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Comparative Assessment of Nanostructured MetalOxides: A Potential Step Forward to Develop ClinicallyUseful 99Mo/99mTc Generators using (n,γ)99MoRubel Chakravartya, Ramu Rama & Ashutosh Dasha

a Isotope Applications and Radiopharmaceuticals Division, Bhabha Atomic Research Centre,Trombay, Mumbai, IndiaAccepted author version posted online: 13 May 2014.Published online: 12 Aug 2014.

To cite this article: Rubel Chakravarty, Ramu Ram & Ashutosh Dash (2014) Comparative Assessment of Nanostructured MetalOxides: A Potential Step Forward to Develop Clinically Useful 99Mo/99mTc Generators using (n,γ)99Mo, Separation Science andTechnology, 49:12, 1825-1837, DOI: 10.1080/01496395.2014.905596

To link to this article: http://dx.doi.org/10.1080/01496395.2014.905596

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Separation Science and Technology, 49: 1825–1837, 2014Copyright © Taylor & Francis Group, LLCISSN: 0149-6395 print / 1520-5754 onlineDOI: 10.1080/01496395.2014.905596

Comparative Assessment of Nanostructured Metal Oxides:A Potential Step Forward to Develop Clinically Useful99Mo/99mTc Generators using (n,γ)99Mo

Rubel Chakravarty, Ramu Ram, and Ashutosh DashIsotope Applications and Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Trombay, Mumbai, India

While the use of nanostructured metal oxides such as nanoti-tania, nanozirconia, nanoalumina, and mesoporous alumina, ascolumn matrices constitutes a successful paradigm in the develop-ment of chromatographic 99Mo/99mTc generators using (n,γ)99Mo,a comparative assessment of their properties is essential not onlyto determine the merits and bottlenecks of each sorbent but alsoto evaluate their usefulness commensurate with the specific activ-ity of (n,γ)99Mo obtained from different sources. Characteristicswhich were compared included the sorption capacity, zeta poten-tial, shelf-life of the generator, radioactive concentration andpurity of 99mTc for radiopharmaceutical applications, and recov-ery of decayed Mo from spent generators. Mesoporous aluminawas identified as the most suitable sorbent for ensuring sustain-able production of clinical grade 99Mo/99mTc generators using lowspecific activity 99Mo.

Keywords 99Mo/99mTc generator; adsorption capacity; columnchromatography; distribution coefficients (Kd);nanosorbents; zeta potential

INTRODUCTIONTechnetium-99m obtained from 99Mo/99mTc generator sys-

tems has reigned as the workhorse of diagnostic nuclearmedicine and today it is the most widely used radionuclidefor single photon emission computed tomography (SPECT)imaging procedures (1–3). It is estimated that over 80% ofthe nearly 30 million diagnostic nuclear medicine studiesare carried out annually with this single radionuclide (4).The dominance of 99mTc in diagnostic nuclear medicine isexpected to remain for the foreseeable future, notwithstand-ing the introduction of new diagnostic radiopharmaceuticalswith other radionuclides. While 99mTc radiopharmaceuticals“lives” at the interface between many disciplines, its depen-dence on 99Mo/99mTc generator is arguably the strongest. The

Received 12 August 2013; accepted 13 March 2014.Address correspondence to Ashutosh Dash, Isotope Applications

and Radiopharmaceuticals Division, Bhabha Atomic Research Centre,Trombay, Mumbai, 400085, India. E-mail: adash@barc.gov.in

widespread use of 99mTc in diagnostic nuclear medicine wouldnot have attained such a pre-eminent status but for 99Mo/99mTcgenerator. The current strategy of availing 99mTc is ensuredfrom 99Mo/99mTc generators either in the hospital where the99mTc will be used or in a centralized radiopharmacy. A vari-ety of 99Mo/99mTc generator systems have been developed andthoroughly investigated during the past few decades amongwhich the column chromatographic generator using a bed ofacidic alumina has emerged the most popular generator systemworld over owing to operational simplicity and user friendliness(1, 2, 5, 6). While the column chromatographic 99Mo/99mTcgenerator continues to reign as the procedure par excellenceand has drawn widespread acceptance, the limited capacity ofalumina (2-20 mg Mo per g of alumina) (7) for taking upmolybdate ions necessitates the use of 99Mo of the highest spe-cific activity available, as can be found in fission produced 99Mo(F 99Mo). Current production capabilities of fission F 99Moare based on the use of highly enriched uranium (HEU) tar-gets in limited numbers of ageing research reactors (8). Withthe ready availability of fission F 99Mo of the required qualityand quantity relatively inexpensively in the world market, alongwith the mature column chromatography generator technology,the need to implement alternative 99Mo/99mTc generator tech-nologies was not felt until recently. A variety of factors, welldescribed in the literature, resulted in the disruptions in fission99Mo supplies in the world market during 2007-2009 (8-14).The utilization of weapons-grade HEU target for the produc-tion of F 99Mo poses proliferation and terrorism risks owing tothe possible acquisition of such material by terrorists or roguestates to make nuclear weapons or improvised nuclear devices(IND) (15-18). The need for phasing out HEU together withthe uncertainty in the continued use of a few ageing reactorsfor the production of F 99Mo necessitates the development ofalternative 99Mo production strategies as well as 99Mo/99mTcgenerator technologies (8–18).

Among several non-HEU reactor options considered,(n,γ)99Mo production is the least intricate route to access 99Mowith negligible generation of radioactive waste, proliferationresistant, inexpensive, and within the reach of most institutions

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1826 R. CHAKRAVARTY, R. RAM, AND A. DASH

having operating research reactors (8). This approach provides99Mo with specific activity ranging from 7.4 to 130 GBq/g(0.2 to 3.5 Ci/g) depending upon the thermal neutron flux of thereactor undertaking irradiation. The tremendous prospects asso-ciated with the use of low specific activity (n,γ)99Mo have led toa considerable amount of fascinating research and a number ofinnovative separation strategies have been developed to obtainclinical grade 99mTc (19). Although the efforts in this endeavorconstitute a step in the right direction, overcoming the prefer-ence of users who are accustomed to the user-friendly columngenerator for over 40 years is the major barrier in propagatingthe alternate generator technologies.

In light of the perceived need to adsorb required amountof (n,γ)99Mo activity within a limited quantity of columnmatrix, the use of high capacity sorbent is not only an inter-esting prospect, but also considered to be a necessary one.The development of high capacity adsorbent represents animportant challenge and can only be possible by technicalbreakthroughs in areas of material science. In spite of manyimpressive advances in the development and use of highcapacity adsorbents (20–22), the efforts turned out futile asthe adsorption capacity of bulk material cannot be improvedbeyond a certain degree owing to the limitation posed bythe density of surface active sites, the activation energy ofadsorptive bonds, and the mass transfer rate to the adsorbentsurface.

