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Exploitation of Nano Alumina for the Chromatographic Separation of Clinical Grade 188Re from 188W: A Renaissance of the 188 W/188Re Generator Technology Rubel Chakravarty,† Rakesh Shukla,‡ Ramu Ram,† Meera Venkatesh,† Avesh Kumar Tyagi,‡ and Ashutosh Dash*,† †
Radiopharmaceuticals Division and ‡Chemistry Division, Bhabha Atomic Research Centre, Mumbai 400 085, India
bS Supporting Information ABSTRACT: The 188W/188Re generator using an acidic alumina column for chromatographic separation of 188Re has remained the most popular procedure world over. The capacity of bulk alumina for taking up tungstate ions is limited (∼50 mg W/g) necessitating the use of very high specific activity 188W (185 370 GBq/g), which can be produced only in very few high flux reactors available in the world. In this context, the use of high-capacity sorbents would not only mitigate the requirement of high specific activity 188W but also facilitate easy access to 188Re. A solid state mechanochemical approach to synthesize nanocrystalline γ-Al2O3 possessing very high W-sorption capacity (500 mg W/g) was developed. The structural and other investigations of the material were carried out using X-ray diffraction (XRD), transmission electron microscopy (TEM), Brunauer Emmett Teller (BET) surface area analysis, thermogravimetric-differential thermal analysis (TG-DTA), and dynamic light scattering (DLS) techniques. The synthesized material had an average crystallite size of ∼5 nm and surface area of 252 ( 10 m2/g. Sorption characteristics such as distribution ratios (Kd), capacity, breakthrough profile, and elution behavior were investigated to ensure quantitative uptake of 188W and selective elution of 188Re. A 11.1 GBq (300 mCi) 188W/188Re generator was developed using nanocrystalline γ-Al2O3, and its performance was evaluated for a period of 6 months. The overall yield of 188Re was >80%, with >99.999% radionuclidic purity and >99% radiochemical purity. The eluted 188Re possessed appreciably high radioactive concentration and was compatible for the preparation of 188Re labeled radiopharmaceuticals.
I
n the recent times, nanomaterials have become immensely exciting materials of interest and have played important roles in a wide variety of scientific disciplines.1,2 The properties of nanomaterials are markedly different from their bulk counterparts which make them scientifically fascinating.1 Such materials exhibit great promise for providing unforeseen advances in nanotechnology in the near future.1 In addition to numerous other applications,1,2 nanomaterials have the potential to provide unprecedented opportunities in developing a new class of sorbents for the preparation of radionuclide generators. One of the specific properties of nanomaterials is that a high percent of the atoms reside on the surface. These surface atoms are unsaturated, exhibit intrinsic surface reactivity, and have a tendency to chemisorb charged species in aqueous solution in order to achieve surface stabilization. The potential of such nanomaterials as a new generation of sorbents in the chromatographic separation of metal ions have been exploited.1,3 9 Additionally, nanomaterials exhibit enhanced mechanical and radiation stability10 13 and are therefore expected to be better sorbents for radiochemical separations than the corresponding bulk materials. The 188W/188Re generator is an excellent source for availing no-carrier-added (NCA) grade 188Re. The potential of 188Re has been explored and demonstrated for a wide variety of therapeutic applications in nuclear medicine.14 The favorable physical and r 2011 American Chemical Society
chemical properties of 188Re14 and its availability from the 188 W/188Re generator with an adequate shelf life makes it an interesting option for clinical use. However, regardless of the attractive properties of 188Re, the widespread application of this excellent radioisotope in clinical context is disadvantageously affected due to the unavailability of cost-effective 188W/188Re generators. 188W can only be produced by double neutron capture with low neutron absorption cross sections [186W(n,γ)187W (σ = 37.9 ( 0.6 b); 187W(n,γ)188W (σ = 64 ( 10 b)] using enriched 186 W target. Because of the rather long half-life of 188W, relatively long irradiation periods are required even for the production of 188 W of modest specific activity.15 188W of appreciable specific activity (150 190 GBq g 1) availed from the high flux reactors (ϕ ∼1015 n cm 2 s 1) can only be used to make clinically useful 188 W/188Re generators. Consequently, the production of 188W is dependent only on the two high flux reactors available in the world, namely, HFIR in Oak Ridge National Laboratory and SM Reactor in Dmitrovgrad, Russia. In view of these limitations, it is imperative to evolve novel approaches to ensure cost-effective production of 188W/188Re generators utilizing lower specific Received: May 18, 2011 Accepted: July 5, 2011 Published: July 05, 2011 6342
