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Applied Radiation and Isotopes 68 (2010) 229–238

Contents lists available at ScienceDirect

Applied Radiation and Isotopes

0969-80

doi:10.1

� Corr

E-m

journal homepage: www.elsevier.com/locate/apradiso

Nanocrystalline zirconia: A novel sorbent for the preparation of 188W/188Regenerator

Rubel Chakravarty a, Rakesh Shukla b, A.K. Tyagi b, Ashutosh Dash a,�, Meera Venkatesh a

a Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Mumbai-400085, Indiab Chemistry Division, Bhabha Atomic Research Centre, Mumbai-400085, India

a r t i c l e i n f o

Article history:

Received 24 March 2009

Received in revised form

28 August 2009

Accepted 16 October 2009

Keywords:

Distribution ratio

Nanocrystalline

Post-elution concentration188W/188Re generator

Zeta potential

43/$ - see front matter & 2009 Elsevier Ltd. A

016/j.apradiso.2009.10.031

esponding author. Tel.: +91 22 25595372; fa

ail address: adash@barc.gov.in (A. Dash).

a b s t r a c t

Nanocrystalline zirconia, a novel high capacity sorbent material was synthesized and tested for its

utility in the preparation of 188W/188Re generators. The structural investigation of the material was

carried out using X-ray diffraction, surface area determination, FTIR and TEM micrograph analysis.

Various experimental parameters were optimized to separate 188Re from 188W. The capacity of the

material was found to be �325 mg W/g at the optimum pH. A chromatographic 188W/188Re generator

was developed using this material from which 480% of 188Re generated could be eluted with 0.9%

saline solution, with high radionuclidic, radiochemical and chemical purity and appreciably high

radioactive concentration suitable for radiopharmaceutical applications.

& 2009 Elsevier Ltd. All rights reserved.

1. Introduction

Rhenium-188 (188Re) is an attractive therapeutic radionuclidedue to its reasonable half life (16.9 h), high-energy beta radiation(Ebmax=2.118 MeV), low abundance (15.8%) of 155 keV photonsand convenient availability in the form of 188W/188Re generator inhigh specific activity. Being a congener of 99mTc, the chemistry ofRe is similar to Tc, which is an additional advantage for workingwith molecules that have shown promising results as 99mTc-radiopharmaceuticals. The low energy (155 keV) gamma emissionenables imaging for monitoring in-vivo localization and dosi-metric calculations (Jeong and Knapp, 2008; Knapp, 1998). Theattractive physical properties of 188Re and its production from along-lived parent Tungsten-188 (188W, T1/2=69.2 d), from agenerator with an adequate shelf-life, makes it an interestingoption for clinical use. Unfortunately, 188W can be produced onlyby double neutron capture with low absorption cross-sections[186W(n,g)187W (s=37.970.6 b); 187W(n,g)188W (s=64710 b)].Further, owing to rather long half-life of 188W, relatively longirradiation periods are required even for the production of 188W ofmodest specific activity (Knapp et al., 1994a, b). However, 188W,from the high flux reactors (f�1015 n cm�2 s�1) can be used tomake 188W/188Re generators to obtain ‘no carrier added’ 188Re.

ll rights reserved.

x: +91 22 25505151.

Most of the commercially available 188W/188Re generators areakin to the 99Mo/99mTc generators using alumina columns, wheretungsten is retained on the alumina column and 188Re is elutedwith 0.9% NaCl solution (Perego et al., 2007; Dadachova et al.,1995; Kamioki et al., 1994; Knapp et al., 1994; Knapp andMirzadeh, 1994; Coursey et al., 1990; Callahan et al., 1989).However due to the low specific activity of 188W, the 188Reobtained from 188W/188Re generators is dilute with low radio-activity concentration. Consequently, it often requires an addi-tional concentration step (Sarkar et al., 2009; Mansur et al., 2006;Jackel et al., 2005; Mushtaq, 2004; Guhlke et al., 2000; Tanaseet al., 1997) for clinical applications.

Although preparation of 188W/188Re generators using aluminasorbent remains the main commercial procedure, alternativepathways such as 188W/188Re gel generators based on matricessuch as zirconium or titanium tungstate (Dadachov et al., 2002,1994; Dadachov and Lambrecht, 1995) have also been exploited.In the last few years, a number of alternative sorbents with highercapacity for W such as gel metal oxide composite, hydroxyapatiteand polymeric zirconium compound (PZC), have been developedand exploited for the preparation of 188W/188Re generators(Monroy-Guzman et al., 2009; Iller et al., 2007a, b; Matsuokaet al., 2005). Recently, our group (Chakravarty et al., 2009) hasdemonstrated the feasibility of developing an electrochemical188W/188Re generator. However, these recent techniques have yetto reach the commercial stage for clinical applications. Develop-ment of alternative sorbents for 188W/188Re generators still

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R. Chakravarty et al. / Applied Radiation and Isotopes 68 (2010) 229–238230

remains an interesting challenge. Thus, in the search for a novelhigh capacity sorbent for use in 188W/188Re generators, we carriedout the work reported here.

