Mesoporous Alumina (MA) Based Double Column Approach forDevelopment of a Clinical Scale 99Mo/99mTc Generator Using(n,γ)99Mo: An Enticing Application of NanomaterialRubel Chakravarty,† Ramu Ram,† Ratikant Mishra,‡ Debasis Sen,§ S. Mazumder,§

M. R. A. Pillai,† and Ashutosh Dash*,†

†Radiopharmaceuticals Division, ‡Chemistry Division, §Solid State Physics Division, Bhabha Atomic Research Centre,Mumbai 400 085, India

*S Supporting Information

ABSTRACT: This paper describes the utility of mesoporous alumina (MA), a high capacity nanomaterial based sorbent, for thedevelopment of a clinical grade 99Mo/99mTc generator using (n,γ)99Mo. Synthesis of MA was performed using a glucose templatein an aqueous system. Structural characterization of the nanosorbent was carried out by analytical techniques such as X-raydiffraction (XRD), small-angle X-ray scattering (SAXS), atomic force microscopy (AFM), scanning electron miscroscopy (SEM),transmission electron microscopy (TEM), thermogravimetry-differential thermal analysis (TG-DTA), Fourier transform infrared(FTIR) spectroscopy, and Brunauer−Emmett−Teller (BET) surface area analysis. The material synthesized was mesoporous andnanocrystalline, with average crystallite size of 2−3 nm with a large surface area of 230 ± 10 m2 g−1. In order to evaluate thesurface charge of MA in aqueous solution, the zeta potential was determined at different pH environments. Adsorptioncharacteristics of the sorbent such as time course of the adsorption, distribution ratios of 99Mo and 99mTc ions, Mo sorptioncapacity under static and dynamic conditions, 99Mo adsorption pattern and 99mTc elution pattern were determined to assessits effectiveness in the preparation of 99Mo/99mTc generator. The measured distribution ratio values indicate that 99Mo is bothstrongly and selectively retained by MA at acidic pH and 99mTc could be readily eluted from it, using 0.9% NaCl solution. Thestatic sorption capacity and practical sorption capacity under dynamic conditions of MA was determined to be 225 ± 20 and168 ± 12 mg Mo per gram of sorbent, respectively. With a view to realize the scope of developing clinical scale generator, a noveltandem column generator concept was used in which two 99Mo loaded columns were connected in series. In this method 99mTceluted from the first column was fed to the second column to achieve higher radioactive concentration (RAC) as well as purity of99mTc. A 26 GBq (700 mCi) 99Mo/99mTc generator was developed using (n,γ)99Mo having specific activity of ∼18.5 GBq(500 mCi)/g of Mo. The 99mTc eluted from the generator possessed high radionuclidic, radiochemical, and chemical purity andwas amenable for the preparation of 99mTc-labeled radiopharmaceuticals. The technology can be adapted by those countrieshaving research reactors with flux >1 × 1014 n·cm−2·s−1 to produce 99Mo by (n,γ) route. The capacity of the generator can bescaled up to 260 GBq (7 Ci) using (n,γ)99Mo produced from a reactor with flux >1 × 1015 n·cm−2·s−1.

■ INTRODUCTION

Technetium-99m (99mTc), availed from 99Mo/99mTc generators,is the most widely used diagnostic medical radioisotope in theworld. Over 30 million patient studies worldwide (half of whichare in the United States alone) are performed annually using99mTc-based radiopharmaceuticals.1−3 While the column chro-matographic generator using a bed of acidic alumina has emergedas the most popular source for availing 99mTc,2,4 the limited ca-pacity of alumina for 99Mo (2−20mgMo per gram)5 necessitatesthe use of fission 99Mo (F 99Mo) which has very high specificactivity. Current production capabilities of fission F 99Mo arebased on the use of highly enriched uranium (HEU) targets inlimited numbers of aging research reactors.6−11 In light of theperceived proliferation risk posed by the use of HEU as targetstogether with the vulnerability of long-term availability of irra-diation services from a few aging nuclear reactors for productionof F 99Mo, a variety of alternative non-HEU based options arebeing evaluated intensely to ensure a constant and reliable supplyof 99Mo to the nuclear medicine community, albeit most of thetechnologies are yet to be developed.12−14 The US government

is giving the highest priority for the development of non-HEU based technologies for the preparation of 99Mo/99mTcgenerators.15,16

An alternative to the fission based production of 99Mo, which istime tested since the early days of 99Mo/99mTc generators, isthrough neutron activation of molybdenum, referred to as(n,γ)99Mo. It is the least intricate route to access 99Mo withnegligible generation of radioactive waste, which is proliferationresistant, inexpensive, and within the reach of most institutionshaving operating research reactors.12,17,18 Despite the impressiveattributes, the relatively low specific activity (LSA) of (n,γ)99Mo[0.35−3.5 Ci g−1 (13−130 GBq g−1), while using reactors havingflux of 1 × 1014−1 × 1015 n·cm−2·s−1] emerged as the majorimpediment for its utilization in the existing alumina basedchromatographic generator. A number of separation strategies

Received: April 4, 2013Revised: July 12, 2013Accepted: July 22, 2013Published: July 22, 2013