dx.doi.org/10.1021/ac201232m | Anal. Chem. 2011, 83, 6342–6348
Analytical Chemistry activity 188W which can be produced in many countries having operational medium neutron flux (∼1014 n cm 2 s 1) research reactors. The most reliable method for the preparation of 188W/188Re generators is based on an alumina based column chromatographic approach, wherein 188W is absorbed on alumina matrix and 188Re is selectively eluted using 0.9% NaCl solution at regular intervals.14 Because of the limited sorption capacity of alumina (maximum 50 mg W/g),14 188Re availed from alumina based 188 W/188Re generators is of low radioactivity concentration, if low specific activity 188W is used. This in turn would require post elution concentration of the 188Re eluate16 20 resulting in a fairly complex system, leading to chemical impurities, high dose rates, and low reliability. Though, automated systems for the concentration of 188Re eluate have been developed,21,22 the high cost involved in the operation of the complex automation systems escalates the production cost of 188Re and renders it costineffective. Alternatively, several sorbents like hydroxyapatite, the hydrous oxides of zirconium, titanium, manganese, tin(IV), and cerium, silica gel, the AG 1-X12, and AG 50 W-X12 ionexchange resins and activated charcoal were studied to determine their suitability for the preparation of 188W/188Re generators.23,24 Unfortunately, all these materials were ineffective to improve W-sorption capacity compared to alumina. The other pathways such as 188W/188Re gel generators based on matrixes such as zirconium or titanium tungstate25 27 could retain higher W-content than alumina, but the 188Re elution performance was inferior compared to the alumina based systems. In the past few years, numerous high capacity sorbents, such as synthetic alumina, polymeric titanium oxychloride (PTC), and polymeric zirconium compound (PZC), have been developed for the preparation of 188 W/188Re generators.24,28 33 However, these recent techniques have yet to reach the commercial stage for clinical applications. The excellent properties of nanomaterials based sorbents for the preparation of radionuclide generators were first exploited by our group.34 38 As an ongoing effort toward developing highly efficient radionuclidic generators for biomedical applications, herein we report the synthesis, characterization of nanocrystalline γ-alumina (γ-Al2O3) by a solid state mechanochemical route and its utilization as a column material in the preparation of a 188 W/188Re generator. The performance of a clinical-scale 188 W/188Re generator system and evaluation of the quality of 188 Re for radiopharmaceutical applications have been discussed.
’ EXPERIMENTAL SECTION The synthesis and characterization of γ-Al2O3 was carried out as per the details provided in the Supporting Information. The sorption characteristics of 188W and 188Re ions on γ-Al2O3 were studied adopting the standard radiochemical procedures.33,34 A process demonstration run was carried out by developing a 11.1 GBq (300 mCi) 188W/188Re generator, as per the details provided in the Supporting Information. The elution performance of the generator was evaluated for a period of 6 months, which is the expected shelf life of a 188W/188Re generator. The radionuclidic and radiochemical purities of 188Re were evaluated by standard radiometric methods.34,35 In order to determine the presence of Al ions contamination in the 188Re product (chemical impurities), the 188Re samples were allowed to decay for 20 days. The trace levels of Al ions contamination in the decayed samples were determined by inductively coupled plasma-atomic emission spectroscopy (ICP-AES). Further, 188Re was used to prepare
ARTICLE
Figure 1. XRD pattern of γ-Al2O3.