These limitations can be circumvented by the use ofnanomaterials as new generation adsorbents. Nanomaterialsdiffer from micro-sized and bulk materials not only in the scaleof their characteristic dimensions, but also in the fact that theypossess new physical properties and offer new possibilities. Oneof the specific properties of nanomaterials is that a high percentof the atoms of the nanoparticle is on the surface. The surfaceatoms are unsaturated and can therefore bind with other atomsand therefore possess high chemical activity. The enhancementin specific surface area and associated surface energy offersthe scope of realizing unusually high capacity. Nanoparticulatemetal oxides by virtue of intrinsic surface reactivity, high sur-face areas, and acid base properties seems to be the mostpromising class of material suited for such applications (23).Our group was the first to tap the potential of nanoparticulatemetal oxides as a new class sorbent in the preparation of chro-matographic 99Mo/99mTc generators using (n,γ)99Mo (23-28).In this context, the utility of nanotitania (TiO2), nanozirco-nia (ZrO2), nanoalumina (γ-Al2O3), and mesoporous alumina(meso-Al2O3) have been profusely explored and elaboratelydescribed (25–28).

While each nanoparticulate metal oxide in its own strengthhas the capability to adsorb 99Mo in a chromatography columnand elute clinical grade 99mTc, their adsorption capacity differs.Since every institution has a reactor with different neutron fluxto irradiate MoO3, the specific activity of (n,γ)99Mo obtained[7.4 to 130 GBq/g (0.2 to 3.5 Ci/g)] differs. Therefore, eachnanoparticulate metal oxide would be expected to have a

place in their own right for developing 99Mo/99mTc genera-tors. In order to evolve holistic and long-lasting approaches toprepare clinical-scale 99Mo/99mTc generators for the immediatefuture and for long-term requirements, a comparative study ofthese new materials was considered worthwhile investigatingnot only to determine their merits and bottlenecks but also toevaluate their adaptability to use 99Mo produced from differentsources with a wide range of specific activities.

In this current work, we describe a comparative studyof these materials with respect to adsorption capacity for99Mo, their potential to develop 99Mo/99mTc generator using(n,γ)99Mo of different specific activities, purity, and qualityof 99mTc eluted from these generators for radiopharmaceuticalapplications.

EXPERIMENTALMaterials and Equipments

Reagents such as hydrochloric acid, ammonium hydroxide,ammonium carbonate, etc., were of analytical grade and wereprocured from S.D. Fine Chemicals, Mumbai, India. Analyticalgrade titanium tetrachloride, zirconium oxychloride, aluminumnitrate, aluminum isopropoxide, and isopropyl alcohol wereobtained from E. Merck, Mumbai, India. HPLC grade waterwas purchased from E. Merck, Germany. Paper chromatog-raphy (PC) strips (3 MM Chr, 20 mm width) were purchasedfrom Whatman International Limited, England. Lyophilizedkits of dimercaptosuccinic acid (DMSA), methylene diphos-phonate (MDP), ethyl cysteinate dimer (ECD), ethylenedicysteine (EC), [2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3,2,1]-oct-2-yl]methyl](2-mercaptoethyl)amino]ethyl]amino]ethanethiolato(3-)-N2,N29,S2,S29]oxo-[1R-(exo-exo)](TRODAT-1), tetrofosmin, diethylene triamino pentaaceticacid (DTPA), and 2-methoxy isobutyl isonitrile (MIBI) wereobtained from the Board of Radiation and Isotope Technology(BRIT), India.

An HPGe detector (Canberra Eurisys, France) coupled toa multichannel analyzer was used for analysis of 99mTc inthe presence of 99Mo. The zeta-potential of the nano particleswere measured using a Zetasizer Nano ZS/ZEN3600, MalvernInstruments Ltd., UK. The chemical analysis for the determi-nation of trace level of metal contaminations was done usingInductively Coupled Plasma-Atomic Emission Spectroscopy(ICP-ES JY-238, Emission Horiba Group, France). The surfacearea and the pore size analysis of the nanomaterials were carriedout by the standard BET technique with N2 adsorption usingQuantachrome, Autosorb-1 analyzer, Canada.

Production of 99MoThe target material, natural MoO3 (2.5 g) in the form of

powder (spectroscopic grade), was packed in an Al capsule,sealed by cold-welding method, checked for leakage by qualitycontrol procedures, and neutron irradiated at a position having

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NANOSORBENTS BASED 99MO/99MTC GENERATORS 1827

neutron flux of ∼9.6 × 1013 n cm−2 s−1 in the Dhruva reac-tor for 1 week. After irradiation, the target was dissolved in50 mL of 3 M NaOH solution at 80◦C. The activity of the 99Mosolution was assayed in an ion-chamber.

Synthesis and Structural Characterization of theNanosorbents

Syntheses of nanotitania (TiO2), nanozirconia (ZrO2),nanoalumina (γ-Al2O3), and mesoporous alumina (meso-Al2O3) were carried out as reported earlier (25-28). In order tostudy the reproducibility of the synthesis protocols, the mate-rials were synthesized in several batches and their structuralcharacteristics were evaluated.

Determination of the Distribution Coefficients (Kd) of99MoO4

2− and 99mTcO4− Ions for the Nanosorbents

The distribution coefficients (Kd) of MoO42- and TcO4

−ions for the nanosorbents were determined by batch processat different pH, using 99Mo and 99mTc radiotracers. In eachexperiment, 100 mg of sorbent was suspended in 11 mL solu-tion containing the radioactive metal ions, in a 20 mL sealedvial. The vials were shaken in a wrist arm mechanical shakerfor 1 h at 25◦C and then filtered. The activities of the solu-tion before and after equilibration were measured in a HPGecounter using an appropriate γ-ray peak (140 keV for 99mTcand 181 and 740 keV for 99Mo). The distribution ratios werecalculated using the following expression:

Kd = (Ai-Aeq)V

Aeq mmL.mg−1

where Ai is the initial total radioactivity of 1 mL the solution,Aeq is the unadsorbed activity in 1 mL of the solution at equi-librium, V is the solution volume (cm3), and m is the mass(g) of the sorbent. In order to determine the time required toattain adsorption equilibrium, the Kd values of MoO4

2- ionswere studied as a function of time at pH 3.

Determination of Zeta Potential of NanosorbentsIn order to study the zeta-potential of the nanomaterial

based sorbents, 5 mg of the respective sorbent was addedto 50 mL of de-ionized water, and the pH of the suspensionwas adjusted using HClO4 and HNO3. Zeta-potential of thesuspensions at different pH was measured at 25◦C in triplicate.