Nanoparticles are expected to provide unprecedented oppor-tunities to develop and hold the promise of creating newmaterials for chromatographic applications. One of the specificproperties of nanomaterials is that a high percent of the atomsreside on the surface. These surface atoms are unsaturated,exhibit intrinsic surface reactivity and have a tendency tochemisorb charged species in aqueous solution in order to achievesurface stabilization. The potential of such nanomaterials as newgeneration of sorbents in the chromatographic separation ofmetal ions (Cumbal et al., 2003; Okuyama and Lenggoro, 2003;Sarkar et al., 2003; Vassileva and Furuta, 2001; Manning et al.,1998; Hiraide et al., 1997; Ragai and Selim, 1987) have beenexploited. However, researches about the preparation of radio-nuclidic generators using nanoparticles are seldom reported.Keeping parity with the modern trends and to tap the potential ofnanomaterials as a sorbent in the relatively unexplored field ofradionuclide generators, we earlier synthesized and characterizeda noble sorbent, polymer embedded nanocrystalline titania (TiP)for its possible application in the preparation of 99Mo/99mTc(Chakravarty et al., 2008) and 188W/188Re (Chakravarty et al.,2009) generators. In this communication, we report the synthesisand characterization of nanocrystalline zirconia and its utilizationas a column material in the preparation of 188W/188Re generator.

2. Experimental

2.1. Chemicals

Reagents such as hydrochloric acid, ammonium hydroxide, etc.were of analytical grade and were procured from SD FineChemicals, Mumbai or BDH (India). Zirconyl chloride(ZrOCl2 �8H2O) and isopropyl alcohol (A.R grade) were obtainedfrom E. Merck, Mumbai, India. Stannous chloride and DMSA wereobtained from Sigma Chemical Company, USA. Na2H2HEDP wasobtained from Sigma (St. Louis, MO). Paper chromatography stripswere purchased from M/s. Whatman, UK. Flexible silica plates(coating thickness 0.25 mm) were from J.T. Baker ChemicalCompany, USA.

Tungsten-188 (specific activity 159 GBq/g) as sodium (188W)tungstate was procured from the State Scientific Centre of RussiaResearch Institute of Atomic Reactors (PSUE) in Dmitrovgrad,Russia, through an IAEA Coordinated Research Project.

2.2. Equipment

X-ray diffraction studies were carried out on a Philips X-raydiffractometer (Model PW 1927 Amsterdam, Netherlands). Thesurface area and the pore size analysis were carried out usingQuantachrome, Autosorb-1 analyzer (Quantachrome Instruments,FL 33426 USA). FT-IR spectra of the synthesized sorbent wererecorded in a JASCO FT/IR-420 spectrometer. TEM was recordedby TEM, JEOL FX microscope (Jeol Ltd., Tokyo, Japan) on thepowder sample. The zeta potential of the nanoparticles wasmeasured using a zeta potential analyzer (Zetasizer Nano ZS/ZEN3600, Malvern Instruments Ltd., UK). The chemical analysisfor the determination of trace level of metal contaminations wasdone using inductively coupled plasma-atomic emission spectro-scopy (ICP-AES Model JY-238, Emission Horiba Group, France). AnHPGe Multichannel analyzer, coaxial photon detector system,Canberra Eurisys, France with a 1.5 keV resolution at 1333 keVand range from 1.8 keV to 2 MeV was used for analysis of 188W in

the presence of 188Re and also for quantitative estimation. Theradioisotope levels were determined by quantification of the188Re 155 keV (15%) and 188W 291 keV (0.4%) photo peaks.

2.3. Synthesis of nanocrystalline zirconia

Nanocrystalline zirconia was synthesized by controlled hydro-lysis of ZrOCl2 �8H2O in iso-propyl alcohol medium. The rawmaterial ZrOCl2 �8H2O was dissolved in 80% iso-propyl alcohol.The 20% ammonia solution in iso-propyl alcohol medium wasadded drop-wise to the well-stirred solution until completeformation of the white precipitate, which was subsequentlyrefluxed for 12 h. The precipitate obtained was washed withdistilled water, dried at 100 1C and calcined at 600 1C for 2 h.

2.4. Structural characterization

Characterization of the sorbent was carried out using differentanalytical instruments. X-ray diffraction measurements (10–701)were carried on the powder for the crystallite size estimation,using monochromatized Cu-Ka radiation. Silicon was used as anexternal standard for correction due to instrumental broadening.The surface area and the pore size analysis were carried out by thestandard BET technique with N2 sorption using Quantachrome,Autosorb-1 analyser. The preparation of samples for TEM analysisinvolved sonication in ethanol for 5 min and deposition on acarbon coated copper grid.

2.5. Chemical stability

The chemical stability of the nanocrystalline zirconia wasassessed in several mineral acids and bases, such as HCl, HNO3,NaOH and NH4OH. 1 g of the dry sorbent material was placed in50 mL solvent of interest and kept for 24 h with continuousshaking at room temperature. Subsequently it was filtered and thelevel of Zr metal ions in the solvent was determined by ICP-AES.

2.6. Determination of the distribution ratios (Kd)

Distribution ratios (Kd) of WO2�4 and ReO�4 species in the

nanocrystalline zirconia were measured at different pH, using188W and 188Re radiotracers. In each experiment, 200 mg ofsorbent was suspended in 20 mL solution containing 188WO2�

4 or188ReO�4 ions as radiotracer, in a 50 mL stoppered conical flask,shaken in a wrist arm mechanical shaker for 1 h at 25 1C and thenfiltered. The activities of the solution before and after equilibra-tion were measured in a well type NaI(Tl) counter usingappropriate window ranges (100–200 keV for 188Re and 250–350 keV for 188W). The distribution ratios were calculated usingthe following expression

Kd ¼ðAi � AeqÞV

Aeqm

where Ai is the initial radioactivity of 1 mL the solution, Aeq is theunadsorbed activity in 1 mL of the solution at equilibrium, V is thesolution volume (mL) and m is the mass (g) of the adsorbent.

2.7. Determination of the time of equilibration

In order to study the time dependence of sorption of 188W ontonanocrystalline zirconia, distribution ratio (Kd) of 188WO2�

4 in0.001 M HNO3 solution was determined at different time inter-vals, as described above. The Kd values (mean of three experi-ments) were taken as an indication of the progress of the sorption

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R. Chakravarty et al. / Applied Radiation and Isotopes 68 (2010) 229–238 231

process. The time when Kd remained unchanged, was taken as theindication of the attainment of equilibrium.