Article

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exist for the separation of clinical grade 99mTc from 99Mo in orderto utilize (n,γ)99Mo .4,12,17−20 While there is no scientific reasonagainst using alternative 99mTc separation strategies, overcomingthe preference of the users who are accustomed to the user-friendly column generator for over 40 years is the major barrier inpropagating the alternate technologies.Hence, the development of column generators using higher

capacity sorbents is important to utilize the more widely pro-ducible (n,γ)99Mo. In this regard, polymeric zirconiumcompound (PZC),21 polytitanium oxychloride,22 and aluminafunctionalized with a sulfate moiety23 are important contribu-tions. However, the promise of making 99Mo/99mTc generatorsusing these sorbents in a clinical context is yet to be realized.Nanomaterials by virtue of huge surface to volume ratios, defect-rich morphology, porosity, favorable adsorption characteristics,and enhanced surface reactivity can be used as high capacitysorbents for column chromatography generators.19,24 The utilityof nanomaterial based sorbents in the development of99Mo/99mTc generators is an idea that has been first reportedby our group.25−27 While the use of nanomaterial based sor-bents constitutes a successful paradigm of 99Mo/99mTc gener-ator technology, the need to prepare a generator having activity>18.5 GBq (500 mCi) usable in nuclear medicine departmentsposes technical challenges. By combining the unique propertiesof nanomaterials and tailoring the generator operation strategy inan appropriate manner, the feasibility of developing a clinical-scale 99Mo/99mTc generator using (n,γ)99Mo is demonstrated inthis paper.Herein, we report the synthesis and structural characterization

of mesoporous nanoalumina (MA) and its utilization for thedevelopment of a 26 GBq (700 mCi) 99Mo/99mTc generatoradopting a double column approach. The advantages of the dou-ble column approach over a conventional single column ap-proach are highlighted and the suitability of 99mTc eluted fromthe generator for the preparation of radiopharmaceuticals aredemonstrated.

■ EXPERIMENTAL SECTION

The synthesis and characterization of mesoporous nanoalumina(MA) was carried out as per the details provided in SupportingInformation S1. Molybdenum-99 was produced by irradiation ofnatural MoO3 (2 g) at a neutron flux of∼9.6× 1013 n·cm−2·s−1 inthe Dhruva reactor for 1 week. The production and radio-chemical processing of 99Mo is described in SupportingInformation S2. The sorption characteristics of 99Mo and99mTc ions on MA were studied adopting the standardradiochemical procedures as described in Supporting Informa-tion S3.24,26 The process demonstration runs were carriedout by developing two 99Mo/99mTc generators, each of 26 GBq(700 mCi), by adopting two approaches, namely (a) singlecolumn approach and (b) double column approach (Figure 1).The details regarding the preparation of these generators areprovided in Supporting Information S4. The elution perfor-mance of these generators was evaluated for a period of 2 weeks,which is double the expected shelf life of a commercial99Mo/99mTc generator. The radionuclidic and radiochemical pu-rities of 99mTc were evaluated by standard radiometric methodsas described in Supporting Information S5.24,26 In order todetermine the level of Al ion contamination in the 99mTc product(chemical impurities), the 99mTc samples were allowed to decayfor 7 days, and the samples were analyzed by inductively coupledplasma atomic emission spectroscopy (ICP-AES). Further,

99mTc was used for the preparation of radiopharmaceuticalsusing standard cold kits of dimercaptocuccinic acid (DMSA),methylene diphosphonate (MDP), and ethylene dicysteine (EC)adopting the procedures specified for formulation of such kits.The adsorbed Mo could be desorbed from the spent generatorcolumn by passing 3 M NaOH solution adopting the procedurereported by us earlier.24,26

■ RESULTS AND DISCUSSIONIn order to reduce reliance on F 99Mo, a variety of alternativeoptions including both reactor and accelerator paths are evolvingfor sustainable production of 99Mo or 99mTc directly for clinicaluse.12 The possible alternative reactor options which are underactive consideration include fission production of 99Mo from lowenriched uranium (LEU) targets, aqueous homogeneous reactor(AHR), target fuel isotope reactor (TFIR) concept, and(n,γ)99Mo production. Some of the accelerator options underconsideration are photofission of uranium targets, photon-induced transmutation by the 100Mo(γ, n)99Mo reaction, directcyclotron production of 99mTc and accelerator-driven subcritical(ADS) assembly. Their comparative advantages, disadvantages,technical challenges, present status, future prospects, securityconcerns, economic viability, and regulatory obstacles are well-described in the literature.12 Among the various availableoptions, the use of (n,γ)99Mo seems to be attractive becausesimple target dissolution capabilities will suffice and are withinthe reach of most countries operating research reactors that havegood geographic distribution around the world. Notably, thissource of 99Mo is independent of existing supply chains andwould provide an emergency backup. It would offer immediatebenefits, with the smallest practical hurdles for implementation.It is pertinent to point out that irrespective of the specific activityof 99Mo used in the 99Mo/99mTc generator; the 99mTc producedis always no-carrier-added (NCA).Enormous progress in nanoscience and nanotechnology has

offered the prospect of using nanomaterial as a new generationadsorbent in the development of 99Mo/99mTc column generatorusing (n,γ)99Mo. In view of this, assessing the potential ofnanomaterial is not only an interesting prospect but may also be a

Figure 1. Schematic diagram of the double column 99Mo/99mTcgenerator.