Determination of the Mo-Adsorption Capacity of theNanosorbentsStatic Adsorption Capacity

The static adsorption capacity of each nanosorbent wasdetermined by batch equilibration method by taking 0.5 galiquots of accurately weighed sorbent in a stoppered conicalflask containing 50 mL of sodium molybdate solution (10 mg

of Mo mL−1) and spiked with ∼3.7 MBq (100 μCi) of 99Mo.The sorbent was kept in contact with the radioactive solution byshaking the conical flask using a mechanical shaker for 30 minat room temperature. At the end, the contents were filteredthrough a Whatman filter paper (No. 542). The activities of99Mo in the solution before and after adsorption were estimatedby using HPGe detector coupled to a multichannel analyzer, bymeasuring the counts at 181 and 740 keV peaks correspondingto 99Mo in 1 mL aliquots. All measurements were carried out at25

◦C in triplicate. The adsorption capacity was calculated using

the following expression:

Capacity = (Ao-Ae)V.Co

Ao mmg/g

where Ao and Ae represented the radioactivity of 99Mo in 1 mLof supernatant solution before and after adsorption, respec-tively, Co was the total Mo content (10 mg) in 1 mL of solutionbefore adsorption, V was the volume of solution, and m was themass (g) of the sorbent.

Dynamic Adsorption CapacityThe dynamic adsorption capacity of each nanosorbent and

99Mo-breakthrough patterns were assessed by passing sodiummolybdate solution (10 mg Mo mL−1) at pH 3, spiked with99Mo radiotracer through borosilicate glass columns of dimen-sion 6 cm × 1 cm (i.d.) with sintered disc (G0) at the bottomcontaining 1 g of respective sorbent at a flow rate of 2 mLmin−1. From the feed 99Mo solution, 1 mL was kept as ref-erence and the eluted solution was collected in 1 mL aliquots.The radioactivity associated with the reference solution (Ao), aswell as each fraction (Ai) was measured in a HPGe detector bycounting the 181 and 740 keV peaks of 99Mo. The adsorptioncapacity of nanosorbent for Mo under dynamic conditions wasestimated by the study of the breakthrough profile determinedusing these data.

Development of 99Mo/99mTc GeneratorsThe 99Mo/99mTc generators (Fig. 1) were prepared using the

nanosorbents as reported by us earlier (25–28). Four borosili-cate glass columns, each of dimension 6 cm × 1 cm (i.d.), withsintered disc (G2) at the bottom was packed with 4 g of respec-tive nanosorbent (preconditioned at pH 3 using 0.001 N HNO3)and kept in a lead shielded container. All the operations werecarried out in the closed cycle system using connecting tubes.Input/output connections were made with standard teflon tub-ings of 1 mm inner diameter and connectors. The generator col-umn, connectors, and connection tubings were integrated withina small portable lead shielded unit throughout experimentaluse for radioprotection purpose. Only the feed and output vialswere accessible externally. The generator columns containingTiO2 and ZrO2 were loaded with 3.7 GBq (100 mCi) of 99Mowhile the Al2O3 and meso-Al2O3 columns were loaded with

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1828 R. CHAKRAVARTY, R. RAM, AND A. DASH

Mo/ Tcactivity adsorbed

Nanosorbent Generatorcolumn

Leadshielding

Salinesolution

Tceluate

99m

Needles

Filter

99m99

FIG. 1. Schematic diagram of 99Mo/99mTc generators prepared usingnanosorbents.

9.25 GBq (250 mCi) of 99Mo. The 99Mo solution in sodiummolybdate form was maintained at pH 3. The loaded columnswere washed with 500 mL of 0.9% NaCl solution at a flow rateof ∼10 mL min−1. Subsequently, after allowing adequate time(24 h) for 99mTc build up, the columns were eluted with 0.9%NaCl solution at a flow rate of 2 mL min−1. In order to examinethe elution profile of each generator, the eluates were collectedas 2 mL aliquots and each fraction was counted for gammaactivity. The performances of the generators were evaluated fora period of 2 weeks, by periodic elution at 24 h intervals.

Quality Control of 99mTc EluateThe evaluation of the radionuclidic purity and radiochemical

purity of 99mTc were carried out adopting the procedures asdescribed earlier (23–28). The pH of 99mTc eluate was mea-sured on each elution using suitable pH papers and also a pHmeter. The presence of trace levels of Al3+ ions as chemicalimpurities in 99mTc eluate was estimated by the analysis ofthe decayed 99mTc samples using Inductively Coupled Plasma-Atomic Emission Spectroscopy (ICP-AES).

To evaluate the labeling efficacy, 99mTc eluted from the gen-erator was used to prepare complexes of DMSA, MDP, ECD,EC, TRODAT-1, tetrofosmin, DTPA, and MIBI using standardcommercial lyophilized kits.

Recovery of Mo from the Spent 99Mo/99mTc GeneratorThe spent 99Mo/99mTc generators were washed with saline,

and the Mo was desorbed by passing NaOH solution containingH2O2 (15 mL of 5 M NaOH solution + 1 mL of 30% H2O2) ata flow rate of ∼1 mL min−1.

RESULTSProduction of 99Mo

Typically in one batch, ∼31.4 GBq (850 mCi) of 99Mo wasproduced when 2.5 g of natural MoO3 was irradiated at a fluxof 9.6 × 1013 n cm−2 s−1 for 7 days, which corresponds to aspecific activity of ∼18.5 GBq (∼500 mCi) per g of Mo. Thisvalue is more than what is expected theoretically (26 GBq),probably due to the contributions from epithermal neutrons.The contribution of the epithermal neutron is not practicableto evaluate in a multi-purpose research reactor. The data thusrepresent the typical yields of 99Mo in regular batches follow-ing the weekly operational cycle of the Dhruva research reactor.The irradiated target was dissolved in 3 M NaOH solution at80◦C which formed a colorless and transparent solution within10 to 20 minutes.

Syntheses and Structural Characterization ofNanosorbents

The methods adopted for the synthesis of all thenanosorbents are facile, economical, fast, provide good yields,can easily be scaled-up to gram quantities, and achievable underamenable conditions. The materials obtained in all the casesare granular with adequate mechanical strength and exhibitedfree flowing characteristics, suitable for chromatographic appli-cations. All the precursors used in the synthesis are availablecommercially. More than 20 batches of each nanosorbent wereprepared and the reproducibility of the synthesis procedurewas assessed by the study of the structural characteristics asreported earlier. The synthesis and structural characteristics ofthe nanosorbents are summarized in Table 1. The structuralcharacteristics of the nanosorbents remained consistent in allthe batches.

