereas postelution concentration (PEC) orpurification procedures26−36 have tangible benefits to renderthe daughter radionuclide useful for radiopharmaceuticalapplications, the scope of using alternative separation strategieswhere this step can be avoided is a credible proposition. Thedevelopment of alternative separation strategies represents animportant challenge and can only be overcome by technicalbreakthroughs in areas of separation science. Over the past fewdecades, the evolution of a number of alternative separationstrategies has revolutionized the development of radionuclidegenerators.12,19−21

Among the available alternative separation strategies thathave evolved, the prospects of using electrochemical separationtechnique in the development of radionuclide generatorsseemed to be an intuitive proposition and holds significantpromise.4,37 Electrochemical separation strategy exploits thedifference between the standard reduction potentials of theparent and daughter radionuclides, to separate the daughterradionuclide of interest under the influence of controlledapplied potential. This approach stands at the threshold of anexciting leap forward in generator technology and is poised tochange its landscape in the future. This elegant separationstrategy neither requires high specific activity parent radio-nuclide nor is susceptible to radiation damage inflicted by highLET radiation and can be used to overcome limitations ofcolumn chromatography-based separation technique. Herein,we attempt to present a concise and comprehensive review onthe latest research and development activities on electro-chemical separation strategy, which is expected to pave the wayfor developing state-of-the-art radionuclide generators adapt-able to existing and foreseeable clinical demands. In thefollowing sections, the electrochemical separation principle,different types of electrochemical radionuclide generatorsdeveloped to date, current status, and future perspectives arediscussed. Conspicuous harnessing of the electrochemicalseparation strategy will not only reinvigorate the radionuclidegenerator technology but can foster the sustainability of thisnovel concept.

■ RADIONUCLIDE GENERATORBefore a discussion of electrochemical radionuclide generatorsin detail, it is pertinent to throw some light on the basics ofradionuclide generators, parent−daughter nuclear equilibrium,and the intimate relationship that exists between them. Thiswill be beneficial for the readers to understand the role ofelectrochemical separation in the development of radionuclidegenerators.A radionuclidic generator is a self-contained system (Figure

1) housing an equilibrium mixture of a parent−daughterradionuclide pair and designed to provide the daughterradionuclide formed by the decay of a parent radionuclide,which is free from the parent.6,7,20,21 The parent−daughternuclear relationships offer the possibility to separate the short-lived daughter at suitable time intervals. Overviews of theprinciple, criteria for the selection of parent−daughter pairs,radioactive equilibrium, and the growth and equilibrium of thedaughter radionuclide with the parent radionuclide have beenelaborately discussed in recent reviews.6,7,20,21

In light of the explicit need to separate the daughterradionuclide free from the parent radionuclide with suitable

yield, selection of an appropriate radiochemical separationprocess is not only a necessity but also a determinant for thesuccess of radionuclide generators. Several requirements needto be fulfilled for effective separation of daughter radionuclide,and in general the process should be fast and reproducible andprovide daughter radionuclides of required purity in highradiochemical yield. There is a steadily expanding list ofseparation procedures, each with different characteristics, whichare currently being used or can potentially be used forradionuclide generator technology. An overview of theprinciple, utility, and relative strengths and weaknesses of theabove radiochemical separation processes with respect to99Mo/99mTc generators are elaborated in a recent review that,in principle, can be extended to all other radionuclide generatorsystems.12 Regardless of the separation strategy adopted, theprocess of obtaining daughter radionuclides should remainsimple and flexible.Once the activity of the daughter is recovered from the

mixture, the daughter activity begins to grow again until itsactivity level reaches a maximum and is in equilibrium with theparent radionuclide. The growth and separation of the daughterradionuclide can be continued as long as there are usefulactivity levels of the parent radionuclide available. Theradionuclide generator provides the scope of separatingdaughter radionuclides any time before equilibrium is reached,and the activity levels of the daughter recovered will depend onthe time elapsed since the last separation.Table S1 in the Supporting Information summarizes the

characteristics of several key radionuclide generator systemsthat are being routinely used and could be useful to providedaughter radionuclides for a variety of research and clinicalapplications.6

Figure 1. Schematic diagram of the electrochemical radionuclidegenerator setup.

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■ PRINCIPLE OF ELECTROCHEMICAL SEPARATION

The electrochemical separation process exploits the differencesin the standard reduction potential of metal ions to separate themetal ion of interest under the influence of an applied potential.A mixture of metal ions having adequate difference in theirformal potentials values in an electrolytic medium can bemutually separated by selective electrodeposition of one metalon an electrode surface under the application of the appliedpotential. With regard to the application of an electrochemicalseparation process for preparation of radionuclide generator, itrequires careful control of the applied potential to achieveselective electrodeposition of daughter radionuclide on ametallic electrode. In this process, the potential of the workingelectrode is maintained constant (or within a narrow range) byregulation of the voltage applied to the cell in such a way topermit the quantitative deposition (by reduction) of thedaughter radionuclide on an electrode surface, from a suitableelectrolyte solution containing parent−daughter mixture. Theparent radionuclide is generally more difficult to reduce in thatelectrolytic medium. The electrodeposited daughter radio-nuclide then can be conveniently recovered in a small volumeof solution of interest, and the electrode can be reused forsubsequent deposition of the daughter radionuclide. The key tosuccess in the electrochemical technique is to select anappropriate electrobath and to identify how this approach canbe successfully applied to separate the daughter radionuclidefrom a solution containing parent−daughter radionuclideswithin a reasonable period of time (1−2 h).Advantages of Electrochemical Separation Strategy