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necessary one for the ongoing efforts to create a foundation. Thespecific objectives of the present investigation were, first, to selecta synthesis protocol amenable for large scale preparation ofMA; second, to ensure that the material possesses enhanced99Mo sorption capacity and is capable of releasing 99mTc withhigh yield and minimal 99Mo breakthrough upon elution withnormal saline (0.9% NaCl solution); and third, to demonstratethe applicability of MA to prepare a clinical scale 99Mo/99mTcgenerator using (n,γ)99Mo. A step-by-step systematic approachhas been followed to achieve the overall goal.Synthesis of MA.While a broad panoply of methods, such as

nanocasting, the use of room temperature ionic liquids, thesurfactant self-assembly approach, the hydrothermal processing,sol−gel method, controlled precipitation of boehmite by hy-drolysis of aluminum salts and alkoxides, etc., have been reportedfor the synthesis of mesoporous nanoalumina,28,29 the require-ment of strictly controlled synthesis conditions along withpostsynthesis treatments emerged as the major road block toundertake large-scale preparation of the nanosorbent. Never-theless, these synthesis methods are not only cumbersome butalso expensive routes of preparing nanomaterials. The facilesynthesis method using glucose template reported by Xu et al.30

was adopted for this purpose as it uses inexpensive precursorsand at the same time is amenable for large-scale synthesis. Thekey step involved in this “one-pot” synthesis protocol consists ofhydrolysis of aluminum isopropoxide in aqueous solution ofglucose in which glucose acts as a strong chelating agent as well asa pattern material to direct the mesophase formation.31 The firststep of the calcination process consists of a thermal decom-position of aluminate−glucose precursor leading to the liberationof water. During calcination, the glucose molecule is oxidized togluconic acid which contains carboxylic acid group in one endand five linear hydroxyl groups that participate in the com-plexation of Al3+ ions (aluminate−glucose precursor) leading tothe formation of a carbonaceous material. With further increaseof temperature (∼500 °C), the precursor is decomposed intoCO2 and H2O with liberation of a large amount of heat. Theformation of nanoporous material with high surface area is adirect result of the liberation of gases during calcination.32

In one typical batch, ∼10 g of material was obtained. Thematerial was granular, possessed sufficient mechanical strength,and exhibited free-flowing characteristics and was, therefore,amenable for column chromatographic applications. About 50batches of synthesis were performed, and reproducible resultswere obtained in all the batches.Structural Characterization of MA. In order to obtain

information on the structure, and particle size of the sorbent,the sample was subjected to X-ray diffraction (XRD), small-angleX-ray scattering (SAXS), scanning electron microscopy (SEM),energy dispersive X-ray spectroscopy (EDS), transmission elec-tron microscopy (TEM), atomic force microscopy (AFM), andBrunauer−Emmett−Teller (BET) surface area analysis. The XRDpattern of the mesoporous alumina is shown in Figure 2. TheXRD pattern of the alumina powder gives a broad humplikebackground in the 2θ range 20°−40° which was followed by twosmall broad peaks at 2θ = 45.81° and 66.86°. These two peakscould be assigned to (400) and (440) plane of the cubic alumina(space group Fd3m, a = 7.905 Å). Other major peaks are mergedin the background.The average diameter of MA nanoparticles was found to be

2−3 nm, which was calculated from the full width at half-maximum of the (400) peak at 2θ = 45.81 using Debye−Scherrer’s equation:

λθ

=θ

DB

0.9cos2 max

where D is the average crystallite size in nanometers, λ is thecharacteristic wavelength of X-ray used (1.5406 Å), θ is thediffraction angle, and B2θ is the angular width in radius at anintensity equal to half of the maximum peak intensity.The SEM image of MA (Figure 3) shows wormhole-like

network skeleton indicating that the material is porous. Thechemical characterization of MA was carried out by energydispersive X-ray spectroscopy (EDS), which shows peaks corre-sponding to Al and O. The absence of C peaks reveals that theglucose template could be completely removed during thecalcination step. The AFM micrograph as depicted in Figure 4indicated that the particle size of the prepared MA was extremelysmall. From the color contrast of the graphs (Figure 4a) theaverage crystallite size was found to be in 2−3 nm range. Thehistogram depicting the number of particles as a function ofparticle size (Figure 4b) indicates that the particles are quiteuniform in size and shape with a distribution ranging 2−3 nm,having an average particle size of 2.5 nm. The TEM micrographof MA is shown in Figure 5. TEM investigations corroborate thatthe material is nanocrystalline and highly agglomerated. Theaverage particle size as determined by TEM was also in the rangeof 2−3 nm. Thus, the average particle size of MA as determinedby AFM and TEM measurements was found to be in agreementwith the results obtained from XRD.It is pertinent to point out that size mentioned above is the

average crystallite size of the primary particles. After the cal-cination step, the dried lump obtained was crushed and sievedto obtain free-flowing particles of 50−100 mesh size (149−297 μm). Thus, MA is agglomerated and made up of 2−3 nmprimary particles.The infrared absorption spectrum (Figure 6) of synthesized

sorbent showed a broad absorption peak in the range 3600−3000 cm−1, which is due to the sum of the contributions ofhydroxyl groups and water molecules. The absorption peak at1645 cm−1 was due to the bending mode of OH− group attachedto thematrix. The bands at 1550, 1411, 856, and 611 are attributedto different vibrational modes of Al−O−Al and Al−O bond.The surface area measurements and the pore size distribution

of the sorbents were carried out by the standard BET technique.The surface area of MA was found to be 230 ± 10 m2 g−1. Thesurface area of MA is not very high because the nanoparticles areagglomerated (as seen from TEM). However, agglomeration to acertain extent is essential for its use as a sorbent matrix in apacked chromatography column. Very fine particles without

Figure 2. XRD pattern of MA.