2.8. Determination of zeta potential

As the sorption of WO2�4 and ReO�4 ions on the nanocrystalline

zirconia matrix could be related to the charge distribution on thematrix, we studied the zeta potential of adsorbents under variedpH conditions. The 5 mg of adsorbent was added to 50 mL of de-ionized water and the pH of the suspension was adjusted usingHClO4 and HNO3. Zeta-potential of the suspensions at different pHwas measured with a combination of laser Doppler velocimetryand phase analysis light scattering (PALS). Smoluchowsky con-stant F(Ka) of 1.5 was used to calculate the zeta potential valuesfrom the electrophoretic mobility. All measurements were carriedout at 25 1C in triplicate.

2.9. Capacity measurement

2.9.1. Static sorption capacity

The ion exchange capacity of the nanocrystalline zirconiasorbent for W was determined by batch equilibration method. The0.5 g of accurately weighed sorbent were taken in a glassstoppered conical flask and equilibrated with 50 mL of sodiumtungstate solution (10 mg of W/mL) spiked with �10mCi(370 kBq) of 188W for 1 h at room temperature. At the end, thecontents were filtered through a Whatman filter paper (No. 542).The activities of 188W in the solution before and after absorptionwere estimated by using a HPGe detector coupled to a multi-channel analyzer, by measuring the counts at 291 keV peakcorresponding to 188W in 1 mL aliquots. All measurements werecarried out at 25 1C in triplicate.

The capacity was calculated using the following expression

Capacity¼ðC0 � CeÞV

m

where, C0 and Ce represented initial and equilibration concentra-tions of W respectively, V was the volume of solution and m wasthe mass (g) of the sorbent.

2.9.2. Determination of breakthrough pattern and dynamic sorption

capacity

In order to estimate the W sorption capacity under dynamicconditions, a borosilicate glass column of dimension 15 cm�0.4cm (i.d.) with a sintered disc (G2) at the bottom was packed with0.5 g of the synthesized adsorbent. After the column wasconditioned with 0.01 M HNO3, sodium tungstate solution (10 mgW/mL), spiked with 188W tracer (37 KBq/mL) was allowed to passthrough the column at a rate of 0.25 mL/min. The 1 mL of thissolution was kept as reference (C0). The effluent was collected infractions of 1 mL aliquots (C). The 188W activity in the reference(C0) and effluent fractions were determined by measuring the291 keV g-ray peak of 188W in a HPGe detector. The ratio of thecount rate ‘C’ of each 1 mL effluent to the count rate ‘C0’ of 1 mL ofthe original feed W solution was taken as the parameter to followthe sorption pattern.

2.10. Preparation of 188W/188Re generator

A borosilicate glass column of dimension 15 cm�0.4 cm (i.d.)with a sintered disc (G2) at the bottom was packed with 2 g ofnanocrystalline zirconia in a lead shield. It was preconditionedwith nitric acid at pH 2. The column was then loaded with1.85 GBq (50 mCi) of 188W solution maintained at pH 2. Thecolumn was then washed with 10 column volumes of 0.9% NaCl

solution. Subsequently, after allowing adequate time (2–3 days)for 188Re build up, the column was eluted with 0.9% NaCl solutionat a flow rate of 0.5 mL/min to study the elution behavior of 188Refrom the column. In order to examine the elution profile, theeluate was collected as 1 mL aliquots and each fraction wascounted for gamma activity. Gravity flow was employed through-out. All runs were performed at an ambient temperature. Theperformance of the generator was evaluated for a period �6months.

2.11. Quality control of 188Re eluate

2.11.1. Radionuclidic purity

Radionuclidic purity of the samples was assessed using acalibrated HPGe detector coupled to a multichannel analyzer. The188W present in 188Re eventually decays and forms a 188W/188Reequilibrium mixture that can be quantified by measuring the188Re present. The 188W contamination level in 188Re wasquantified by allowing the separated 188Re samples to decay for15 days and then measuring the 155 keV g-ray peak, correspond-ing to emission from 188Re daughter which in turn corresponds tothe level of 188W contaminant. The results were further confirmedby counting the decayed samples for a long time (6 h) andmeasuring, the 291 keV g-ray peak of 188W.

2.11.2. Radiochemical purity

To evaluate the radiochemical purity of 188ReO�4 , 5mL ofactivity was applied on paper chromatographic strips (Whatman12 cm�1 cm) at 1.5 cm from the lower end. The strips weredeveloped in 0.9% saline. After chromatography, the paper stripwas dried, cut in to 1 cm segments, placed in test tubes andcounted in a NaI(Tl) scintillation counter.

2.11.3. Chemical purity

In order to determine the presence of Zr ions contaminatingthe 188Re product (chemical impurities), the 188Re samples wereallowed to decay for 20 days. The trace levels of Zr metalcontamination in the decayed samples were determined by ICP-AES. Under the optimum conditions for ICP-AES determination, alinear calibration graph was obtained from five referencesolutions in the concentration range of 0.5–10 ng mL�1 ofzirconium. The Zr concentrations in the decayed 188Re sampleswere determined by ICP-AES using the above calibration graph ofthese standard solutions.

2.11.4. Labeling efficacy188Re from the generator was used to prepare complexes of

dimercaptosuccinic acid (DMSA) and hydroxyethylidene dipho-sphonate (HEDP) as per the reported procedures (Castronovo andRonald, 1972; Kothari et al., 1999a, b; Blower et al., 1996; Lin etal., 1999).