in Preparation of Radionuclide Generators. The clec-trochemical separation strategy possesses the followingadvantages.• The electrochemical route offers the scope of utilizing

parent radionuclide of any specific activity. Because theelectrode selectively deposits NCA daughter radionuclide, theparent nuclide specific activity is essentially irrelevant.• The process is basically an oxidation−reduction reaction in

which the electron brings about separation without the use ofexternal chemical reagents. The process is consistent with theprinciples of “green chemistry”.• Recovery of valuable parent isotopes after electrolysis is

quantitative, which not only offers the scope of storing theparents for regrowth of daughter radionuclides for subsequentrecovery 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 damageoften encountered in column chromatography generators. Asthe daughter radionuclide is selectively electrodeposited on ametallic electrode, radiolytic damage is precluded.• The process offers a means of availing daughter radio-

nuclide of high radioactive concentration. Electrodepositingonly the minute mass of the daughter radionuclide on theelectrode surface enables one to recover the daughterradionuclide in a small volume of solution that may beconveniently 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 ofradiolytic damage of the adsorbent.11

• Separation efficiency and product purity remain unchangedon 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 Strat-

egy in Preparation of Radionuclide Generators. Despiteits excellent attributes, the applicability of the electrochemicalseparation process in the preparation of radionuclide generatorshas certain limitations, which are outlined below.• Skilled manpower well versed in both electrochemistry and

radiochemistry is required, which might not be easily found in ahospital 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 ofparent 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 theelectrode material upon electrodeposition.• After electrodeposition, the daughter radionuclide should

be loosely adhered on the electrode surface, so that it can beeasily recovered in the desired medium with minimum chemicalmodifications.• An automated module and a dedicated shielded facility are

required for the production of clinically useful amounts ofdaughter radioactivity.Despite these limitations, the electrochemical separation

procedure not only holds promise as an innovative approachbut has the potential to revolutionize radionuclide generatortechnology. This separation strategy has the potential to harborboundless possibilities and bring innovation in radionuclidegenerator technology. The interest in electrochemical separa-tion will vary according to the parent−daughter radionuclidepair considered.

■ FACTORS INFLUENCING ELECTROCHEMICALSEPARATION

Realization of electrochemical separation process for thedevelopment of radionuclide generator technology is not atrivial process and poses formidable scientific and technicalchallenges. Any electrochemical separation strategy needs to beevaluated thoroughly to assess its prospects of success. Theinherent determinant for the success of an electrochemicalseparation process resides in the identification of theexperimental parameters that influence the separation processand their optimization to ensure selective deposition ofdaughter radionuclide onto an electrode. A more holisticunderstanding of the experimental factors that governs theelectrochemical separation process will not only drive theinnovation forward but also empower future developments.Experimental parameters expected to influence the success ofelectrochemical separation are discussed in the following text.

Applied Potential. The success of an electrochemicalseparation strategy depends on the difference in the formal



electrode potentials of the parent and daughter ions and on theapplication of a suitable potential (voltage). Successfuloutcomes are best achieved when the formal electrode potentialof the parent ion is more negative than the formal electrodepotential of the daughter ion or, in other words, the parent ionis more difficult to reduce compared to the daughter ion. Toachieve selective electrodeposition of the daughter radionuclidefrom the parent−daughter mixture, the applied potential shouldbe more negative than the formal reduction potential of thedaughter ion and at the same time more positive compared tothe formal reduction potential of the parent ion in thatparticular medium.Electrolyte. The electrochemical separation strategy

requires an electrolyte in which the parent−daughter radio-nuclide is dissolved and remains electroactive. The concen-tration of the electrolyte solution depends on the specificactivity of the parent radioisotope. In principle, there is norestriction on the maximum concentration of the electrolytesolution because the daughter radioisotope that is electro-deposited is always in NCA form (micromolar concentrationeven for Ci level of activity), irrespective of the specific activityof the parent radioisotope. However, it must be ensured thatthe parent radioactivity should always be completely soluble inthe requisite volume of electrolyte which can be contained inthe electrolysis cell and no salting-out effect should ever beobserved 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 theelectrolysis is performed plays a crucial role in determining theoutcome. Generally, the formal electrode potential of aparticular ion in a given electrolytic medium is governed byits tendency to form complexes in that medium. With a view toachieve selective electrodeposition of daughter radionuclide, itis of utmost importance to choose an appropriate electrolytecapable of maintaining a substantial difference in the formalelectrode potential of the two ions. In an effort to ease theselective electroreduction of a particular ion, the scope of usinga suitable complexing agent in the electrolyte solution has beenseen as an intuitive strategy.38 To maintain the appliedpotential within the “electrochemical potential window”, it isof paramount importance to prevent the electrolytic degrada-tion of the electrolyte during the course of electrolysis.39,40