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agglomeration are not suitable for column chromatographyapplication as such materials are impervious to the flow of liquid.Therefore, agglomerated MA was chosen in place of other highersurface area (unagglomerated) mesoporous nanoparticles

Small-angle X-ray scattering (SAXS) is an important non-destructive tool to probe the density fluctuations in condensedmater.33 Figure 7 shows the SAXS profile of the specimen. Toobtain the pore size distribution, SAXS data were analyzed in the

Figure 3. (a) SEM image of MA. (b) EDS spectrum of MA.

Figure 4. (a) AFM micrograph of MA. (b) Histogram depicting the number of particles as a function of particle size.

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Figure 5. TEM micrograph of MA.

Figure 6. FTIR spectra of MA.

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light of a polydisperse ensemble of spherical particles under localmonodisperse approximation.34 For such a case, I(q) is expressedas

∫=μ

I q C P q R D R S q R R R( ) ( ( , ) ( ) ( , ) d )0

6(1)

where P(q, R) represents the form factor of a spherical pore ofradius R, i.e.,

=−

P q RqR qR qR

qR( , )

9(sin( ) sin( ))( )

2

6

D(R) represents the pore size distribution, i.e.,D(R) dR indicatesthe probability of having pores with radius R to R + dR. In thepresent case, a standard log-normal distribution was assumed.S(q, R) represents the interpore structure factor, and a fractaltype structure factor35 was assumed in the present case. C is ascale factor, independent of q, and depends on the scatteringcontrast and the number density of the density fluctuation.Equation 1 was fitted to the scattering data in order to estimatethe pore size distribution. The fitted curve is plotted inFigure 7 in order to compare the same with the experi-mental scattering profile. The model fits reasonably well to thescattering data signifying the presence of a mesoporousstructure. The estimated pore size distribution is plotted inFigure 8, which shows that the pore size of MA is in the rangeof 2−3 nm.Thermal analysis of MA (Figure 9) indicates that the sample

undergoes continuous mass loss from room temperature to800 °C, accompanied by an endothermic peak. This masschange could be attributed to the initial loss of adsorbed waterfollowed by decomposition of aluminum hydroxide, which couldnot be detected by XRD. Appearance of a small exothermic peakat 945 °C may be due conversion of metastable γ-alumina tostable α-alumina.Chemical Stability of MA. In view of the explicit need to

use the sorbent for column chromatographic procedure, it isimperative to establish the chemical stability ofMA to ensure thatit resists chemical degradation during column operation. Theresults from the study by solubility tests showed that MA wasinsoluble in dilute mineral acids and alkalis as only negligibleamount of Al ions (<0.1 ppm) were detected in the filtrate whenanalyzed by ICP-AES. This is well below the permissible limit(<10 ppm) of Al3+ ions in 99mTc, for its use in the preparation ofradiopharmaceuticals.36 The excellent stability of the materialprecludes the selective depletion of sorbent during columnoperation and at the same time ensures that it does not lead toaddition of chemical impurities in the eluate, which mightcompete with 99mTc species during radiolabeling with ligandsand biomolecules for preparation of radiopharmaceuticals.

Production of 99Mo. Typically in one batch, ∼31.4 GBq(850 mCi) of 99Mo was produced when 2.5 g of natural MoO3was irradiated at a flux of 9.6 × 1013 n·cm−2·s−1 for 7 days, whichcorresponds to a specific activity of ∼18.5 GBq (∼500 mCi) pergram of Mo. This value is more than what is expectedtheoretically (26 GBq), probably due to the contributions fromepithermal neutrons. For calculation of the yield of 99Mo, onlythe thermal neutron cross-section (0.13 b) for the 98Mo-(n,γ)99Mo reaction was taken into consideration. The resonanceintegral for the 98Mo(n,γ)99Mo reaction due to epithermalneutron contribution is∼7 b. The contribution of the epithermalneutron was not taken into account in the theoretical calculationsas the flux of such neutrons in a multipurpose research reactor isnot exactly known. The data thus represent the typical activityyields of 99Mo likely to be produced in regular batches followingthe weekly operational cycle of the Dhruva research reactor ofour institute. The irradiated target was dissolved in 3 M NaOHsolution at 80 °C which formed a colorless and transparentsolution within 10−20 min.

Study of the Adsorption Behavior of MA. Thedistribution ratios (Kd) of MoO4

2− and TcO4− ions were

determined at various pH values using MA, and the results aresummarized in Table 1. The Kd values are the measure ofpartitioning of 99mTc and 99Mo between MA and aqueous phasesand account for the physical and chemical adsorption processes

Figure 7. SAXS data from the specimen plotted in double logarithmicscale.

Figure 8. Pore size distribution as obtained from the fitting of the modelto the experimental data.

Figure 9. Thermogram of MA.

