Generator Integrated System: Elution–Purification–Concentration Integration

Ethylenediaminetetraacetic acid) for detection of blood–brain barrier integrity and ⁶⁸Ga-PLED (PLED N, N’-bis(pyridoxyl)ethylenediamine-N, N’-diacetic acid) or ⁶⁸Ga-EDTA for renal function investigation. ⁶⁸Ga-based targeting PET radiopharmaceuticals under phase III clinical trial are ⁶⁸Ga-DOTA-NOC (DOTA 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid, NOC 1-Nal³-octreotide), ⁶⁸Ga-DOTA-TATE (DOTA 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid, TATE [tyr³, thr⁸]-octreotide), ⁶⁸Ga-DOTA-lanreotide, and ⁶⁸Ga-DOTA-TOC (DOTA 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid, TOC D-phe¹-tyr³-octreotide), which are used for PET imaging of several subtypes of somatostatin receptors for imaging of neuroendocrine tumors; ⁶⁸Ga-DOTA-bombesin for PET imaging of gastrointestinal stromal, colon, and prostate cancer; and ⁶⁸Ga-AMBA (AMBA DO3A-CH(2)CO-G-[4-aminobenzoyl]-QWAVGHLM-NH(2)) for study on NMB (non-peptide neuromedin B) and GRP-R (gastrin releasing peptide receptors) bombesin receptors on medullary thyroid cancer.

In terms of nuclear physics, ⁶⁸Ga is considered as a second important β⁺ emitter (after ¹⁸F) efficiently used in PET imaging with the following favorable characteristics: High positron abundance and good PET imaging resolution are the most important features of ⁶⁸Ga when used for biomedical imaging. Decay via β⁺ particles (with the 511-keV annihilation gamma-ray of 178.2% intensity) occurs in 89.14% of atoms. The 836.02-keV positron radiation gives a PET imaging resolution of about 2.3 mm (bone) to 11.5 mm (lung) for living tissues (compared with 0.65–2.7 mm in the case of ¹⁸F). These values are well within the system resolution of modern PET cameras (4–5 mm) and even high-resolution PET systems (3 mm). A further advantage is that there is no associated gamma impact on PET images. The insignificant amounts of associated gamma emissions (0.03407%) falling into the commonly used PET energy window of 350–700 keV have almost no impact on PET images. From the radiation point of view, ⁶⁸Ga conforms well with conventional radiation safety. The Γ_20keV exposure rate constant of 0.179 μSv.m²/MBq.h (compared with 0.188 μSv.m²/MBq.h for ¹⁸F) makes use of ¹⁸FDG [(¹⁸F)fluorodeoxyglucose] standard radiation safety automatic infusion systems feasible. In terms of economy and convenience of use, ⁶⁸Ga offers the advantages of cost-effectiveness and on-demand availability: The long-lived parent nuclide ⁶⁸Ge can deliver cost-effective PET imaging due to the generator shelf-life of approximately 2 years. The ⁶⁸Ge/⁶⁸Ga generator also renders ⁶⁸Ga-based PET radiopharmacy independent of an onsite cyclotron. This means that this generator is ideally suited to on-demand availability of β⁺ emitters for biomedical experiments and clinical targeting imaging, both in remote PET centers without a cyclotron and even in cyclotron-operating PET centers. The ability to formulate kits and the simplicity/elegance of its use are further good reasons to use ⁶⁸Ga in daily clinical practice. It is predicted by experts that ⁶⁸Ga will become the ^99mTc for PET/CT (X-ray computed tomography, also Computed tomography). The potential for provision of kit-formulated precursors along with a ⁶⁸Ga generator, similar to ^99mTc in vivo kits, will make this generator become the mainstay for nuclear medicine molecular imaging in the very near future.

To date, various ⁶⁸Ge/⁶⁸Ga generator systems have been developed using two different techniques. First, solvent extraction techniques using acetyl acetone-carbon tetrachloride/dilute HCl solution and 8-hydroxyquinoline/chloroform have been applied by different research groups (Erhardt and Wetch 1978).

Column technique-based ⁶⁸Ge/⁶⁸Ga generators were developed using different sorbents as generator column packing materials and either alkaline or acidic solutions or aqueous solutions containing complexing agents as eluents to separate ⁶⁸Ga by elution from its parent nuclide ⁶⁸Ge, which was immobilized on the column.