Determination of the Distribution Coefficients (Kd) of99MoO4

2– and 99mTcO4− Ions for the Nanosorbents

In order to evaluate the selective adsorption ability of thenanosorbents and to optimize the conditions for maximumuptake of 99MoO4

2− ions, the Kd values of 99MoO42− and

99mTcO4− ions were determined using the nanosorbents at dif-

ferent pH and the results are summarized in Table 2. The tableshows that the Kd values of 99Mo are maximum at around pH 2-4 in case of all the sorbents, which indicates that this pH rangeis optimum for 99Mo adsorption on nano metal oxides. In thispH range, the Kd values of 99MoO4

2− ions are highest for meso-Al2O3 and lowest for TiO2. The Kd values of ZrO2 is slightlyhigher than that of TiO2. However, the Kd values of these sor-bents are significantly lower than that of γ-Al2O3. Though,γ-Al2O3 and meso-Al2O3 have the same chemical composition,the Kd values for 99MoO4

2– ions on meso-Al2O3 are 8-10 timeshigher than on γ-Al2O3. This is probably due to the porous tex-ture of meso-Al2O3 which helps in permeation of the ions insidethe pores.

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NANOSORBENTS BASED 99MO/99MTC GENERATORS 1829

TABLE 1Synthesis and structural characteristics of the nanosorbents

Structural characteristics

Sorbent Synthesis methodCrystallitesize (nm)

Pore size(nm)

Surface area(m2/g)

TiO2 Controlled hydrolysis of TiCl4 in isopropylalcohol

5 ± 1 0.4 ± 0.1 30 ± 2

ZrO2 Controlled hydrolysis of ZrOCl2 underalkaline conditions

8 ± 2 0.4 ± 0.1 340 ± 20

γ-Al2O3 Mechanochemical reaction of Al(NO3)3 and(NH4)2CO3

5 ± 1 0.4 ± 0.2 250 ± 10

meso-Al2O3 Hydrolysis of Al(C3H8O)3 in presence ofglucose template, followed by calcination

2 ± 1 3 ± 1 230 ± 12

n = 10; ‘±’ indicates standard deviation.

TABLE 2Distribution coefficients (Kd) of 99Mo and 99mTc ions at different pH

Kd

99Mo 99mTc

pH/ medium TiO2 ZrO2 γ-Al2O3 meso-Al2O3 TiO2 ZrO2 γ-Al2O3 meso-Al2O3

1 146 ± 55 292 ± 74 12129 ± 578 22100 ± 900 3 ± 1 3 ± 2 3 ± 2 5 ± 32 1888 ± 412 2959 ± 187 22295 ± 718 198100 ± 600 14 ± 2 14 ± 3 14 ± 3 14 ± 33 4892 ± 128 6119 ± 228 26611 ± 228 249000 ± 600 41 ± 6 35 ± 1 35 ± 5 46 ± 54 3620 ± 575 5605 ± 178 25960 ± 778 211100 ± 700 33 ± 2 29 ± 4 29 ± 4 39 ± 45 2257 ± 656 5250 ± 903 21852 ± 594 110300 ± 100 3.2 ± 0.9 2.7 ± 0.8 2.7 ± 0.8 1.7 ± 0.56 74 ± 28 174 ± 18 11174 ± 818 91000 ± 200 0.3 ± 0.1 0.3 ± 0.1 0.3 ± 0.1 0.3 ± 0.17 14 ± 4 34 ± 2 10874 ± 628 8 ± 2 0.2 ± 0.1 0.1 ± 0.1 0.1 ± 0.1 0.1 ± 0.18 11 ± 2 10 ± 1 1890 ± 199 5 ± 1 0.5 ± 0.1 0.6 ± 0.2 0.6 ± 0.2 0.6 ± 0.20.9% NaCl 2165 ± 77 2708 ± 59 12276 ± 521 93500 ± 500 0.3 ± 0.2 0.2 ± 0.1 0.2 ± 0.1 0.2 ± 0.1

n = 3, ‘±’ indicates standard deviation.

It is interesting to note that in case of all the nanosorbentsmuch higher Kd values were observed in 0.9% NaCl solution(pH ∼7) compared to what was observed at pH 6-7 solution.It may be pointed out here that for determination of Kd valueof 99Mo at pH 7, deionized water was chosen as the mediumwhich has negligible amount of H+ ions. Though the pH of0.9% NaCl solution is ∼7, it has much higher concentrationof positively charged (Na+) ions compared to deionized water.The positively charged Na+ ions probably adhere to the sur-face of the nanosorbents resulting in overall positive charge andthe MoO4

2– ions are adsorbed due to electrostatic attraction.On further increase in pH beyond 7, the negative charge on thesorbent surface cannot be condoned by adherence of Na+ ionsand therefore negligibly low Kd values for MoO4

2- ions wereobserved.

Irrespective of the differences in Kd values, all thenanosorbents demonstrated high adsorption affinity for99MoO4

2– ions with the negligible Kd value of 99mTcO4− in

0.9% NaCl. Therefore, 99mTc can be selectively separated from99Mo using chromatographic columns containing any one of thenanosorbents.

In order to determine an optimum contact time required forthe complete adsorption of the 99Mo on the nanosorbents, thetime course of the adsorption process was studied by followingthe Kd values at different time intervals at room temperaturewhich is an indication of the progress of the adsorption pro-cess. Figure 2 depicts the time course of the Kd values of 99Moions on the nanosorbents as a function of time. As inferredfrom the curves, contact times of 30 min for TiO2, 5 minfor ZrO2, 10 min for γ-Al2O3, and 20 min for meso-Al2O3

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1830 R. CHAKRAVARTY, R. RAM, AND A. DASH

0.0

TiO2

Kd

Time (min)

0.0

ZrO2

0

gamma-Al2O3

0 10 20 30 40 50 60

0 10 20 30 40 50 60

0 10 20 30 40 50 60

0 10 20 30 40 50 60

0

3 x 105

2 x 105

1 x 105

3 x 104

8.0 x 103

6.0 x 103

4.0 x 103

2.0 x 103

6.0 x 103

4.0 x 103

2.0 x 103

2 x 104

1 x 104

meso-Al2O3

FIG. 2. Mo sorption kinetics of nanosorbents.

were maintained in order to attain adsorption equilibrium in thebatch processes.

Determination of Zeta Potential of NanosorbentsThe zeta potential which corresponds to the electrical charge

on the sorbent surface was determined at different pH inan attempt to investigate the adsorption characteristics of thenanosorbents. Figure 3 shows the measured zeta potential ofthe nanosorbents at different pH of background electrolyte. Thecharge which forms on nano metal oxide surface may arisefrom the dissociation of ionogenic groups in the particle surfaceexposed to the surrounding medium of a given composition.In case of TiO2, γ-Al2O3 and meso-Al2O3, the zeta potentialvalue is positive in the pH range 1-6 whereas in case of ZrO2

the value is positive between pH 1 and 4. On further increaseof pH the plot passes through zero zeta potential (iso-electricpoint) and then it develops negative zeta potential. Because ofthe positive charge on the surface at lower pH, the sorbents canstrongly attract the predominant species Mo7O6-

24 present (29,30) at this pH range.