Over the years, we have witnessed an intense activity andtremendous progress toward the use of a variety of organicelectrolytes and room temperature ionic liquids (RTILs) owingto their ability to offer wide electrochemical windows and highconductivities. Although the use of such electrolytes constitutesa successful paradigm of performing electrolysis over a widerange of potential,41,42 the organic framework of such solventsemerged as the primary impediment that continues to thwartefforts for their use in radionuclide generators owing tosusceptibility of the electrolyte to radiolysis in the presence ofintense radiation. The radiolytic products not only affect theseparation efficacy of the electrochemical process but alsorender the electrolyte unsuitable for subsequent electrolysis. Inview of this premise, assessing the potential of an aqueouselectrolyte is not only an interesting prospect but may beviewed as a necessity for the development of radionuclidegenerator technology. Whereas the use of aqueous electrolyteleads to the evolution of hydrogen gas as a result of electrolysisof water and also reduces the current efficiency of the process,the ability to produce a nonadherent deposit of the daughterradionuclide represents an advantageous attribute. In view of

the explicit need to quantitatively recover the daughterradionuclide from the electrode surface and to render theelectrode amenable for subsequent electrolysis, a weak adhesionbetween the deposit and the electrode surface is critical for itssuccess in radionuclide generator. Prior to electrolysis, it isessential to warm the electrolyte with constant purging of aninert gas to ensure that it is free from radiolytic gaseousproducts.

pH of the Electrolyte. The pH of the aqueous electrolyteis one of the critical characteristics that need to be optimizedfor successful and reproducible electrodeposition of daughterradionuclides. 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 asuitable buffer for maintaining the pH of the electrolyte duringthe course of electrolysis. However, it must be ensured thechosen buffer does not interfere in the electrochemical process.

Choice of Electrode. Spurred by the perceived need torecover the daughter radionuclide free from trace metal ions,the scope of using electrodes made from inert metal seemedsagacious. A useful attribute of the inert material electrode is itsability to retain its chemical characteristics on repeatedexposure to electrolyte medium for a prolonged period oftime. The process of identifying and selecting an appropriateelectrode material primarily resides in its ability to resistoxidation/reduction and withstand the intense radiation duringthe course of multiple electrolyses over an extended period oftime. Among the various materials available and investigated,gold and platinum electrodes are the most preferred materialsowing to their high conductance, proven chemical inertness,excellent radiation stability, and ease of fabrication into desiredshapes and sizes.

Temperature of the Electrolyte. The effect of temper-ature of the electrolyte bath on the electrodeposition ofdaughter radionuclide needs to be evaluated on a case-by-casebasis. The temperature of the electrolyte bath is usuallymaintained well below its boiling point during the course ofelectrolysis. Sometimes it may be necessary to carry out theelectrolysis in a water-jacketed glass cell, having provision forcirculation of cold water to maintain the temperature of theelectrolyte.43

Time of Electrolysis. To preclude the decay loss ofdaughter radionuclide and the deposition of extraneousimpurities, the electrolysis time needs to be optimizedjudiciously. Additionally, if electrolysis is carried out for along time period, the cathodic deposit in the presence ofelectric current might convert into a phase that may be stronglyadherent to the electrode surface and hence may be difficult toleach out from the electrode for subsequent use.34,44

Although electrochemical separation is a discipline requiringmanpower well versed in both electrochemistry and radio-chemistry and a number of experimental parameters need to beoptimized, the reward at the end of the road is sufficient tojustify the effort. The parameters influencing the separation ofthe daughter from the parent in the electrochemical radio-nuclide generator systems studied to date, the electrochemicalreactions involved, and the final chemical form in which thedaughter radionuclide is separated are summarized in Table S2in the Supporting Information.



■ POTENTIALLY USEFUL ELECTROCHEMICALRADIONUCLIDE GENERATOR SYSTEMS

The interest in the use of electrochemical radionuclidegenerator will vary according to the scenarios considered.This section provides a brief overview of the various types ofelectrochemical radionuclide generators investigated. Table S3in the Supporting Information reviews the performance of theelectrochemical radionuclide generator systems explored andalso highlights the potential applications of the daughterradionuclide obtained from these generators. Each radionuclidegenerator investigated has its own distinct feature as eachparent−daughter radionuclide pair has different chemicalcharacteristics. Each radionuclide generator on its own mighthave the capability to provide daughter radionuclide suitable foruse in nuclear medicine.