2.12. Recovery of enriched 186W from the spent generator

The spent generator was washed with saline, and the W wasdesorbed with 5 M NaOH solution containing H2O2 (15 mL of 5 MNaOH solution+1 mL of 30% H2O2) as per the reported methodadopted for alumina (Mushtaq, 1996). The flow rate of the eluantwas �0.5 mL/min. The eluate was collected as 1 mL aliquotsthroughout the elution, and each sample was counted for gammaactivity. Then, all the fractions were pooled together and the totalactivity of 188W eluted was determined in a HPGe detector.

ARTICLE IN PRESS

10

m

m

mtt

t

mm

m

mm

mm

m

m

mInen

sity

(a.

u.)

m = monoclinic phase t = tetragonal phase

2θ (degrees)20 30 40 50 60 70

Fig. 1. XRD pattern of nanocrystalline zirconia.

R. Chakravarty et al. / Applied Radiation and Isotopes 68 (2010) 229–238232

2.13. Simulated study for the separation of Re from a W/Re carrier

added solution, equivalent to �37 GBq (1Ci) of 188W and 188Re

The effects of macroscopic amounts of tungsten on theefficiency of chromatographic separation of 188Re using nano-crystalline zirconia sorbent were investigated by using W/Remixture containing inactive carrier W and Re equivalent to �37 GBq (1 Ci) 188W in equilibrium with 188Re. The mixture wasspiked with an equilibrium mixture of 188W/188Re containing3.7 MBq (100mCi) of 188W and 188Re. This simulated solution wasprepared by dissolving 292 mg of WO3 (equivalent to 37 GBq of188W at 159 GBq/g of W specific activity) and 1.45mg (equivalentto 37 GBq of 188Re) of ammonium perrhennate in 2 M NaOH. Theresultant solution was evaporated to dryness and then recon-stituted with 0.001 M HNO3 solution. The mixture was loaded in aborosilicate glass column [15 cm�0.4 cm (i.d.)] containing 2.5 g ofnanocrystalline zirconia adopting the procedure outlined above.188Re was eluted with 5 mL of 0.9% saline solution under the sameconditions as in the previous studies. The efficiency of 188Reelution and the 188W breakthrough were determined.

3. Results

The goal of the present study was to evaluate the merits ofnanocrystalline zirconia sorbent in the preparation of 188W/188Regenerator system. In order to demonstrate the reliability of thisnew sorbent and to validate the parameters for sorption of 188Wand separation of 188Re, we have optimized various processparameters.

3.1. Preparation of the sorbent

It was necessary to stir the reaction mixture of zirconylchloride in isopropyl alcohol and ammonia solution vigorously toprevent agglomeration and obtain nanocrystalline zirconia.Refluxing the precipitate for 12 h, at a moderate temperature(�96 1C) facilitates the stabilization of the zirconia nanoparticles.This procedure results in reliable synthesis of the final product.After establishing appropriate synthesis procedure, severalbatches of nanocrystalline zirconia sorbent were prepared. Thematerial produced was sieved to obtain 40–60 mesh particles(0.25–0.42 mm). The product obtained in all the batches wasgranular with adequate mechanical strength for reliable fixed-bedcolumn operation.

It was observed that nanocrystalline zirconia was insoluble inwater, dilute mineral acids and alkali (up to 6 M) as o0.1 ppmlevels of Zr were detected in the filtrate when analyzed by ICP-AES. It is clear that no appreciable amount of dissolution tookplace and the sorbent was fairly stable in most of the dilutemineral acids and alkalis. There was no turbidity when thesorbent was suspended in water for 24 h. This characteristicshows that the adsorbent can be safely used for generatorpreparation.

3.2. Structural investigations

In order to obtain information on the structure of the sorbent,the specimen was subjected to X-ray diffraction, I.R. spectra,surface area and TEM analysis. The XRD pattern of the nanocrys-talline zirconia is shown in Fig. 1. The average diameter of wasfound to be 15 nm, which was calculated from the full width athalf-maximum of the peak using Debye Scherrer’s equation

D¼0:9l

B2y Cosymax

where D is the average crystal size in nm, l is the characteristicwavelength of X-ray used (1.5406 A), y is the diffraction angle, andB2y is the angular width in radius at an intensity equal to half ofthe maximum peak intensity. The X-ray diffraction studiesshowed that nanocrystalline zirconia prepared by this methodconsists of two phases, of which the major crystalline phase ismonoclinic zirconia. The minor phase is tetragonal zirconia. Thistetragonal modification could be stabilized due to the excesssurface energy possessed by the nanosized material. The TEMmicrograph indicated that the nanocrystalline zirconia preparedwas crystalline and agglomerated (Fig. 2(b)). It was also observedfrom the TEM that the particles are quite uniform in size andshape. The average particle size of nanocrystalline zirconia asdetermined by TEM measurement (Fig. 2(a)) was found to be inthe range of 15–20 nm which is in accordance with the resultsobtained from XRD.

Fig. 3 shows the FTIR spectra of the product, indicating a broadabsorption peak situated in the range 3600–3000 cm�1, whichcan be attributed to the sum of the contributions of hydroxylgroups and water molecules. The absorption band centered ataround �1614 cm�1 can be attributed to the bending mode ofOH� group attached to the matrix. The band at 490–501 cm�1 isattributed to Zr–O–Zr bond. The presence of a small peak at�2300 cm�1 may be due to carbon dioxide trapped inside thebulk structure of the nano oxide.

The surface area measurements and the pore size distributionof the sorbents were carried out by standard BET technique. Thesurface area of nanocrystalline zirconia was found to be 45 m2/g.The average pore size was determined to be �4 A. Uniform poresize was observed in this synthesized sorbent.