The variation in zeta potential of the nnaocrystalline metaloxides with pH can be explained by the fact that the metaloxide particles are hydrated and covered by amphoteric sur-face hydroxyl groups which can undergo reaction with eitherH+ or OH− and develop positive or negative charges on thesurface depending on the pH of the external solution (29, 30).At low pH, these hydroxide groups become protonated and themetal oxide surface develops a positive charge. In weakly acidicsolution, molybdate ions polymerize as follows:

0 2 4 6 8 10

–60

–40

–20

0

20

40

60

Isoelectric point

Zet

a po

tent

ial (

mV

)

pH of medium

TiO2

ZrO2

gamma-Al2O3

meso-Al2O3

FIG. 3. Variation of zeta potential of nanosorbents at different pH.

7 MoO2-4 + 8 H+ � Mo7O6-

24 + 4H2O (29, 30)

Therefore, based on this speciation, strong attraction betweenthe positively charged metal oxide surface and Mo7O6−

24 is antic-ipated which accounts for the maximum Kd value for 99Mo atpH 2-4, in all the nanosorbents. Since TcO4

− has lower charge(−1), it is less strongly attracted by the sorbent compared toMo7O6−

24 and hence the lower Kd value. As these polymoyb-date ions start transforming to pertechnetate ions (99mTcO4

–),

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NANOSORBENTS BASED 99MO/99MTC GENERATORS 1831

the binding would get weaker and the TcO4− ion gets easily

eluted out in 0.9% NaCl solution.It may be pointed out here that the zeta potential measure-

ments carried out after adjusting the pH of deionized water doesnot provide the real charge on the surface of the nanosorbentsat pH range suitable for 99Mo sorption. The presence of otherions in the medium is susceptible to alter the zeta potentialvalue of the nanosorbents at this pH range. Our pursuit of zetapotential measurement was driven mainly to obtain a generaltrend as well as to assess the surface charge developed on thenanosorbents to account for the sorption of negatively chargedpolymolybdate ions. The actual ionic strength of the radioac-tive 99Mo solution would depend on a number of factors such asamount of target used for irradiation, target chemical form, irra-diation conditions, radiochemical processing method adopted,etc., and hence cannot be generalized. However, the presentfindings on the general trend of the zeta potential values of thesenanosorbents would be of considerable importance to optimizethe experimental conditions for loading 99Mo in the generatorcolumn.

Determination of the Mo-Adsorption Capacityof the Nanosorbents

The adsorption capacities of the nanosorbents, as determinedunder both static and dynamic conditions, are summarized inTable 3. The 99Mo breakthrough profiles of the nanosorbentsdetermined under dynamic conditions demonstrate their prac-tical usability as column material for 99Mo/99mTc generatorand the results are illustrated in Fig. 4. As seen from the fig-ure, the breakthrough capacity of all the nanosorbents is muchhigher than that of bulk alumina (2–20 mg Mo/g) (7). The tablealso compares these values with the adsorption capacities ofother alternate high capacity sorbents based on bulk materialreported and briefly describes their advantages and limitations.Molydenum-99 can be adsorbed on most of the other alternatesorbents only under batch equilibrium (static) conditions due totheir slow adsorption kinetics. Though the adsorption capacitiesof PZC and hydrotalcite under static conditions are apprecia-bly high, the protocol for preparing clinical-scale 99Mo/99mTcgenerators using sorbent matrices preloaded with 99Mo underequilibrium conditions can not be recommended due to difficul-ties in handling of radioactive material. This will not only causeassociated radioactive contamination problem but also increasethe radiation exposure to the personnel involved. Furthermore,even if the generator is prepared, the operating performancethereof is likely to deteriorate on elution with normal salinesolution under dynamic condition.

Among the nanosorbents, meso-Al2O3 demonstrated thehighest adsorption capacity and is comparable to that ofsynthetic alumina sorbent reported earlier (20, 22, 25-28,31-35). However, 99mTc obtained from synthetic alumina based99Mo/99mTc generators contain a significant amount of 99Moimpurity and requires a post-purification approach prior to

its utilization for radiopharmaceutical preparation. Moreover,99Mo/99mTc generator of tracer level activity was developedusing synthetic alumina and its actual utilization in preparationof a clinical scale generator is yet to be demonstrated.

Though the Kd values of 99Mo ions on meso-Al2O3 at pH 2-3 were ∼10 times higher than on using γ-Al2O3, the adsorptioncapacity of meso-Al2O3 is slightly higher than that of γ-Al2O3.This slightly higher adsorption capacity might be attributed tothe porous nature of meso-Al2O3. However, the size of thepores (2-3 nm) might not be adequate for percolation of thebulky Mo7O6-

24 ions inside the sorbent matrix and therefore theadsorption capacity is not significantly increased. Further, theadsorption capacity of meso-Al2O3 is 2-2.5 times higher thanthat of TiO2 and ZrO2, despite of demonstrating much higherKd values for 99Mo ions. In this context, it is worthwhile topoint out that Kd values were determined using trace quanti-ties of 99Mo ions to evaluate their affinity towards the sorbent.The molybdate ions in trace quantities are unable to saturatethe adsorption sites of the sorbent. The adsorption process ofthe nano metal oxide sorbents is a combination of physical andchemical interaction which is primarily dependent on the parti-cle size, pore size and their distributions, diffusion coefficients,and ability to form a chemical bond on the solid surface. Whiledetermining the adsorption capacity, a concentrated molybdatesolution spiked with 99Mo was used, with intent to saturatethe binding sites available in the sorbent. Once the adsorptionsites were saturated, further uptake of 99Mo ions was inhib-ited. This is primarily dependent on surface area and bindingforces present within the particles of the sorbent. Therefore,the adsorption capacity of meso-Al2O3 is only ∼2-3 timeshigher compared to TiO2 and ZrO2, in spite of demonstratingsignificantly higher Kd values.

Development of 99Mo/99mTc GeneratorsThe performance of the nanosorbents as column matrices for

99Mo/99mTc generator was evaluated by developing four gen-erators. After 99Mo loading onto the generator columns, theywere washed with 500 mL of saline in order to allow concernsregarding 99Mo breakthrough during the subsequent elutions ofthe generators. The generators were regularly eluted at 24 hinterval over a period of 1 week. The elution profiles of allthe four generators are illustrated in Fig. 5. It can be seenfrom the figure, that the elution profile of TiO2 based genera-tor is the sharpest as > 75% of 99mTc activity could be elutedout in just 4 mL of saline solution. In case of other genera-tors (using ZrO2, γ-Al2O3, and meso-Al2O3) the first 2 mLof eluate contained negligible amount of activity and couldtherefore be discarded. The majority (> 80%) of 99mTc activ-ity could be eluted out in subsequent 6 mL of saline solution.The maximum radioactive concentration of 99mTc obtainedfrom TiO2, ZrO2, γ-Al2O3, and meso-Al2O3 based generatorswere ∼0.49 GBq mL−1, 0.34 GBq mL−1, 1.1 GBq mL−1,and 1.2 GBq mL−1, respectively. Thus, 99mTc could be availed

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1832 R. CHAKRAVARTY, R. RAM, AND A. DASH

TABLE 3Comparison of alternate sorbent materials reported for 99Mo/99mTc generator

Adsorption capacity (mg Mo/g)

Sorbent Static Dynamic Remarks Ref.