90Sr/90Y Generator. There is a great deal of interest in theuse of 90Y for targeted radionuclide therapy owing to itsfavorable characteristics such as emission of high-energy β−

radiations (Eβ‑max 2.28 MeV, no γ emissions), suitable half-life(64.1 h), and its decay to a stable daughter product, 90Zr.11,14

The use of a 90Sr/90Y generator in targeted radionuclidetherapy is attractive due to the following reasons:• The 28.8 year half-life of the parent 90Sr not only ensures

cost-effective availability of 90Y for long periods of time(potentially up to 10 years or even longer) but also obviates thereliance on local reactor production capabilities.• The highly energetic β− radiations emitted by 90Y have the

advantage of relatively long-range tissue penetration andhomogeneous dose distribution in large size tumors.• The 64 h half-life of 90Y is a valuable asset for reducing

toxicity risks during therapy as well as providing the scope ofpreparing 90Y-labeled radiopharmaceuticals.• In light of the perceived need to prepare high specific

activities targeting agents (antibodies, peptides, etc.) topreclude any unwanted pharmacological consequences ortarget saturation, the scope of using NCA 90Y obtained from90Sr/90Y generators is a necessity.• Yttrium ion (Y3+) has a relatively simple chemistry, and its

suitability for forming complexes with a variety of chelatingagents is well established. A well-established coordinationchemistry based on bifunctional chelators (BFC) has been thebasis for 90Y radiopharmacy. 90Y3+ forms complexes with BFCswith high affinity, which in turn makes it possible to preparehigh specific activity 90Y-labeled peptides or other biomoleculesconjugated to the BFC.• The parent radionuclide 90Sr, which is a long-lived fission

product, is available in large quantities from spent fuel.• The availability of a reliable 90Sr/90Y generator would

facilitate unlocking the vast therapeutic potential of 90Y.There are several well-established radiopharmaceuticals

based on monoclonal antibodies, peptides, and particulateslabeled with 90Y, which are in regular use for the treatment ofsome forms of primary cancers and arthritis.11,45 Thetremendous prospects associated with the use of 90Sr/90Ygenerators along with the challenge of providing 90Y of requiredquality amenable for targeted radionuclide therapy have led to asubstantial amount of captivating research and innovativestrategies.11,14 Whereas the use of the column chromatographytechnique constitutes a successful paradigm for the preparationof radionuclide generator systems, its utility for the 90Sr/90Ysystem is limited owing to denaturation of the column matrixresulting from energy deposition of the high LET β− particles

emanating from decay of the 90Sr as well as 90Y. Radiationdegradation of the chromatographic matrix not only willdecrease the performance in terms of product yield over timebut also often results in 90Sr breakthrough in the eluate.46 Theinadvertent presence of 90Sr in the generator-derived 90Yemerged as the major impediment for the preparation ofradiopharmaceuticals owing to the radiotoxicity of 90Sr.Strontium-90 (t1/2 = 28.8 years) is known to be a bone seekerwith a maximum permissible body burden (MPBB) of only 74kBq (2 μCi).46,47 This translates to a limit of 74 kBq of 90Sr in37 GBq of 90Y, assuming that a patient may be administered amaximum activity of 37 GBq of 90Y in his/her entire lifetime. Amore prudent approach to promote the beneficial use of 90Y intherapy is to develop 90Sr/90Y generators based on alternativeseparation techniques. In the quest for an innovative approach,within the realm of separation technology, the scope of using anelectrochemical separation technique seemed appropriate.48

In view of the necessity to achieve a satisfactory degree ofseparation of 90Y from 90Sr, resorting to two-step electrolysiswas found to be effective.48 The two-step electrolysis enabledextraordinarily high decontamination factors to be achieved.Platinum seemed to be the best choice for the electrode andwas hence adopted here. The first electrolysis was performedfor 90 min in 90Sr(NO3)2 feed solution maintained at pH 2−3,applying a potential of −2.5 V (100−200 mA current) withrespect to saturated calomel electrode. After the firstelectrolysis, the cathode was removed without switching offthe voltage, washed with acetone, and transferred to a newelectrolysis cell containing fresh electrolyte solution (0.003 MHNO3) and a new platinum electrode. The polarity of theelectrodes was reversed, and the electrolysis process wasrepeated for another 45 min. The 90Sr(NO3)2 solution after thefirst electrolysis is stored for growth of 90Y and future recovery.The two-step electrolysis provides the scope for obtaining 90Ywith acceptable radionuclidic purity. The 90Y deposited on thecircular cathode after the second electrolysis was dissolved inacetate buffer to obtain 90Y acetate, suitable for radiolabeling.The noteworthy feature on the use of the electrochemicalseparation technique was to achieve a high overall yield (>90%)of 90Y.Owing to the stringent requirement of very high radio-

nuclidic purity (90Sr/90Y activity ratio <10−5) of clinically useful90Y, the activity of 90Sr in the electrochemically separated 90Ysolution was carefully analyzed using an extraction paperchromatographic (EPC) technique to ensure that it was wellwithin acceptable limits.49,50 Yttrium-90 was applied on thechromatographic paper, which was developed in 0.9% NaClsolution (saline). The extractant, 2-ethylhexyl-2-ethylhexylphosphonic acid (KSM-17), retained Y3+ tightly at the pointof application (Rf = 0), whereas Sr2+ migrated with the solventfront, resulting in a clear separation. The 90Sr activity present atthe solvent front, as measured using the liquid scintillationcounter, was compared to the total applied activity todetermine the radionuclidic purity of 90Y. Yttrium-90 obtainedfrom the electrochemical generator had high radionuclidicpurity with barely 30.2 − 15.2 kBq (817 − 411 nCi) of 90Sr per37 GBq (1 Ci) of 90Y (0.411−0.817 ppm).The electrochemical 90Sr/90Y generator was scaled up to 4.44