3.3. Time dependence of sorption

The time dependence of the sorption of 188W ions onnanocrystalline zirconia was measured at pH 3 to determine thetime required to attain equilibrium. The plot of Kd vs. time isdemonstrated in Fig. 4. The curve revealed that the equilibriumwas attained at 15 min at room temperature. Accordingly, acontact time of 15 min was kept to attain the exchangeequilibrium in the batch process.

3.4. Determination of distribution ratio (Kd)

In order to explore the potential of this sorbent in thepreparation of 188W/188Re generator, distribution studies (Kd) for188W and 188Re were performed at various pH and the results are

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Fig. 2. TEM micrograph of nanocrystalline zirconia.

4000

% T

rans

mis

sion

(a.u

.)

Wavenumber (cm-1)3500 3000 2500 2000 1500 1000

Fig. 3. FTIR spectra of nanocrystalline zirconia.

00

100

200

300

400

500

600

700

Dis

trib

utio

n ra

tio (K

d)

Time (min)5 10 15 20

Fig. 4. Determination of the equilibration time.

Table 1Distribution coefficients (Kd) of 188W and 188Re in different media.

S. No. Medium Kd for 188W Kd for188Re

1 pH 1 14374 673

2 pH 2 469710 3175

3 pH 3 616712 6178

4 pH 4 315714 24712

5 pH 5 13377 o0.01

6 pH 6 12278 o0.01

7 pH 7 2373 o0.01

8 pH 8 1072 o0.01

9 0.9% NaCl 18879 0.270.1

7 represent the standard deviation for five (n=5) batches.

0

-40

-30

-20

-10

0

10

20

30

PZC

Zeta

Pot

entia

l (m

V)

pH

2 4 6 8 10

Fig. 5. Zeta potential of nanocrystalline zirconia as a function of pH.

R. Chakravarty et al. / Applied Radiation and Isotopes 68 (2010) 229–238 233

summarized in Table 1. Experimental results indicated that underall examined experimental conditions, nanocrystalline zirconia isa much better adsorbent for tungstate than for perrhenate anions.The Kd values for tungsten and rhenium increase with decrease inpH and reaches maximum at around pH 2–3. As thenanocrystalline zirconia showed extremely low affinity for 188Recompared to 188W at 0.9% NaCl solution, 188Re formed from thedecay of 188W could be easily eluted with 0.9% NaCl solution.

3.5. Zeta potential

The zeta potential of the sorbent was investigated at pH 1–8 asthe retention of 188W is governed by the surface charge. Fig. 5shows the zeta potential versus pH curves for nanocrystallinezirconia. This study has clearly shown that the surface charge ofthe sorbent varies at different pH values.

The surface charge of nanocrystalline zirconia is positive at pHvalues o4 and becomes increasingly negative with rise in pH. ApH value of �4.5 is the isoelectric point (PZC) of this sorbent

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Table 2Sorption capacity of nanocrystalline zirconia.

Batch No. Nanocrystalline zirconia Coarsened zirconia

Static sorption capacity (mg W/g) Breakthrough capacity (mg W/g) Static sorption capacity (mg W/g)

1 32475 10572 40–50a

2 34577 11176

3 33072 12072

4 36473 10873

5 33874 11277

7 represent the standard deviation for five (n=5) batches.

a Yori and Parera (1998).

00.0

0.2

0.4

0.6

0.8

1.0Amount of sorbent = 500 mg

C/C

0

Amount of W (mg)20 40 60 80 100 120 140 160 180 200 220

Fig. 6. Breakthrough profile of the sorbent.

R. Chakravarty et al. / Applied Radiation and Isotopes 68 (2010) 229–238234

surface in this particular ionic system. This reflects in the higherionic sorption potential for polytungstate anions resulting inpreferential anionic sorption due to their higher charge. Thisindicates that in the pH range o4, columbic attraction can readilytake place, in conjunction with specific chemical sorption,between the sorbent and polytungstate anions.

3.6. Determination of sorption capacity

The sorption capacity of the sorbent was determined bothunder static and dynamic conditions and the results for fivedifferent batches are summarized in Table 2. The sorptioncapacity values of nanocrystalline zirconia for W whencompared with the values reported with coarsened zirconia(Yori and Parera, 1998), are significantly higher, presumably dueto the enhanced specific surface area.

3.6.1. Static capacity of nanocrystalline zirconia

The results of the capacity determination experiment by batchequilibrium method indicated that the amount of W adsorbed wasalways 4300 mg W/g of sorbent at pH 1–4. Based on thisobservation, nanocrystalline zirconia appears to have bettersorption capacity than alumina for 188W, which is �80 mg W/gof alumina (Perego et al., 2007). It also has a far better sorptioncapacity compared to coarsened zirconia, which is �40–50 mg W/g(Yori and Parera, 1998). Due to its higher sorption capacity,nanocrystalline zirconia exhibits greater retention efficiency for188W and is superior to that of the conventionally used aluminaand coarsened zirconia sorbents.

The synthesis method adapted was repeatedly used tosynthesize the sorbent and the static ion exchange capacity ofthe 188W from each lot produced was determined. The valuesobtained were reproducible within experimental errors of o10%,which proves the reproducibility of the method of synthesis.

3.6.2. Dynamic sorption capacity of nanocrystalline zirconia

In order to portray the sorption behavior of 188W in generatorcolumn bed containing nanocrystalline zirconia, the breakthroughcurve was developed at pH �3. A typical breakthrough curve isdepicted in Fig. 6 in which a chromatographic column containing500 mg of nanocrystalline zirconia was used and the solution waspassed at a flow rate of 0.5 mL/min.