complexes of dimercaptosuccinic acid (DMSA) and hydroxyethylidene diphosphonate (HEDP) as per the reported procedures.34,35
’ RESULTS AND DISCUSSION In order to realize the potential of a new sorbent material, systematic studies on synthesis methodology and structural characterization are required. A thorough optimization of various experimental parameters was found to be essential to consistently avail the best possible yield of 188Re with minimal contamination of 188W. Synthesis of γ-Al2O3. Numerous methods for the synthesis of γ-Al2O3 have been reported in the literature, such as hydrothermal processing, sol gel, controlled precipitation of boehmite by hydrolysis of aluminum salts and alkoxides, etc.39,40 However, most of these reported methods are expensive because of the high cost of the starting chemicals. Moreover, the above procedures require very careful control of the synthesis parameters in order to obtain γ-Al2O3 of reliable quality and high yield. In addition, nanomaterials made by these routes are unsuitable for applications requiring large quantities. In order to circumvent these limitations, our attention was turned toward the solid state mechanochemical approach using inexpensive inorganic salts as the starting materials. The singlestep synthesis procedure is reliable, simple, and gives high product yields. In this method the reactants, i.e., aluminum nitrate and ammonium carbonate, were taken in a stoichiometric ratio and were thoroughly ground. During grinding, a selfinitiated and self-sustained reaction starts with the evolution of CO2 gas forming a precursor, which was dried at 100 °C for 5 h and then subjected to calcination at 700 °C for 2 h. The evolution of gases during calcination increased the porosity of the material. The material exhibited good mechanical strength and granular properties and was amenable for column operation. Structural Characterization of γ-Al2O3. The X-ray diffraction (XRD) pattern of γ-Al2O3 is shown in Figure 1. The XRD pattern reveals that the material is nanocrystalline and in γ-phase (cubic).41 The average crystallite size of the nanocrystalline material, as determined by Scherrer’s formula was 5 ( 1 nm. The results obtained from the XRD studies were further 6343
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Analytical Chemistry
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Table 1. Distribution Ratios (Kd) of 188W and 188Re Ions on γ-Al2O3a Kd medium
Figure 3. Particle size distribution of γ-Al2O3 by the DLS study.
corroborated by the transmission electron microscopy (TEM) studies. The TEM micrograph of the sample is shown in Figure 2. It reveals that the material is nanocrystalline and highly agglomerated. The agglomeration of the material is essential in order to utilize it as a column matrix for the preparation of chromatographic generators. Very fine particles without agglomeration are not amenable for such applications as the column beds prepared using such materials are impermeable to the flow of liquid. The surface area of γ-Al2O3 was determined to be 252 ( 10 m2/g, by BET analysis, which was appreciably high. Dynamic light scattering (DLS) results are shown in Figure 3, in which F represents distribution (in percentage) of the agglomerate size (shown by histogram) and U gives percentage of the total number of particles under the given size (represented by a solid line). Studies confirmed a reasonably wide size distribution of particles with a median
188
Re
pH 1
3 382 ( 432
261 ( 6
5 697 ( 264
279 ( 8
pH 3 pH 4
14 194 ( 112 662 973 ( 1 986
398 ( 11 194 ( 7 187 ( 5
pH5
452 833 ( 2 111
pH 6
39 923 ( 567
98 ( 3
pH 7
4 850 ( 448
42 ( 9
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1 222 ( 127
31 ( 6
pH 9
279 ( 12
35 ( 4
pH 10
102 ( 5
3 ( 0.7
pH 11 pH 12
49 ( 1 11 ( 5
2 ( 0.5 0
pH 13
4( 2
0.9% NaCl
Figure 2. TEM micrograph of γ-Al2O3.
W
pH 2
pH 14 a
188
0
0
0
12 904 ( 154
0.2 ( 0.1
n = 3; “(” represents the standard deviation.
agglomerate size around 23 μm, made of primary particles of a size about 5 6 nm. In order to study the nature of agglomeration, the suspension was again ultrasonicated for 10 min and DLS data were recorded. As there was not much change in the agglomerate size, it was inferred that the agglomerates are hard in nature, which is yet another desirable feature of the application of nanosorbents in chromatographic columns. The thermogravimetric (TG) and differential thermal analysis (DTA) curves of precursor are shown in the Supporting Information (Figure S2). The first stage (70 250 °C) corresponds to the removal of adsorbed moisture and elimination of the hydroxyl group for which the DTA scan showed an endothermic peak over this temperature range. A drastic weight loss was observed in the TG curve, in the temperature range 250 320 °C, associated with an exothermic peak in the DTA curve. This is attributed to decomposition of the precursor to form nanocrystalline alumina. The decomposition of the precursor is a highly exothermic process as seen from the DTA curve, in which the particles obtained get partially sintered resulting in formation of hard agglomerates, which supports the data obtained by DLS study. On a further increase in temperature, no weight loss was observed and the material was stable up to 1000 °C. Chemical Stability of γ-Al2O3. Chemical stability of γ-Al2O3 is an important parameter for its usefulness as a column matrix for the preparation of radionuclide generators. The chemical stability studies by solubility tests showed that γ-Al2O3 was insoluble in dilute mineral acids and alkalis as only negligible amount of Al ions (