GBq (120 mCi) activity level, and its performance wasevaluated for a period of 2 years.51 Yttrium-90 obtained fromthe generator was used for radiolabeling various BFCs,peptides, and other biological molecules with satisfactoryradiolabeling yields.51−53 The performance of the generator



remained consistently good over this period of 2 years.Therefore, it can be expected that 90Y can be “milked” fromthis generator virtually for an indefinite period of time. Theelectrochemical 90Sr/90Y generator was named “Kamadhenu”,after the Indian mythological cow that gives an unlimitedsupply of milk.A fully automated electrochemical module for the electro-

chemical 90Sr/90Y generator (Kamadhenu) was developed(Figure 2) and is commercially available from IsotopeTechnologies Dresden (ITD) (Germany). The automatedmodule is already in operation in some countries. The abovemodule is designed for the production of up to 1 Ci (37 GBq)of 90Y per day.54

188W/188Re Generator. In recent years, there has beenunprecedented interest in the use of 188Re for therapy by virtueof its favorable nuclear characteristics such as reasonable half-life (16.9 h), high energy beta radiation (Eβmax = 2.118 MeV),emission of a 155 keV γ-ray (15%) suitable for imaging,potential availability in NCA form from a generator, andchemistry similar to that of 99mTc, which is suitable for thepreparation of a wide variety of radiopharmaceuticals.13,55−64

Although the therapeutic application of 188Re is quite promisingand well entrenched, its dependence on a 188W/188Re generatoris considered to be strongest due to the following reasons.• It ensures onsite availability of NCA 188Re on a cost-

effective day-to-day basis.• The 69.4 day half-life of the parent 188W with the in-growth

of 188Re after elution allows use of the generator for a longperiod. A conservative estimate shows that 1.85−2.59 TBq(50−70 Ci) of 188Re can be eluted from a 37 GBq (1 Ci)generator when used over a period of 6 months.• It offers the scope for making a “matched pair” of

therapeutic products similar to the 99mTc.• Commercial availability of freeze-dried kits offers clinicians

the comfort of preparing a wide variety of therapeutic agents.

• It represents an attractive option for countries having noresearch reactor facility and situations where 177Lu and 90Y areunavailable or too expensive.The exciting perspective of the 188W/188Re generators in

radionuclide therapy have led to the development of a numberof innovative strategies in attempts to obtain 188Re in achemical form to meet the requirements of present-day 188Relabeling chemistry.13 The basis for today’s success of 188Re inradionuclide therapy was laid with the development of acolumn chromatographic generator using a bed of acidicalumina by Oak Ridge National Laboratory (ORNL),USA.65−67 Most of the commercially available 188W/188Regenerators are akin to the 99Mo/99mTc generators usingalumina columns, where tungsten is retained on the aluminacolumn and 188Re is eluted with 0.9% NaCl solution for routineclinical practice. The therapeutic applications of 188Re innuclear medicine would not have attained such a preeminentstatus but for the alumina-based 188W/188Re generators.Whereas the 188W/188Re generator technology remains at the

interface between many disciplines, availability of requiredquantity and quality of 188W constitutes the pillars for itssuccess. Although the efforts by ORNL scientists ensuredcommercial availability of 188W/188Re generators for therapyand have drawn widespread praise as a step in the rightdirection, the intricacy involved in the production of 188Wemerged as the major impediment for extensive use of thisgenerator. Tungsten-188 can be produced only by double-neutron capture with low neutron absorption cross sections[186W(n,γ)187W, σ = 37.9 ± 0.6 b); 187W(n,γ)188W (σ = 64 ±10 b)].68 Furthermore, due to the long half-life of 188W (t1/2 =69 days), relatively long irradiation periods are required evenfor the production of 188W of modest specific activity.68

Consequently, 188W from the high flux reactors (ϕ ∼1015 ncm−2 s−1) such as the High Flux Isotope Reactor (HFIR) inORNL, SM Reactor in Dmitrovgrad, Russian Federation, orBR3 Reactor in Belgium can only be used to make 188W/188Re

Figure 2. Fully automated 90Sr/90Y generator (Kamadhenu) commercially available from Isotope Technologies Dresden (Germany). Adapted fromref 11.



generators suitable for clinical use. The specific activity of 188W,produced in the high-flux reactors, ranges from 150 to 190 GBqg−1 of W.68 Therefore, production of high specific activity 188Wwill be the privilege of only those who have access to reactorshaving flux >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/188Regenerators is of low radioactive concentration and must beconcentrated using a suitable postelution concentrationtechnique to make it suitable for radiolabeling with188Re.22−24 The increasing clinical demand for 188Re has ledto the development of automated systems for the concentrationof 188Re eluate.69 However, the high cost involved in theoperation of the complex automation systemsa further increasesthe production cost of 188Re and renders it cost-ineffective forroutine therapeutic use.Development of 188W/188Re generators using low specific

activity 188W produced from a moderate flux reactor amenablefor routine clinical use is the cornerstone for the survival andstrength of 188Re radiopharmacy. With a view to achieve thisobjective, several alternate sorbents such as hydroxyapatite, thehydrous oxides of zirconium, titanium, manganese, tin(IV), andcerium, silica gel, the AG 1-X12 and AG 50 W-X12 ion-exchange resins, and activated charcoal, several sorbents withhigher capacity for W such as gel−metal oxide composites,synthetic alumina, polymeric titanium oxychloride, andpolymeric zirconium compound (PZC) have been studied todetermine their suitability for the preparation of 188W/188Regenerators.70−73 Despite many impressive advances, thepromise of developing 188W/188Re generators using low specificactivity 188W for routine clinical use remains elusive. Probably,the electrochemical approach is the only alternative to developclinical scale 188W/188Re generators using medium to lowspecific activity 188W, which can be produced in medium-fluxreactors.44