From the breakthrough curve, it is possible to determine thecapacity at various values of C/C0. It was observed that after120 mg of W per g of sorbent (n=5) was quantitatively retained bythe column, the breakthrough point was reached. The break-through capacity of nanocrystalline zirconia (120 mg W/g) wasmuch higher than that of alumina (�48 mg W/g) (Lukie et al.,2007). The total capacity of the sorbent under dynamic conditions(at C/C0=0.9, n=5) was found out to be �280 mg of W per g ofsorbent.

3.7. Preparation of 188W/188Re generator

In order to evaluate the performance of nanocrystallinezirconia as a column matrix for 188W/188Re generator, processdemonstration run was performed using 1.85 GBq (50 mCi)aliquots of 188W/188Re and the elution behavior of 188Re wasstudied using 0.9% NaCl solution. The practical utility andseparation capability of 188Re by the sorbent material for long-term generator performance were monitored, by following theelution profile of the generator as shown in Fig. 7. It was observedthat the elution is quite sharp, reproducible and always �90% ofthe total 188ReO�4 available in the generator is eluted within thefirst 3–5 mL volume of normal saline. Fig. 8 summarizes theresults of the operation of the 188W/188Re generator. It is seen thatthe yield of 188Re was about 78–90% on elution with normal salinesolution and the performance of the generator remainedconsistent over a period of 6 months.

The recovery of 188Re from W/Re mixture simulated torepresent 37 GBq (1 Ci) of 188W, was as good when lower amountsof 188W were used. The overall yields of 188Re in the simulatedexperiments were �80% and the 188W breakthrough waso10�3%.

3.8. Quality control of 188Re eluate

3.8.1. Radionuclidic purity

The principal radionuclidic impurity that is expected in the188Re product is 188W. Fig. 8 summarizes the results of theamount of 188W impurity present in the eluate as a percentage of

ARTICLE IN PRESS

00

20

40

60

80

100%

188 R

e el

uted

Volume of eluent (mL)2 4 6 8 10 12

Fig. 7. Elution profile of the generator.

00

20

40

60

80

100

5.0x10-4

5.5x10-4

6.0x10-4

6.5x10-4

7.0x10-4

7.5x10-4

8.0x10-4

8.5x10-4

9.0x10-4

9.5x10-4

1.0x10-3

2

1

Elut

ion

effic

ienc

y (%

)

Time of elution (days)

1: Elution efficiency (%)2: % 188W in 188Re

20 40 60 80 100 120 140 160 180

%18

8 W in

188 R

e

Fig. 8. Elution performance of the generator.

00.0

4.0x104

8.0x104

1.2x105

1.6x105

2.0x105

Acetone medium

Act

ivity

(cpm

)

Distance from the point of application (cm)

DMSA HEDP

0.0

2.0x104

4.0x104

6.0x104

8.0x104

Saline medium

2 4 6 8 10

Fig. 9. Paper chromatographic patterns of 188Re complexes.

00

20

40

60

80

100

% W

elu

ted

Volume of NaOH (mL)2 4 6 8 10 12

Fig. 10. Regeneration of the used generator column.

R. Chakravarty et al. / Applied Radiation and Isotopes 68 (2010) 229–238 235

overall 188Re activity on the day of elution of the generator over aperiod of 6 months. The level of 188W present in the eluate wasalways below 10�3% in different batches, which is well within theacceptable limit of 10�3% (British Pharmacopoeia, 2008).

3.8.2. Radiochemical purity

Separation 188ReO�4 from 188Re in other oxidation states wasachieved by paper chromatography (PC), developed in salinemedium. In this system ReO�4 moves with solution front with Rf,while the other species remains at lower Rf values. ReO2, thereduced Re stays at Rf=0, the point of application. The radio-chemical purity of 188Re eluate as 188ReO�4 was 499%, which waswithin the prescribed limits of Z95% as per the BritishPharmacopoeia (2008).

3.8.3. Chemical purity

The presence of Zr, possibly bleeding from the nanocrystallinezirconia column matrix as analyzed by ICP-AES was as low as(0.0570.01) ppm in the eluate. It is clear from the result that188Re product obtained from this generator is therefore ade-quately free from Zr and could be utilized for the preparation ofradiopharmaceuticals.

3.8.4. Labeling efficacy

In order to examine the suitability of 188ReO�4 obtained fromthis generator for radiolabelling studies, it was complexed withDMSA and HEDP. In both cases, when thin layer chromatography(TLC) was performed using acetone as solvent, the complexremained at the point of application (Fig. 9). Under identicalconditions, 188ReO�4 moved towards the solvent front. However, ifhydrolyzed rhenium (188ReO2) is present, it will also remain at theorigin and hence an additional quality control procedure of TLC in0.9% NaCl solution was essential to estimate this radiochemicalimpurity in the complex. The TLC pattern, using 0.9% NaClsolution as solvent reveals that the free 188ReO�4 as well as thecomplexes migrated with the solvent front, whereas hydrolyzedrhenium remained at the origin. By combining the results of boththe TLCs, the complexation yield was estimated to be 498% inboth the cases.

3.9. Recovery of enriched 186W from the spent generator

Since enriched 188W is very expensive, this process could beeconomically viable if the 186W adsorbed on the nanocrystallinezirconia matrix could be recovered and reused in many cycles of

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operation. Moreover, since nanocrystalline zirconia is not widelyavailable commercially, it is desirable to regenerate the usedgenerator column after the expiry of its shelf-life. Enriched 186Wfrom the exhausted column was recovered using 5 M NaOHsolution (15 mL NaOH solution+1 mL 30% H2O2) adopting theprocedure similar to that reported with alumina (Mushtaq, 1996),and the elution behavior of W, as followed by counting theresidual radioactivity, from the column is shown in Fig. 10. It isseen that the recovery of W is quite fast, and nearly all the 186Wcould be eluted out in the first 4–5 mL of the eluent.