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that are important to arrive at the optimum conditions for theselective retention of 99Mo on MA and 99mTc elution withnormal saline (0.9% NaCl) solution.From the above results, it can be inferred that MA possessed

high affinity for 99MoO42− ions, with negligible affinity for the

99mTcO4− ions. A careful scrutiny of Table 1 shows that the Kd

values of 99Mo are maximum at around pH 2−4 which indicatesthat this pH range is optimum for 99Mo adsorption. The high Kdvalue for 99MoO4

2− ions with the negligible Kd value of99mTcO4

−

in 0.9% NaCl provided the scope for eluting 99mTcO4− with

0.9% NaCl.In an attempt to investigate the sorption characteristics of MA

and to understand the variation in Kd values of99MoO4

2− and99mTcO4

− ions on MA, the zeta potential (ζ) which representsthe surface charge of the adsorbent, at different pH was studied.Figure 10 shows the measured zeta potential of MA at different

pH values of background electrolyte. The charge which forms atthe surface of MA may arise from the dissociation of ionogenicgroups in the particle surface exposed to the surrounding medi-um of a given composition. It can be seen from the figure thatthe zeta potential of the nanosorbent was positive in the acidicpH range and passed through the isoelectric point (zero zeta

potential) between pH 6 and 7 and became increasingly negativewith rise in pH. As inferred from the result, the MA surface ispositively charged at low pH (pH < 6), zero charge at inter-mediate pH (6 and 7), and negatively charged at higher pH(pH > 7). Therefore, both the surface charge of the MA andanionic species of 99Mo would be responsible for determining themagnitude of Kd values, although it was not possible to distin-guish the individual contribution from each of them.The variation in zeta potential of MAwith pH can be explained

by the fact that the MA particles are hydrated and covered byamphoteric surface hydroxyl groups which can undergo reactionwith either H+ or OH− and develop positive or negative chargeson the surface depending on the pH of the external solution.37 Atlow pH, these hydroxide groups become protonated and the MAsurface develops a positive charge. In weakly acidic solution,molybdate ions polymerize as follows38

+ ⇋ +− + −7MoO 8H Mo O 4H O42

7 246

2

Therefore based on this speciation, strong attraction between thepositively charged MA surface and Mo7O24

6− is anticipatedwhich accounts for the maximum Kd value for

99Mo at pH 2−4.In order to determine an optimum contact time required for

the complete sorption of the 99Mo onto MA, the time course ofthe sorption process was studied by following the distributionratio (Kd) at different time intervals at room temperature which isan indication of the progress of the adsorption process. Figure 11

depicts the time course of theKd values of99Mo ions onMA. As it

can be seen, the Kd values increased rapidly with time at thebeginning and remained almost constant after 30 min. Thisindicates that the sorption process is reasonably fast.The adsorption capacity is an important experimental

parameter as it determines the amount of 99Mo that can bequantitatively retained by the sorbent from a given solution and istherefore indicative of the number of active sites available onMAfor sorption of 99Mo ions. The sorption capacities of MA wasdetermined both under static and dynamic conditions. The staticadsorption capacity of MA was determined to be 225 ± 20 mgMo per gram (n = 10). Although the static adsorption capacityrepresents an upper limiting value on the amount of 99Mo ionsthat could be retained on MA, this information is often helpfulto determine the amount of MA that could be used in column fordeveloping the 99Mo/99mTc generator.

Table 1. Distribution Ratios (Kd) of99MoO4

2− and 99mTcO4−

in MAa

Kd

medium (pH) 99MoO42− 99mTcO4

−

1 22100 ± 900 5 ± 32 198100 ± 600 14 ± 33 249000 ± 600 46 ± 54 211100 ± 700 39 ± 45 110300 ± 100 1.7 ± 0.56 91000 ± 200 0.3 ± 0.17 8 ± 2 0.1 ± 0.18 5 ± 1 0.6 ± 0.29 6 ± 2 0.5 ± 0.210 4 ± 1 0.4 ± 0.20.9% NaCl 93500 ± 500 0.2 ± 0.1

an = 3, “±” indicates standard deviation.

Figure 10. Zeta potential of MA at different pH environments.

Figure 11. Variation in Kd values of99Mo ions on MA as a function of

time.

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In order to evaluate the adsorption behavior of 99Mo ionswithin a column bed packed with 4.5 g of MA operating undernonequilibrium conditions, a breakthrough curve was developedby passing 99MoO4

2− solution through the column at a flow rateof 2 mL min−1. The breakthrough curve developed is depicted inFigure 12. It was observed that the breakthrough point was

reached after 182 ± 10 mg of Mo mg was quantitatively retainedper g of sorbent (n = 10) in the column.While the breakthrough capacity represents the behavior of

99Mo loading at pH 2−5, it would not be same while eluting99mTc with 0.9%NaCl solution due to the change in the pH of theexternal solution. Therefore, the maximum achievable sorptioncapacity of MA was determined under dynamic condition atwhich elution of 99mTc is performed to preclude 99Mobreakthrough during the operation of 99Mo/99mTc generator.In this endeavor, after loading the MA column with 99Mo underdynamic conditions, it was washed with 200 mL of 0.9% NaClsolution, to remove the unadsorbed and loosely held 99Mo.

The practical sorption capacity of MA as determined by theaforementioned procedure was found to be 168 ± 12 mg Mo/gof sorbent. This result clearly illustrates the superiority of thismaterial over bulk alumina which has a sorption capacity of2−20 mg Mo per gram.5

As expected, the breakthrough capacity as well as maximumachievable sorption capacity under the dynamic conditions is lessthan the static ion-exchange capacity mainly owing to masstransfer limitations. The determination of the nature of the masstransfer resistance would require further studies and is beyondthe scope of this investigation. In the present case, the maxi-mum achievable sorption capacity was seen as a criterion fordeveloping the 99Mo/99mTc generator system.