With the aim of realizing the selective electrodeposition of188Re from an aqueous 188W/188Re equilibrium mixture in anelectrolysis cell, the selection of composition of the electrolytehas emerged as a crucial factor and a critical step to achievesatisfactory deposition of 188Re species onto working electrodeswithin a reasonable time. Within all of the unknowns anduncertainties related to the multistep complex process thatgovern the reduction of initial ReO4

− species in aqueoussolutions to Re metal, the scope of using an oxalate bath wasfound to be productive.44 Electrolysis was carried out in oxalicacid medium (pH 1−2) by applying a potential of 7 V for 45min, using platinum electrodes. The presence of oxalate ions inthe electrolyte helps in enhancing the reduction of ReO4

− ionsthrough formation of a 1:1 rhenium−oxalato complex.74 Afterthe electrolysis, the cathode containing the 188Re deposit wasremoved and washed with acetone to remove loosely held188W. The deposit was dissolved in 0.1 M HCl to yieldperrhennic acid, which was neutralized and passed through analumina column for further purification. The overall decay-corrected yield of 188Re was >70%. The recovered 188Re hadhigh radiochemical (>97%) and radionuclidic purity (>99.99%)and was suitable for radiolabeling various biomolecules.Repeated electrochemical separation of 188Re from the samestock solution of 188W could be demonstrated for a period of 6months.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 andconcentration in one step but also offers the scope forquantitative recovery of enriched 186W for subsequentutilization. The success of the automated 90Sr/90Y generatorsystem serves as a model, and the technological adaptation formaking 188W/188Re generator system generator offer excitingpossibilities. There is no doubt that soon efforts will be focusedon the development of a fully automated electrochemical188W/188Re generator system, and its utility in radionuclidetherapy will continue to move forward along a path that offersboth greater diversity and higher flexibility.

99Mo/99mTc Generators. The role of 99Mo/99mTc generatorsystems as the exclusive source for availing NCA 99mTc forsingle-photon imaging in diagnostic nuclear medicine needshardly to be reiterated. Technetium-99m remained the“workhorse” of nuclear medicine for several decades and isexpected to retain its status in the foreseeable future,notwithstanding the introduction of new diagnostic radiophar-maceuticals with other radionuclides.75−80 The99Mo/99mTcgenerator systems have not only played an important role inthe evolution of nuclear medicine but also underpin its success.Diagnostic nuclear medicine would not have attained such apreeminent status but for this wonderful radionuclide havingalmost ideal nuclear properties for yielding functional images ofthe internal organs of the body.81−83 Every year, more than 30million patient studies are performed worldwide using 99mTc-labeled radiopharmaceuticals.75 The column chromatographicgenerator using a bed of acidic alumina has emerged as themost popular generator system the world over.12,78,79 Whereasthe column chromatographic 99Mo/99mTc generator continuesto reign as the procedure par excellence and has drawnwidespread users’ acceptance, the limited capacity of alumina(up to 20 mg of Mo per g of alumina) for taking up molybdateions 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 limitednumbers of aging research reactors.84 With the ready availabilityof relatively inexpensive fission 99Mo of required quality andquantity in the world market along with the mature productiontechnology, the need for implementation of alternative99Mo/99mTc generator technologies was not felt until recently.A variety of factors, well described in the literature, resulted inthe disruptions in fission 99Mo supplies on the world marketduring 2007−2009.84−90 The utilization of weapons-gradeHEU for the production of fission 99Mo poses proliferationand terrorism risks owing to the possible acquisition of suchmaterials by terrorists or rogue states to make nuclear weaponsor improvised nuclear devices.91−93 The need for phasing outHEU together with the uncertainty in the continued use of afew aging reactors for the production of fission 99Monecessitates the development of alternative 99Mo productionstrategies as well as 99Mo/99mTc generator technolo-gies.12,84,88,94−98 In this context, a number of alternative 99Moproduction strategies without the use of HEU, such as theaqueous homogeneous reactor (AHR) concept, target fuelisotope reactor (TFIR) concept, direct cyclotron production of99mTc, photofission of 238U, photon-induced transmutation of100Mo, and accelerator-driven subcritical assembly, haverecently been pursued.84 However, most of these approachesare balanced on a fine line, with technical breakthroughs on theone hand and long-term economic viability on the other.