4. Discussion

The overall objective of the present work is to demonstrate thepotential utility of nanocrystalline zirconia as an alternativesorbent, in the preparation of 188W/188Re generator to obtainclinical grade 188Re. The synthesis process reported here isinexpensive, simple, carried out at ambient conditions andamenable for large-scale production. All precursors of thesynthesis process are commercially available. The materialobtained is suitable for chromatographic applications. Initially,most of our studies have focused on morphological and structuralcharacterization of the matrix. The small particles of uniform size,good crystallinity, high surface area and negligible solubility,make this material attractive for chromatographic applications.

Batch experiments were persued to screen the sorptionbehavior and to evaluate the efficacy of the sorbent in columnoperation that are particularly important in generator preparationand operation. The pH value of the solution plays an importantrole with respect to the sorption of 188W and 188Re ions on oxidesurfaces. The effect of pH of the electrolyte on the distributionratios (Kd) value of 188W and 188Re were studied to optimize theexperimental conditions necessary for satisfactory loading of188W feed on the column as well as easy elution of 188Re. The188W ions could be quantitatively retained at a pH of �3, and 0.9%NaCl solution was sufficient for complete elution of 188Re.

The zeta potential (z), which is commonly used to describe thesurface charge of the sorbent that interacts with its surroundingsis a very useful tool to help in the interpretation of the sorptionbehavior. From the result it was observed that the pH value of thefeed solution is supposed to be less than the pHPZC (pH value of�4.5), which leads to the surface possessing positive charges, soas to facilitate the sorption of anionic polytungstate species. Thisobservation is almost in agreement with the Kd studies.

The sorption capacity, indicative of the ability of the sorbent toretain 188W, depends on the number of available sorption siteswithin the matrix. In the present study, we took advantage ofnano sized zirconium oxide clusters in which the sorption sitesare predominantly located on the surface and offer very highsorption capacity per unit mass, because of the high surface area-to-volume ratio. The porous nature of nanocrystalline zirconiafacilitates easy accessibility of sorption sites present internally.The observed capacity of the sorbent is adequate from generatorapplication point of view.

Nanocrystalline zirconia particles contain functional hydroxylgroups such as�Zr–OH in which the zirconium ion boundchemically to the hydroxyl groups. This surface hydroxyl groupsthat are an integral part of the matrix and found within itsstructure are, indeed, the reactive parts which can react with acidor base. These materials can be considered to consist of discretemetal oxide clusters covered by surface hydroxyl groups. Thesurface charges of the nanoparticles are primarily responsible forthe uptake of metal ion. The interaction of nanosized metal oxideparticles with natural aqueous solutions results in the hydroxyla-tion of surface sites, which impart a pH-dependent surface charge.

At low pH, these hydroxide groups become protonated and thematerial surface develops a positive charge. There are variousanionic species of tungsten, varying with pH. At pH49 thepredominant species is WO2�

4 , while at pH 6, the predominantspecies is W12O10�

41 and at a pH between 2 and 4 the speciesW12O6�

39 -predominates (Yori and Parera, 1998; Khalid et al., 2001).These species move from the bulk solution to the surface of thesorbent particles and then are adsorbed on sites created byprotonated surface hydroxyl groups of the matrix to maintainelectro-neutrality. The relative occurrence of sorption process isgoverned by the Zr content of the particles, which controls theirsurface charge density. These indicate that the uptake ofpolytungstate anions at pH below the pHPZC (pH �4.5) dependson the reactivity of the shell of zirconia to form links with themetal ions, the concentration of functional groups to increase theprobability to form the bond, the morphology that provides ahighly porous material that increases the accessibility and thenumber of active sites available for sorption. The open structure ofnanocrystalline zirconia provides several advantages such asrapid diffusion of macromolecules due to the high mass transferand the easy access to reactive hydroxyl groups.

The behavior of nanocrystalline zirconia in a fixed-bed columnoperation at room temperature was studied to predict the masstransport performance in terms of 188W breakthrough point. Itwas seen that the static ion-exchange capacity of a sorbent couldnot be utilized completely under the dynamic conditions mainlydue to mass transfer limitations, such as incomplete external filmdiffusion and/or to intraparticle transfer. The determination of thenature of the mass transfer resistance would require furtherstudies and beyond the scope of this investigation. In the presentcase, the dynamic capacity was seen as a criterion for retentioncapacity of the sorbent in the point-of-use system.

While the performance of this sorbent has been wellcharacterized under normal operating conditions, the suitabilityof the material in the radiation environment, such as those thatmay occur in a radionuclidic generator is the subject of furtherevaluations. In order to integrate the experimental findings and toestablish the utility of the sorbent in radiation environment, it isnecessary to carry out a process demonstration run to evaluatethe behavior of the adsorbent in the presence of intense radiationenvironment with the radiolytic products generated as a result ofradioactive 188W. This experiment would reveal several issuesthat may impact the performance of packed bed. We carried out a6 months operation test and demonstrated the efficacy of thesorbent as well as the purity of the product obtained for clinicalapplication. The elution profile obtained was sharp and highradioactive concentration of 188ReO�4 could be obtained. Repro-ducible recovery of 188Re was observed with a yield Z80%. Thepurity, elution yield of the 188ReO�4 and 188W breakthroughremained nearly unchanged with repeated long term operation. Itis worthwhile to note that during the process demonstration runfor a period of 6 months, no operational problems such asreduction of flow rate, head loss, packed bed compression andchanneling of packed column were observed. Appearance of finesor suspended solids in the effluent from the packed bed due topotential degradation of the sorbent was also not observed. Theresults from the process demonstration run confirms thefeasibility of using fixed bed columns containing nanocrystallinezirconia for the production of 188Re in 0.9% NaCl medium.