Development of 99Mo/99mTc Generator. In an attempt totranslate the laboratory findings into actual practice, oursubsequent efforts were focused toward developing99Mo/99mTc generators using MA. In this effort, two types of99Mo/99mTc generators, one having a single column (containing9 g of MA) and another with two columns (each containing 4.5 gof MA) connected in tandem were prepared. Owing to the lowhydrodynamic resistance of the MA in column operation, it ispossible to connect two generators in a cascade scheme. Whilethe column dimensions and the amount of sorbent used in bothtype of generators remain same, they differ only in the mode ofoperation. The elution profiles of the two types of generatorswere followed and the results are depicted in Figure 13. Thedouble tandem column procedure produces a reasonably sharpelution profile of 99mTc and provides the scope of enhancing theRAC significantly by discarding the first and last 2 mL fractionscontaining negligible amounts of 99mTc activity. Thus, 99mTccould be eluted from the double tandem column generator withradioactive concentration sufficient for clinical use. On the otherhand, a broad elution profile was observed with the single columngenerator which precluded the scope of generator eluatefractionation as every 2 mL fraction contained similar 99mTcactivity.At pH > 6, although the MA surface is negatively charged,

99Mo is still retained by the sorbent during elution with0.9% NaCl solution. This ambiguity could be explained throughthe mechanisms underlying the 99Mo uptake in MA which is

Figure 12. Breakthrough profile of Mo from the MA column by passingMoO4

2− solution (pH 3, 25 mg Mo/mL) at a flow rate of 2 mL min−1.

Figure 13. Typical elution profiles of the 99Mo/99mTc generators. Each fraction comprised 2 mL of eluent.

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conjectured to take place in two steps. The first one may be theelectrostatic attraction of polymolybdate ions on the positivelycharged surface of MA and their subsequent exchange withhydroxyl ions on the MA surface. In the second step, a stablecomplex of the type [AlMo6O24]

8− similar to that reported withbulk alumina might be formed.39 The decay of 99Mo to 99mTc isnot accompanied by any serious disruption of chemical bonds. Asthese polymolybdate ions start transforming into pertechnetateions, which has only −1 charge, the binding would get weaker.The MA matrix does not have a tendency to form any complexwith the pertechnetate species, and therefore, it selectively getseluted out with 0.9% NaCl solution.It was essential to carry out process demonstration runs to

evaluate the behavior of MA in the presence of the intenseradiation environment with the radiolytic products generated as aresult of radioactive 99Mo. The long-term performance andseparation capability of 99mTcO4

− on repeated use were evalu-ated by monitoring the elution profile of the generators afterevery 24 h. Table 2 summarizes the results of operation of the99Mo/99mTc single and double tandem column generators in atypical process demonstration run. It was observed that thedouble tandem column generator gives consistently high yields(>82% of the theoretical yields) of 99mTc over a period of 1 weekwhile the single column generator gave low yields (∼50% of thetheoretical yields). It is worth pointing out here that duringseveral process demonstration runs, no operational problemssuch as reduction of flow rate, packed bed compression, andchanneling in a packed column were observed in both the typesof generators. The appearance of fines or suspended solids in theeffluent from the packed bed due to potential degradation of thesorbent was also not noticed. A 0.22 μm membrane filter wasattached to the generator column (Figure 1) to obtain the 99mTceluate in a sterile form, which is essential for its subsequentclinical utilization.The major advantages of double column 99Mo/99mTc gener-

ator over the single column generator are (a) higher elution yieldof 99mTc and (b) sharper elution profile resulting in higherradioactive concentration of 99mTc eluate. In the case of thedouble column (tandem) generator, each column contained4.5 g of MA loaded with 99Mo. The bed volume of each columnof the tandem generator is just half of that of the single columngenerator which contained 9 g ofMA. Owing to their smaller bed

volume, a lower volume of eluent (0.9% NaCl) is required forelution of 99mTc from each column of the tandem generator. Asthe columns are connected in series, the eluate from the firstcolumn (99mTcO4

− in 0.9% NaCl solution) is then passedthrough the second column containing 99Mo adsorbed in MA.99mTcO4

− ions, eluted from the first column, are not adsorbed inthe sorbent of the second column as it has no affinity for this ionin 0.9% NaCl medium (as revealed by Kd studies, Table 1).However, the Cl− ion present in this solution can selectively eluteout the 99mTcO4

− formed from decay of 99Mo adsorbed in thiscolumn. As a result, the final eluate coming out of the generatorhas high specific volume (radioactive concentration) of 99mTc. Incontrast, owing to the large bed volume of the single columngenerator, a large volume of eluent is required for completeelution of 99mTc resulting in a broader elution profile and lowerradioactive concentration of the 99mTc eluate. Though, the deadvolume of the eluate increases in the double column approach,the overall volume of 0.9% NaCl required is much less than whatwould have been required for elution of the single columngenerator at the same flow rate. The flow rate of elution is animportant concern due to the short half-life (6 h) of 99mTc. It isessential to complete the elution process within few minutes toavoid decay loss of this radioisotope. Moreover, the use of thebulky single column would increase the longitudinal shieldingrequirement and hence would be cumbersome for operation in ahospital radiopharmacy. The two columns of the tandemgenerator can be placed side by side, with hardly any increasein the size of the generator assembly. While this technique ofconnecting two or three 68Ge/68Ga or 188W/188Re generators inseries toward the end of their shelf life has been practiced in thehospital radiopharmacies for the purpose of attaining higherradioactive concentration of 68Ga or 188Re eluates,40−43 there hasbeen no report to date, exploiting its usefulness for developmentof 99Mo/99mTc generator.We could make 26 GBq (700 mCi) 99Mo/99mTc generators by

using (n,γ)99Mo (specific activity of ∼18.5 GBq/g) produced inDhruva reactor at flux of ∼9.6 × 1013 n·cm−2·s−1. It should bepossible to make column generators of >3.5 Ci (130 GBq) byproducing the 99Mo in reactors with >5 × 1014 n·cm−2·s−1 as isthe case with theMissouri University Research Reactor (MURR)in United States. The capacity of the generator could beincreased to ∼7 Ci (260 GBq) by using a reactor having a