Among several non-HEU reactor options considered,(n,γ)99Mo production is the least intricate route to access99Mo with negligible generation of radioactive waste and beingproliferation resistant, inexpensive, and within the reach ofmost institutions having operating research reactors.12,84,97,98

This approach provides 99Mo with specific activity ranging from7.4 to 130 GBq/g (0.2−3.5 Ci/g) depending upon the thermalneutron flux of the reactor undertaking irradiation. However,the relatively low specific activity [0.35−3.5 Ci g−1 (13−130GBq g−1)] of (n,γ)99Mo is the major impediment for itsutilization in the existing alumina-based generators. The scopeof using (n,γ)99Mo is relatively more appealing because simpletarget dissolution capabilities will suffice. This capability iswithin the reach of most countries having operating researchreactors and good geographic distribution around the world.Notably, this source of 99Mo is independent of existing supplychains and would provide redundancy and emergency backup.One important point to note is that irrespective of the specificactivity of 99Mo used, the 99mTc is always NCA and hasessentially the same specific activity. The principal challengetoward utilization of the neutron activation route forproduction of 99Mo was to tackle the extremely low specificactivity of 99Mo produced, for which alternative separationtechniques required to be developed for the preparation of99Mo/99mTc generators.12 An overview of the principle, utility,and relative strengths and weakness of the above are elaboratedin a recent review.12

The success of electrochemical 90Sr/90Y and 188W/188Regenerators not only served as the foundation but also paved theway for realizing the electrochemical separation of 99mTc from99Mo/99mTc mixture.99 This is primarily based on the selectiveelectrodeposition of 99mTc on a platinum electrode by takingadvantage of the difference in formal electrode potentials ofMoO4

2− and TcO4− ions in alkaline media. The preferential

electodeposition of 99mTc relies on applying a potential of 5 Vin 0.1 M NaOH medium for 45 min. With a view to recover the99mTc deposit on the cathode, electrolysis was carried out insaline solution by reversing the polarity of the electrode andapplication of a high positive potential for a few seconds. In thisprocess, the 99mTc deposit could be quantitatively brought intosaline solution wherein 99mTc existed as 99mTcO4

−. To ensurethat the recovered 99mTc was free from trace contamination of99Mo, it was passed through a small column containing acidicalumina. Initially, the electrochemical separation process wasdemonstrated using 9.25 GBq (250 mCi) of 99Mo,99 which wasfurther scaled up to 29.6 GBq (800 mCi) activity level.100 Theoverall yield of 99mTc was >90%, with >99.99% radionuclidicpurity and >99% radiochemical purity. The performance of thegenerator remained consistent over a period of 2 weeks, whichwas comparable to the shelf life of the commercially available(fission 99Mo based) 99Mo/99mTc generators. The compatibilityof the product in the preparation of 99mTc-labeled formulationswas found to be satisfactory. Furthermore, it was demonstratedthat the process was suitable for the separation of clinicallyuseful 99mTc, even from very low specific activity (∼1.85 GBq/mg) 99Mo.100

This state-of-the-art electrochemical separation technology isa major step in a vitally important direction, which also offersexciting opportunities to use 99Mo obtained from photon/proton activation of enriched 100Mo or direct production of99mTc through accelerator route. The encompassing potential

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

■ SUMMARY AND FUTURE PERSPECTIVESWe have depicted here a fascinating world of electrochemicalradionuclide generators wherein separation science and electro-chemistry intersect. The interplay between these two broadresearch domains has not only unveiled bountiful possibilitiesbut also seems poised to bring major breakthroughs inradionuclide generator technology, where the goals areattainable and the payoff of success would be substantial. Inthis review, we have showcased a few radionuclide generatorsfor which the electrochemical separation technique has played acritical role in shaping the radionuclide generator technologyadaptable for clinical use.Although application of the electrochemical separation

process in the development of radionuclide generators is stillin its infancy, its importance has been recognized in recentyears and is expected to grow in the future. A review of thepotential of electrochemical separation technique in thedevelopment of radionuclide generators indicates that theadvances made so far are exciting, their utility is evolving, andthere are no apparent barriers for their clinical adoption. It isnecessary to add new exotic radionuclide generators to itsreservoir to meet the research and clinical demands in theforeseeable future. With the appropriate selection of a parent−daughter radionuclide pair, it would be possible to envision afuture in which the scale and scope of the electrochemicalseparation technique can be tailored to an individual situationto 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 innuclear medicine. As nuclear medicine is moving to theforefront of modern medicine, demands for new radionuclidesare emerging far more quickly than they did over the pastdecade. Because of the pace with which the field of nuclearmedicine is evolving, radionuclide generator strategies need avision for today and tomorrow. An examination of theradionuclide generator technologies indicates that in the livelydebate between the column chromatography and solventextraction techniques, the need for alternative separationtechniques has often been overlooked. These alternativeseparation strategies deserve greater attention not only becausea greater range of options will be needed but also for theadaptability to use high LET radionuclides or parent radio-nuclides produced from different sources with a wide range ofspecific activities.Although it might be true that the radionuclide generator

systems based on alternative separation techniques in dailynuclear medicine practice to date have not lived up to theirinitial optimistic expectations, the outlook of the electro-chemical radionuclide generator concept is bright given currenttrends in the evolution of centralized radiopharmacies concept.The existing modality of using radionuclide generators innuclear medicine centers will diverge, making it likely thatfuture supply in many countries will take place throughcentralized radiopharmacies set up to achieve cGMPcompliance. Central radiopharmacies are manned with skilledstaff, and hence generators based on electrochemical separationtechniques, which need more manipulation, can be readily andunambiguously handled by trained people.Whereas the capital cost of an electrochemical generator is