Zirconium polymers,PZC

60–270 # Very slow kinetics of adsorption, 99Moadsorption possible only at hightemperature, 99Mo/99mTc generatorswere developed using only tracer levelof activity and long-term performanceevaluation is not reported, significant99Mo breakthrough in 99mTc eluate

(20, 31)

Hydrous titaniumdioxide

40 (at room temperature),230 (at 100 ◦C)

# Batch equilibration method at 100 ◦C wasrequired for the preparation of the99Mo/99mTc generator of only14–15 mCi activity level

(32, 33)

Hydrous manganesedioxide

# # Fast adsorption kinetics, 99Mo could beloaded in the column under dynamicconditions. However, only tracer level99Mo/99mTc generators were reported.

(34)

Hydrotalcite 140 # Very slow kinetics of adsorption, 99mTceluted with >100 mL of NaCl solutionwhich is very dilute forradiopharmaceutical applications,99Mo/99mTc generators were developedusing only tracer level of activity

(35)

Synthetic alumina 270 195 Significant 99Mo breakthrough andtandem purification column wasrequired for availing 99mTc withrequisite purity

(22)

TiO2 100 75 99mTc obtained from the 99Mo/99mTcgenerators can directly be used forpreparation of radiopharmaceuticals

(25)ZrO2 250 80 (26)γ-Al2O3 205 156 (27)meso-Al2O3 225 182 (28)

#Not reported.

from each of these generators with appreciable radioactiveconcentration and therefore did not require post-elution con-centration prior to radiopharmaceutical applications, which isan important advantage over the conventional alumina based99Mo/99mTc generator using (n,γ)99 Mo (36). The performanceof the 99Mo/99mTc generators were studied for a period of2 weeks (Fig. 6) and it was seen that the yield of 99mTc was> 75% in all the cases. The yield and flow characteristics of thenanomaterial based generators remained unchanged over thisperiod of time.

Though the elutions were carried out a flow rate to ∼2 mLmin−1, it was observed that when evacuated vials are usedfor elution of 99mTc from the generators (flow rate ∼10 mLmin−1), the elution yield of 99mTc remained comparable andthis phenomenon could be validated. All these nanosorbentsare composed of nanocrystallites agglomerated to form micron

sized particles (50–100 mesh size). Agglomeration is essentialin order to achieve granularity of the material for column chro-matographic use (23, 24, 37). Therefore, there is no concernregarding pressure drop during elution when these nanosorbentsare used in the generator column.

Quality Control of 99mTc EluateRadionuclidic Purity

In order to utilize 99mTc for preparation of radio-pharmaceuticals, the level of 99Mo impurity (parent radioiso-tope) must be < 0.1% (38). The level of 99Mo in 99mTceluate from TiO2 and ZrO2 based generators is ∼10 ordersof magnitude lower than what is present in 99mTc eluate fromγ-Al2O3 and meso-Al2O3 based generators. However, the lev-els of 99Mo impurity in 99mTc eluate from all the generators

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NANOSORBENTS BASED 99MO/99MTC GENERATORS 1833

0.00.20.40.60.81.0 Breakthrough capacity (Ai/Ao ~0.01) = 75 mg Mo/g

Ai/A

O

Amount of Mo passed (mg)

0.00.20.40.60.81.0

Breakthrough capacity (Ai/Ao ~0.01) = 80 mg Mo/g

TiO2

ZrO2

0.00.20.40.60.81.0

Breakthrough capacity (Ai/Ao ~0.01) = 160 mg Mo/g

gamma-Al2O3

0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380

0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380

0 20 40 60 80 100 120 140 160 180 200

0 20 40 60 80 100 120 140 160 180 200

0.00.20.40.60.81.0

Breakthrough capacity (Ai/Ao ~0.01) = 190 mg Mo/g

meso-Al2O3

FIG. 4. Breakthrough profile of 99Mo using different nanosorbents.

20

0

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 220

10

20

30

40

50

60

70

Cum

ulat

ive

elut

ion

yiel

d of

99m

Tc

(%)

Elution yield

Cumulative yield

Al2O3

ZrO2

TiO2

Elu

tion

yie

ld o

f 99

mT

c (%

)

Volume of 0.9% NaCl solution passed (mL)

TiO2

ZrO2

gamma-Al2O3

meso-Al2O3

MA

FIG. 5. (a) Elution yield of 99mTc (%) and (b) cumulative elution yield of99mTc (%) from 99Mo/99mTc generators prepared using different nanosorbents.

are well within the stipulated limit and are hence suitable forclinical administration.

Radiochemical PurityTo separate pertechnetate from 99mTc in other oxidation

states, paper chromatography (PC), developed in saline mediumwas used. The radiochemical purity of 99mTcO4

− eluted fromall the four generators was > 98% of the total 99mTc activity,which was also within the prescribed limits of ≥ 95% as perthe pharmacopoeias (38).

0

20

40

60

80

100

Elu

tion

yie

ld (

%)

Time of elution (day)

TiO2

ZrO2

gamma-Al2O3

meso-Al2O3

0 1 2 3 4 5 6 7 8 9 10 11 12 13

0 1 2 3 4 5 6 7 8 9 10 11 12 13

0

1

2

3

4

5

6

7

FIG. 6. Elution performance of the 99Mo/99mTc generators prepared usingdifferent nanosorbents.

Chemical PurityThe presence of chemical impurities in the form of bleeding

of the column matrix was analyzed by ICP-AES. The amountof metal contamination detected in case of eluates from TiO2,ZrO2, γ-Al2O3, and meso-Al2O3 based generators were always< 0.1 ppm, which were well below the permissible limit (38)and the 99mTc eluates could directly be used for the prepa-ration of radiopharmaceuticals without any post-purificationprocedure.

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1834 R. CHAKRAVARTY, R. RAM, AND A. DASH

pH Compliance of 99mTc EluateThe pH of 99mTc eluate as measured after each elution was

always between 6.5-7 and it remained unchanged over theperiod of 2 weeks.

Labeling EfficacyIn order to examine the suitability of 99mTcO4

−obtained from the generators for the preparation of radio-pharmaceuticals, the eluates were used for the preparationof 99mTc-radiopharmaceuticals using lyophilized kits. Thesekits were chosen as they are readily available commercially.Moreover, these radiolabeled kits are the most widely used99mTc-based radiopharmaceuticals in nuclear medicine depart-ments worldwide for diagnosis of various diseases adoptingSPECT. The complexation yields were estimated to be >

98% in case of all the ligands and while using 99mTc elutedfrom all the 4 generators. However, it may be mentioned herethat the results of labeling efficacy have only to be used assupportive evidence of quality of 99mTc and its suitability forthe preparation of a wide variety of other radiopharmaceuticalsis yet to be demonstrated.