Table 2. Elution Performances of (a) Double Column and (B) Single Column 99Mo/99mTc Generators over a Period of 1 Week

(a)

elutionno.

time of growth(h)

theoretically expected activity of 99mTc GBq(mCi)

activity of 99mTc obtained GBq(mCi)

elution yield(%)

99Mo impurity in 99mTc(%)

1 22 24.8 (668) 22 (594) 89 5 × 10−3

2 24 19.2 (522) 16.4 (434) 83 2 × 10−3

3 25 15 (410) 12.8 (346) 84 4 × 10−3

4 24 11.8 (320) 10.4 (280) 87 3 × 10−3

5 24 9.2 (250) 7.6 (206) 82 4 × 10−3

6 23 7.2 (196) 6.2 (166) 85 3 × 10−3

(b)

elutionno.

time of growth(h)

theoretically expected activity of 99mTc GBq(mCi)

activity of 99mTc obtained GBq(mCi)

elution yield(%)

99Mo impurity in 99mTc(%)

1 22 24.14 (650) 13.26 (367.2) 56 5 × 10−3

2 24 19.72 (537.2) 7.14 (200.6) 38 2 × 10−3

3 25 15.3 (414.8) 9.18 (248.2) 60 4 × 10−3

4 24 11.9 (329.8) 6.46 (180.2) 55 3 × 10−3

5 24 9.52 (258.4) 5.1 (125.8) 52 4 × 10−3

6 23 7.48 (207.4) 2.72 (81.6) 40 3 × 10−3

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neutron flux of 1 × 1015 n·cm−2·s−1 such as the Oak RidgeNational Laboratory (ORNL) reactor in United States or the SMreactor at Dmitrovgrad in the Russian Federation. While theauthors do not advocate the use of enriched 98Mo routes,however, if 96% enriched 98Mo is used, most medium fluxresearch reactors can be used for making 99Mo suitable formaking column generators by using MA and the double tandemcolumn approach developed by us.Quality Control of 99mTc to Evaluate Its Suitability for

Radiopharmaceutical Applications. Quality assessment of99mTc availed from the 99Mo/99mTc generator is of paramountimportance in order to determine its suitability for thepreparation of radiopharmaceuticals. The level of radionuclidicimpurities present in 99mTc, primarily due to the breakthrough ofthe parent radionuclide 99Mo, was determined by γ-spectrometryusing HPGe detector coupled with a multichannel analyzer(MCA). The freshly eluted samples of 99mTc did not show anypeaks corresponding to 99Mo or any other radionuclide (resultsshown in Supporting Information S5). In order to quantify thetrace level of 99Mo impurities present in 99mTc, the 99mTc sampleswere allowed to decay for 48 h. In γ-spectrometry using freshlyeluted samples of 99mTc, the peaks (181, 366, 740 keV)corresponding to 99Mo were masked by the intense γ-peak(140 keV) of 99mTc. From the γ-spectrometric analysis of thedecayed 99mTc samples, the level of 99Mo impurity was quantifiedto be <10−3% (results shown in Supporting Information S5). Thelevel of 99Mo impurity in 99mTc remained consistently low duringthe shelf−life of the generator. No γ-ray peaks corresponding toany other radionuclides were observed even in the decayedsample analysis, proving that 99mTc was free from otherradionuclidic impurities.Radiochemical purity is an essential parameter which

determines the oxidation state in which 99mTc is present in thesolution. The presence of 99mTc in pertehnetate form (+7 state)is desirable as this species can easily be converted to otheroxidation states prior to complexation with suitable ligands. Theradiochemical purity as determined by paper chromatographywas >99% of 99mTc in pertechnetate form, which was within theprescribed limits as per the pharmacopoeias.36 The level of Al3+

ions present as chemical impurity in the 99mTc eluate wasdetermined to be <0.1 ppm which is significantly less than theprescribed limit.36 The negligibly small level of chemical impuritypresent in 99mTc would not interfere in the subsequentradiolabeling procedures.In order to examine the suitability of 99mTcO4

− for the prep-aration of radiopharmaceuticals, the eluate was used for thepreparation of 99mTc−DMSA, 99mTc−MDP, and 99mTc−ECusing lyophilized kits. These kits were chosen as they are readilyavailable commercially. Moreover, these radiolabeled kits are themost widely used 99mTc-based radiopharmaceuticals in nuclearmedicine departments worldwide for diagnosis of variousdiseases adopting single photon emission computed tomography(SPECT). The complexation yields were estimated to be >98%in all the cases (results presented in Supporting Information S5).Recovery of Mo from the Spent 99Mo/99mTc Generator.