much higher than that of a conventional radionuclide generator



based on column chromatography or solvent extractionconcept, it is a one-time investment and the same system canbe used repeatedly for several years. Only the electrolytesolution consisting of the parent−daughter mixture needs to bereplenished after decay of the parent radioactivity to a levelwhen it is no longer useful for generator application. In theevaluation of the cost of an electrochemical generator, it iscustomary to use “life cycle cost/benefit analysis”. The scope ofusing an electrochemical generator system is enticing as it iscapable of providing measurable returns on the investments inthe long run. Payback is substantial not only from the capitalinvestment but also in the form of higher productivity andbetter quality of product. Minimal radioactive waste disposalproblem is an added advantage, which will reduce the paybacktime and add an extra dimension to its value. This strategyconstitutes an effective way of realizing a 90Sr/90Y generatoramenable for use in hospital radiopharmacies where most of theconventional separation approaches have been provenineffective. Also, the electrochemical separation approachrepresents a viable, cost-effective means of producing clinicallyuseful 99mTc and 188Re even from their low specific activityprecursors. From long-term perspectives, the electrochemicalradionuclide generator approach is expected to be cost-effective, realistic, implementable in a centralized radio-pharmacy, and thus capable of providing pharmaceuticalgrade radionuclides in a seamless manner for routine use innuclear medicine.The electrochemical generator technology is an open

technology without any intellectual property rights (IPR)issues and provides the scope to commercial companies forreaping the rewards of this technological innovation. The futureof electrochemical radionuclide generators is inextricably linkedto the development of an automated system. The practicaladvantages of automation include reduction in radiation dose tooperators, process robustness as well as product reproducibility,consistent performance of the generator system, traceability ofthe complete process, including documentation of all processparameters and functions, and better control of sterility andapyrogenicity of the generator-derived radionuclide. Automa-tion is therefore an appealing vision for the ongoing efforts tocreate a foundation as well as advancement of electrochemicalgenerator technology in nuclear medicine. Successful imple-mentation of automation would not only ensure a sustainedgrowth but also empower future developments. To advanceautomation, continuous interaction between users andmanufacturers is warranted to define the requirements and,consequently, specifications. Operation steps of each generatorneed to be examined scrupulously, and automation has to beappropriately explored. It may be worth noting that efforts bycommercial companies in devising an automated 90Sr/90Ygenerator have been fruitful and have drawn widespread praiseas a step in the right direction to meet the demand for 90Y innuclear medicine. The foreseeable integration of automation toother systems is perhaps not far from reality and well poised totake a major leap forward in closing the gap betweenrequirements and capabilities.Radionuclides obtained from electrochemical radionuclide

generators are considered to be approved pharmaceuticalingredients (APIs) as they are used as a starting material for thepreparation of radiopharmaceuticals for human use andtherefore subjected to regulatory approval with a view toensure quality and safety. The emphasis on quality is mostprominently manifested by the fact that not only the

radionuclides obtained from the generators have to meet strictspecifications but also the separation processes and associatedaccessories must fulfill preset criteria. Nonetheless, to beeffective in addressing the particular regulatory barriers,electrochemical radionuclide generator technologies must becustomized to local legislative, regulatory, and institutionalconditions for which a comprehensively designed and correctlyimplemented quality assurance system is of utmost importance.Change is needed to institute a paradigm shift toward

adapting the electrochemical separation technique in radio-nuclide generator technology to address the needs of thenuclear medicine. Although this groundbreaking electro-chemical radionuclide generator technology has passed manymilestones and made considerable inroads, without doubt thisis just the tip of the iceberg and further excitement in this fieldis awaiting. Clinical realization of this paradigm-changingconcept requires effective harnessing of technology, inspiredvision from scientists, and leading-edge engineering to producefunctional radionuclide generators for nuclear medicine. It isthe responsibility of all stakeholders, including researchscientists, clinicians, radiopharmacists, hospitals, and industries,to share a common platform to harness the immense potentialof electrochemical radionuclide generator technology to make ita mainstream device for clinical use.

■ ASSOCIATED CONTENT

*S Supporting InformationCharacteristics of different types of radionuclide generators.This material is available free of charge via the Internet athttp://pubs.acs.org.

■ AUTHOR INFORMATION

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

NotesThe authors declare no competing financial interest.

■ ACKNOWLEDGMENTS

Research at the Bhabha Atomic Research Centre (BARC) ispart of the ongoing activities of the Department of AtomicEnergy, India, and is fully supported by government funding.We express our sincere thanks to Dr. M. R. A. Pillai, formerHead, Radiopharmaceuticals Division, BARC, for his efforts toharness the utility of electrochemical separation strategy in thedevelopment of radionuclide generators in our laboratory. Weare thankful to Dr. Gursharan Singh, Associate Director (I),Radiochemistry and Isotope Group, BARC, for his constantencouragement and support.

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