Recovery of Mo from the Spent 99Mo/99mTc GeneratorWhile we do not advocate the use of enriched 98Mo route for

production of 99Mo due to the high cost of the target material, itis worthwhile to point out that target enrichment of ≥ 96% aug-ments the production yield and the specific activity of 99Mo by afactor of ∼4. The expensive nature of such targets necessitatestheir recovery from the spent generator columns for effectiveuse of resources. Also, this is important from radioactive wastemanagement point of view as the spent generator columns cannot be discarded without removing the 99Mo sorbed in it. It waspossible to recover > 90% Mo from the exhausted generatorcolumns by passing 16 mL of NaOH solution (15 mL NaOHsolution + 1 mL 30% H2O2). Addition of H2O2 to the NaOHsolution was essential to facilitate the oxidation of Mo ions andthus facilitated its elution. Washing of the spent generator withphysiological saline before the Mo elution with NaOH solutionwas also required to remove most of the generated 99mTc andpromote depolymerization of molybdate ions adsorbed on thesorbent surface to favor Mo desorption.

DISCUSSIONWhile 99mTc is the most commonly utilized medical

radioisotope in diagnostic nuclear medicine, the supply chainof its precursor 99Mo is highly dependent on the irradiationservices from a few aging research reactors in the world (1,8-14). Consequently, the supply chain of 99Mo is highly vul-nerable due to increase in number of planned and unplannedclosures of these reactors for repairs as a result of techni-cal problems or safety concerns. A variety of factors, well

described in the literature resulted in the disruptions in fis-sion 99Mo supplies in the world market during 2007–2009(8-14). Although this crisis has now passed, this has not onlyhighlighted the fragile nature of the current strategy of 99Moproduction and supply but also raised concerns on the over-reliance on the few aging reactors for this purpose. In orderto overcome these unforeseeable problems, a number of newoptions are being currently pursued which include both reactorand accelerator-based approaches such as aqueous homoge-neous reactor (AHR) concept, target fuel isotope reactor (TFIR)concept, direct cyclotron production of 99mTc, photo fissionof 238U, photon-induced transmutation of 100Mo, and acceler-ator driven subcritical assembly (8). The comparative advan-tages, disadvantages, technical challenges, present status, futureprospects, security concerns, economic viability, and regulatoryobstacles of these strategies are elaborated in a recent review(8). While most of these 99Mo production strategies obvi-ously hold promise as innovative approaches, they are balancedon a fine line, with technical breakthroughs on the one handand long-term economic viability on the other. Among severaloptions proposed, the scope of using (n,γ)99Mo is relativelymore. Though the use of (n,γ)99Mo seems attractive, the rel-atively low specific activity [7.4 – 130 GBq/g (0.2 – 3.5 Ci/g)]emerged as the major impediment that continue to thwart effortsfor its utilization in the existing bulk alumina based generators.In this context, the progressive fusion of nanomaterial basedsorbents and column chromatographic separation technique hasnot only unveiled exhilarating possibilities but also raised theprospect of developing new generation 99Mo/99mTc generatorsadaptable to the existing and foreseeable needs. With a sensi-ble strategy and sustained determination, the scope of makingnanomaterial based column chromatography 99Mo/99mTc gen-erators using (n,γ)99Mo could readily be implementable in avery short period of time.

At the intersection of adsorption capacity of thenanosorbents and specific activity of (n,γ)99Mo lies a numberof possibilities to realize the scope of developing clinical scale99Mo/99mTc generators. As the dynamic adsorption capacitiesof these paradigm changing nanosorbents differ from eachother quite significantly, it is imperative to interplay betweenthe adsorption capacity of the nanosorbent and specific activityof (n,γ)99Mo and decide on an option that is most appropriatefor a given situation. In the light of emerging concerns tomaintain the radioactive concentration of eluted 99mTc froma 99Mo/99mTc generator to an acceptable level, it is recom-mended not to use > 4–5 g of sorbent for preparation of the99Mo/99mTc generator. As the specific activity of (n,γ)99Mothat could be produced in Dhruva reactor (φ = ∼9.6 × 1013

n.cm−2.s−1) of our Centre is ∼18.5 GBq (500 mCi)/g, it waspossible to make 3.7 GBq (100 mCi) generators using TiO2

and ZrO2 sorbents and 9.25 GBq (250 mCi) generators usingγ-Al2O3 and meso-Al2O3. Considering this specific activity,either γ-Al2O3 or meso-Al2O3 is a better choice and appearsto have edge over TiO2 and ZrO2. However, if higher specific

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NANOSORBENTS BASED 99MO/99MTC GENERATORS 1835

activity (n,γ)99Mo, available in other research reactor centersare used, then TiO2 and ZrO2, despite their lower dynamicadsorption capacities compared to γ-Al2O3 or meso-Al2O3,may provide good option to prepare clinical scale 99Mo/99mTcgenerators. All these nanosorbents were unaffected by the radi-ation damage during the period of operation of the 99Mo/99mTcgenerators. This might be attributed to the higher radiation sta-bility of such materials. Radiation endurance of nanomaterialsis due to complete recombination of all radiation-inducedvacancies and interstitials. Since surfaces are perfect defectsinks, nanoporous materials, due to their high surface-to-volume ratio, have the potential to resist radiation (39).

The specific activity of 99Mo as expected from differentreactors in the world, are based on the flux conditions andthe maximum activity of 99Mo/99mTc generator that can beprepared using each nanosorbent are summarized in Table 4.While the authors do not advocate the use of enriched 98Moroutes; however, if 96% enriched 98MoO3 target is used formaking (n,γ)99Mo in medium flux research reactors, clinicalscale 99Mo/99mTc generator can be easily prepared using anyone of the nanosorbents. Also, the use of metallic target suchas Mo metal powder provides the scope of producing higheractivity of 99Mo for a given mass of target. However, theintricacy involved in the irradiated target processing emergedas the major impediment that restricted its use. The require-ment of an elaborate complex target dissolution process in aremotely controlled processing facility is the major roadblockin this direction. Therefore, the use of MoO3 target is recom-mended for (n,γ)99Mo production as irradiated target can beeasily dissolved in NaOH solution.

While the use of MoO3 target is the obvious choice in termsof simplicity in target processing, the scope of using spectro-scopic grade high purity MoO3 constitute a reliable propositionas the concomitant presence of Sb impurities in ppm level in

MoO3 might lead to the formation of 122Sb and 124Sb (40).Nevertheless, their contribution is of minor consequence asmost of the metallic impurities exist as cations and hence willnot be retained by the nanomaterial based sorbents during the99Mo loading into the generator owing to positively chargedsurface of the nanomaterials at acidic pH. Also, the trace levelsof these ions, if attached on nanomaterial surface, gets elutedout on washing the generator column with saline solution afterloading the 99Mo activity onto it. Therefore, the presence ofthese radionuclidic impurities in the MoO3 target is inconse-quential as far as the radionuclidic purity of 99mTc solutionobtained from these generators is concerned.