The use of enriched 98Mo target for 99Mo production constitutesa positive step because target enrichment of ≥96% augments theproduction yield as well as the specific activity of 99Mo by a factorof ∼4. The concept of using 99Mo obtained from enriched targetalong with double tandem column generators with MA seemedvery attractive as it offers higher specific activity (n,γ)99Mo. Thepayoff for the successful implementation of this strategy will be

the convenience of making high activity generators amenable foruse in central radiopharmacies.While the use of enriched 98Mo is appealing, it necessitates its

recovery from the spent generator not only because of the effec-tive use of resources, but also from a radioactive waste manage-ment point of view. In light of the necessity to recycle enriched98Mo targets to the maximum extent practicable, developmentof an effective method for recovering the enriched 98Moadsorbed on the spent 99Mo/99mTc generators with MA isimportant. Hence, procedures for removing Mo prior to disposalof the generator columns were pursed. It is possible to recover>90% Mo from the exhausted MA column by passing 16 mL of5MNaOH solution (15mLNaOH solution + 1mL 30%H2O2).Addition of H2O2 to the NaOH solution is essential to ease theoxidation of Mo ions and thus facilitates its elution. Washing ofthe spent generator with physiological saline before the Moelution with 5MNaOH solution is also required to remove mostof the generated 99mTc and promote depolymerization of mo-lybdate ions adsorbed on the sorbent surface to favor Modesorption.The mechanism of desorption of Mo from the MA column

could be explained by the zeta potential values of MA as well asthe molybdate species. In the region of basic pH, alkalineconditions, the surface electric charge of MA becomes negativeand at the same time depolymerisation of polymolybdate anionicspecies took place resulting in simple MoO4

2− ions. Therefore analkaline condition of the external solution is conducive fordesorption of negatively charged MoO4

2− ions owing toelectrostatic repulsion of MoO4

2 and the negatively chargedMA surface. The eluted Mo solution was acidified by addingexcess of concentrated HNO3 to precipitate molybdenum oxide.The resulting precipitate was filtered, washed with distilled water,and then dried at 200 οC.This reported method of developing the 99Mo/99mTc gen-

erator using MA and low specific activity (n,γ)99Mo represents anew paradigm, and regulatory approval of 99mTc as an approvedpharmaceutical ingredient (API) obtained from this generatorwould, of course, be a prerequisite for clinical use. This noveltechnology represents the emergence of a new exemplar ofavailing 99mTc amenable for preparation of current generation of99mTc radiopharmaceuticals with the existing freeze-dried kits.

■ CONCLUSIONS

A potential pathway to rationally synthesize MA suitable forpreparation of a clinical-scale 99Mo/99mTc generator has beenestablished. The material synthesized was granular with ade-quate mechanical strength and free-flowing characteristics forcolumn operation, nanocrystalline with average crystallite size of2−3 nm, mesoporous, and possessed reasonably high surfacearea (230 ± 10 m2·g−1). The practical sorption capacity ofthe material under dynamic (column-flow) conditions was 168±12 mg Mo·g−1, which is sufficiently high for preparation of99Mo/99mTc generators of activity >18.5 GBq (500 mCi). Underthe optimized conditions, the objective of arriving at large-scalepreparatory conditions for MA and its utility in the developmentof a clinical-scale (26 GBq) 99Mo/99mTc generator with (n, γ)99Mo,using a novel tandem column operation strategy has been achieved.Technetium-99m could be obtained from the generator in >80%yields with high radionuclidic (>99.99%) and radiochemicalpurity (>99%). The compatibility of the product in the prepara-tion of 99mTc-radiopharmaceuticals was evaluated by radio-labeling standard kits with >95% yield. The reliability of this

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approach was amply demonstrated by development of 99Mo/99mTcgenerators in several batches, where the performance of eachgenerator remained consistently good for over a period of 1 weekwhich is the normal shelf life of such generators. Thus, theconcept of exploiting MA column matrix along with and thetandem column operation strategy seemed attractive as it retainsthe convenience of a column based generator system and offersthe scope of using (n,γ)99Mo. With the importance of 99mTc indiagnostic nuclear medicine firmly established, we envisionthat the reported method could become a viable mode of the99Mo/99mTc generator system in the years to come. It is expectedthat this technology, once mature, will ensure a reliable and long-term sustainability of 99mTc supply in the future. The payoff forthe successful implementation of this strategy will be anincreased supply and reduced cost of 99mTc.

■ ASSOCIATED CONTENT*S Supporting InformationDetails on the synthesis and characterization of MA, productionand radiochemical processing of 99Mo, development of99Mo/99mTc generators, and quality control of 99mTc to determineits suitability for radiopharmaceutical preparation. This material isavailable free of charge via the Internet at http://pubs.acs.org.

■ AUTHOR INFORMATIONCorresponding Author*E-mail: adash@barc.gov.in. Phone: +91-22-25595372. Fax:+91-22-25505151.NotesThe authors declare no competing financial interest.

■ ACKNOWLEDGMENTSResearch at the Bhabha Atomic Research Centre is a part of theongoing activities of the Department of Atomic Energy, India,through government funding. The authors gratefully acknowl-edge the Sophisticated Analytical Instrumentation Facility(SAIF), Indian Institute of Technology Bombay (IITB),Powai, Mumbai, for FTIR, SEM, and TEM analysis of thenanomaterial. The authors are also grateful to the AnalyticalChemistry Division, Bhabha Atomic Research Centre, Mumbai,India, for determination of surface area of mesoporous aluminaand for ICP-AES analysis of the solutions.

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