For radiopharmaceuticals preparation, 188Re must exhibitacceptable radiochemical and radionuclidic purity. Paper radiochromatography technique was used in our study to evaluate theradiochemical purity as it is rapid, simple and fairly accurate.Determination of the 188W breakthrough in the 188Re eluate wascarried out using HPGe gamma spectrometric technique. Owing tothe very high activity of 188Re at the time of elution, the intense

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155 keV g-ray peak of 188Re could mask the feeble 227 keV (0.22%)and 291 keV (0.4%) peaks of 188W. Therefore, the eluates werecooled for 14 days to allow the decay of 188Re and then subjectedto high-resolution gamma-ray spectrometric investigation. Thelevel of the long-lived radionuclidic impurity burden in 188Reobtained from the generator, due to 188W, appears to beadequately low (o10�3%) and within the permissible limit(10�3%), rendering it useful in the preparation of radiopharma-ceuticals. As the generators described in this paper were preparedfrom Zr based sorbent, we ascertained that Zr present in theeluted 188Re were well within acceptable limits (o1 ppm), usinga sensitive method, such as ICP-AES. Thus, the radiochemical,radionuclidic and chemical purity of 188ReO�4 were well within theacceptable limits. The 188Re obtained from the generator,complexed with DMSA and HEDP with 498% yields indicatingthe compatibility for radiopharmaceuticals preparation.

Another important aspect of this article is the recovery of theenriched 186W from the spent generator for its reuse as targetmaterial. In view of the precious nature of enriched 186W, allattempts to recover it and reuse are warranted. Recovery of theisotopically enriched 186W for further neutron irradiation is animportant part of the economical production and use of 188W.Based on the reported results on recovery of sorbed metal ionsfrom alumina (Mushtaq, 1996), we explored similar strategy torecover 186W from the spent column using 15 mL of 5 M NaOHcontaining 1 mL of 35% H2O2. It was observed from the zetapotential experiment that the surface electrical charge ofnanocrystalline zirconia at acidic pH is positive and can adsorbthe negatively charged polytungstate anions. However, atpH45, the surface electrical charge is neutral or negative, andtherefore sorption of W would be unfavorable. Further as pH ofthe external solution rises, depolymerisation of polytungstateanionic species would be expected to takes place. ThereforeWO2�

4 ions could be desorbed from the column by NaOH.Addition of H2O2 to the NaOH solution promotes the oxidationof W sorbed on the nanocrystalline zirconia in a reduced state asa result of radiation and chemical changes caused by the ionizingradiation and thus facilitates their elution. When the activity ofthe 188W decreases below a certain value, it is no longer usefulfor medical application. The generator column can not bediscarded without removing the radioactive 188W. Hence, theprocedure for removing 186W along with 188W from the columnprior to disposal was also important from the waste disposalpoint of view.

The results of the study for the separation of 188Re from a188W/188Re carrier added solution simulating 37 GBq (1 Ci)generator, provides an insight into the efficiency of separationof 188Re from 188W/188Re mixture at higher levels of activity.However, in order to utilize nanocrystalline zirconia for thepreparation of an usable 37 GBq (1 Ci) generator system, the effectof radiation at higher level of activity on the performance of thismaterial needs to be demonstrated. Owing to its unparalleledmechanical and thermal stability, nanocrystalline zirconia is usedas an advanced ceramic material (Wang et al., 2006; Venkates-waran et al., 2005). Therefore, we are confident to be able toaddress all the issues regarding radiation stability of this sorbentto obtain 37 GBq (1 Ci) of 188Re in a form suitable for direct clinicalapplications.

The method of production of 188Re from a generator, contain-ing nanocrystalline zirconia sorbent possessing high absorptioncapacity is seen to have merits similar to using semi enriched186W produced in moderate flux research reactors. The otherbenefits of nanocrystalline zirconia sorbent are (1) rapid packingdue to the high density of the sorbent which settles in a fewminutes, (2) rigidity which allows the use of high flow rateswithout pressure increase or shrinking or swelling of the sorbent

and (3) 188W bleeding was negligible due to the stable chemicallink of the 188W species to the matrix.

The present results can be of interest from the point of view ofidentifying novel inexpensive sorbent for 188W/188Re generatorthrough careful manipulation of synthesis procedure that couldeasily be adapted. Due to its operational simplicity, and therepeated usability of the expensive 186W, this new high capacitysorbent material is a promising candidate for the preparation of188W/188Re generators.

5. Conclusions

This investigation demonstrates that nanocrystalline zirconiais a promising sorbent with significant ion-exchange capacity for188W and could be an attractive option for the preparation of188W/188Re generators. The 188W/188Re generator prepared usingthis nanocrytalline zirconia sorbent provides carrier-free 188Re (as188ReO�4 ) on elution with 0.9% NaCl solution, which is physiolo-gically compatible. The sorbent was stable and the performance ofthe generator remained consistent over a period of 6 months. Theintroduction of nanomaterials in the development of 188W/188Regenerator system is undoubtedly a significant step forward toproduce clinical grade 188Re and therefore further, developmentof these strategies is warranted. Applications of this approach forthe development of other generator systems are also the suitableareas for further research.

Acknowledgements

The authors are grateful to Dr. V. Venugopal, Director, Radio-chemistry and Isotope Group, Bhabha Atomic Research Centre forhis support to this program. The authors also acknowledge Dr.V.K. Manchanda, Head, Radiochemistry Division and Dr. (Ms.) S.Ray, Head, Uranium Extraction Division of this centre forproviding their facilities for the determination of zeta potentialand ICP analyses respectively.

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