Though, the activity levels of the indigenously developed99Mo/99mTc generators using nanosorbents are much lowerthan what is achievable in commercially available fission 99Mobased generators, they could still be of interest and utility dueto their ability to offer 99mTc of requisite purity amenable forradiopharmaceutical preparation. The scope of using such gen-erators would be of considerable value for countries havingoperational research reactors to produce (n,γ)99Mo and not hav-ing access to fission 99Mo. In order to diminish losses fromdecay as well as freight costs, it is advantageous to spread 99Moproduction facilities throughout the world. The InternationalAtomic Energy Agency (IAEA) database provides a summaryof 251 research reactors currently in operation worldwide (41)and indicates that 75 of these reactors already involved inradioisotope production could be used for (n,γ)99Mo produc-tion. Also, the geographic distribution of these reactors is quitegood. It is envisaged that the nanosorbent based strategy wouldserve in good stead for ensuring the availability of 99mTc using(n,γ)99Mo. This source of 99Mo is not only independent ofexisting supply chains, but also likely to reduce reliance on fis-sion 99Mo and provide an emergency backup. It is pertinentto mention here that the use of high flux reactors would be a

TABLE 4Specific activity of 99Mo produced under different flux conditions and the maximum activity of the 99Mo/99mTc generators that

can be prepared using the nanosorbents

Activity of 99Mo/99mTc generator prepared using 4 g ofeach nanosorbent GBq (mCi)

Type ofreactor

Flux(n. cm−2. s−1) Example

∗Approximatespecific activity of

99Mo expected[GBq (mCi)/g) TiO2 ZrO2 γ-Al2O3 meso-Al2O3

Low flux 1 × 1014 Dhruva reactor inIndia

18.5 (500) 5.6 (150) 5.9 (160) 11.1 (300) 13.3 (360)

Mediumflux

5 × 1014 Missouri UniversityReactor in UnitedStates

92.5 (2500) 28.0 (750) 29.6 (800) 55.5 (1500) 66.6 (1800)

High flux 1 × 1015 HFIR in United Statesand SM reactor inRussia

185 (5000) 56.0 (1500) 59.0 (1600) 111.0 (3000) 133.0 (3600)

∗It is assumed that natural MoO3 was irradiated for 7 d.

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1836 R. CHAKRAVARTY, R. RAM, AND A. DASH

positive step to augment the production yield and the specificactivity of (n,γ)99Mo. This could pave the way for prepar-ing 99Mo/99mTc generators having capacity > 37 GBq (1 Ci)adopting this approach (Table 4) and these generators are ade-quate for commercial supply and clinical use even assumingdecay of part of the 99Mo in the generator while it is transportedfrom the manufacturer to the user end.

With the emergence of professionally run central radio-pharmacies, the existing modality of using 99Mo/99mTc gen-erators in nuclear medicine centers is expected to undergo aparadigmatic shift from the present designs. Radiopharmacyoperations have matured over the years, thanks to the evolu-tion of [18F]FDG. While the number 99Mo/99mTc generatorsrequired will be reduced drastically in such set up, the activ-ity levels per generator will be significantly higher than thepresent one. Because of the pace in which 99Mo/99mTc gen-erators scene is changing, the generator technology strategiesneed a vision for today and tomorrow. In order to sustain thediagnostic nuclear medical imaging services using 99mTc, itis of utmost importance to nurture the column chromatogra-phy separation technique in an appropriate manner to respondto the foreseeable changes in generator design and users pro-file. It is envisaged that any one of the nano structured metaloxides discussed in this paper can be adapted for makinghigh activity generator using F 99Mo without altering the gen-erator design, although the shielding requirements might behigher.

Evolution and continued success of chromatography99Mo/99mTc generators, since its inception has been, in largepart, due to technological advancements. Change is neededto institute a paradigm shift toward adapting the new gen-erator technologies. Among the different factors contributingto the success of nanomaterial based 99Mo/99mTc generators,development of automated modules is of crucial importance.Automation of the separation procedure deserves greater atten-tion not only because a greater range of generator options willbe needed but also offers several advantages, including reduc-ing the radiation exposure to working personals, reduce theprobability of human errors, consistent separation performance,and a log of the steps performed. This strategy must be hastenedfurther to expand its scope.

As the nanomaterial based 99Mo/99mTc generators repre-sents a new paradigm, regulatory approval of generator pro-duced 99mTc as an approved pharmaceutical ingredient (API),of course, be a prerequisite for clinical use. Any new col-umn chromatography 99Mo/99mTc generators will require ademonstrated pharmaceutical equivalence of 99mTcO4

− to thatobtained from an alumina column chromatographic generatorcontaining F 99Mo. Nonetheless, to be effective in address-ing the particular regulatory barriers, new generators must becustomized to local legislative, regulatory, and institutionalconditions. The payoff for the successful implementation ofthis strategy will be an increased supply and reduced cost ofpharmaceutical grade 99mTc.

CONCLUSIONSIn conclusion, the utility of nano structured metal oxides

as new generation high capacity adsorbent, at the interfaceof chemistry and the separation sciences, has not only stimu-lated the progress in 99Mo/99mTc generator technology, but alsounveiled myriads of opportunities to drive innovation. Althoughthe usefulness of nano structured metal oxides for chromatog-raphy separation has been relatively less explored, 99Mo/99mTcgenerators using this class of adsorbent are highly desirableand may take the lead in coming years and there are no tech-nical barriers for their adoption. With the appropriate selectionof suitable nano structured metal oxide commensurate with thespecific activity of (n,γ)99Mo it would be possible to envision afuture where the scale and scope of 99Mo/99mTc generator canbe tailored to address the need of nuclear medicine community.In light of these premises and promising results demonstrated,huge steps forward will be made during the coming decade toempower future development of 99Mo/99mTc generator tech-nologies. We have surmounted few roadblocks but withoutdoubt the end of the road stretches into the distance. We haveevery reason to believe that this article will inspire and stimu-late scientists and researchers across the globe to develop yetmore innovative nanomaterial based sorbents for 99Mo/99mTcgenerators.

ACKNOWLEDGEMENTSThe authors would like to express their sincere thanks

to Dr. Gursharan Singh, Associate Director, Radiochemistryand Isotope Group (I), Bhabha Atomic Research Centre, for hisvaluable support to this program.

FUNDINGResearch at the Bhabha Atomic Research Centre (BARC)

is part of the ongoing activities of the Department of AtomicEnergy, India, and is fully supported by government funding.

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