Among the column techniques applied, the following are worth mentioning: An organic ion exchanger resin (Bio-Rad AG1-X8) column-based ⁶⁸Ga generator with elution of dilute HF solution as well as synthetic chelate resin (condensation of pyrogallol and formaldehyde) column-based ⁶⁸Ga generators have been studied (Neirinckx and Davis 1980; Neirinckx et al. 1982; Neirinckx and Davis 1981a, b; Schuhmacher and Maier-Borst 1981). Recently, solid-phase extraction resins have been studied for ⁶⁸Ga generator production. Dipentyl pentylphosphonate (UTEVA) resin was used for selectively retaining ⁶⁸Ga in 4 M HCl solution while ⁶⁸Ge remained unadsorbed, followed by eluting the ⁶⁸Ga from the column with 0.1 M HCl solution (McAlister and Horwitz 2009). Diaion CRB 02 resin (N-methyl-d-glucamine) was studied for selective immobilization of ⁶⁸Ge, with elution of ⁶⁸Ga performed with a citrate solution (Hsin-Li 2009). Unfortunately, the radiation degradation sensitivity of the organic matrix of both ion exchange resins and solid-phase extraction resin was unfavorable over the expected lifetime of the ⁶⁸Ga generator (around 2 years).

Alumina column combined with elution with 0.005 M EDTA solution (Greene and Tucker 1961; Kopecky et al. 1973) or high-temperature-treated alumina column combined with elution with 0.1–0.2 M HCl solution (Egamediev et al. 2000; Kopecky and Mudrova 1974) has also been applied for ⁶⁸Ge/⁶⁸Ga generator development. Alumina column-based ⁶⁸Ga generators with alkaline solution elution have also been patented (Lewis and Milford 1982). The high content of Al³⁺ ion in the ⁶⁸Ga eluate, the use of complexing agent EDTA-containing solution for elution, and ⁶⁸Ga eluate of low specific volume are the major disadvantages for labeling PET radiopharmaceuticals.

Silica gel was among the earliest sorbents studied for ⁶⁸Ga generator preparation (Caletka and Kotas 1974; Lievens and Hoste 1974; Neirinckx and Davis 1979). Recently, an improved technology using silica gel as a nonmetallic sorbent for ⁶⁸Ga generator production has been developed. As a result of this development, ITG company is commercializing a silica gel-based ⁶⁸Ga generator today.

A tin dioxide column-based ⁶⁸Ga generator using elution with 0.6–1.0 M HCl solutions has been developed and is among the currently used generator systems (Aardaneh and Van der Walt 2006; Loc’h et al. 1980; Waters et al. 1983; McElvany et al. 1984). Tin dioxide column-based generators with 0.6 M HCl solution elution are now commercialized by IDB Holland BV. However, the high content of metallic ion impurities in the ⁶⁸Ga eluate, the use of stronger acidic solution for the elution, and the ⁶⁸Ga eluate of low specific volume are undesirable factors for processing of coordination chemistry labeling of PET radiopharmaceuticals.

Titanium dioxide, silicon dioxide, glass microsphere sorbent, and cerium dioxide column-based ⁶⁸Ga generators with 0.1 M HCl solution elution have been reported in literature (Kozlova et al. 1994; Neirinckx and Davis 1979; Bao and Song 1996; Erhardt and Wetch 1992). Besides the low specific volume of ⁶⁸Ga eluate obtained, the problem of metallic impurities from dissolution of the column packing materials remains to be solved. Presently, commercial ⁶⁸Ge/⁶⁸Ga generators are available. These generators are based on a modified titanium dioxide column with 0.1 M HCl solution elution, commercialized by Eckert and Ziegler Eurotope GmbH-Berlin and Cyclotron Co. Ltd., Obninsk.

Hydrous zirconium oxide column-based ⁶⁸Ga generators with 0.1–0.5 M HCl or HNO₃ solution elution have been studied (Pao et al. 1981; Neirinckx and Davis 1979). Undesirable large volumes of eluents were necessary to elute ⁶⁸Ga from the zirconium dioxide column, and low ⁶⁸Ga elution yield was reported. An improved technology using nanozirconia sorbent to immobilize ⁶⁸Ge followed by ⁶⁸Ga elution with 0.01 M HCl solution has recently been developed (Chakravarty et al. 2011). Despite leaching of Zr⁴⁺ ions from the sorbent substrate, which may require more peptide DOTA-TATE to achieve high-yield labeling, the encouraging results are under evaluation.

A tetravalent lanthanide oxide CeO₂ was studied for immobilizing ⁶⁸Ge for ⁶⁸Ga generator preparation (Bao and Song 1996). However, the adsorption/elution performance of this sorbent remains far from practical application in useful ⁶⁸Ga generator production.

Polyantimonic acid column-based ⁶⁸Ga generators developed using elution with sodium oxalate solution are unsuitable for radiolabeling targeted radiopharmaceuticals due to stable complex formation of ⁶⁸Ga ions with oxalate ions (Arino et al. 1978).

The development of a valuable ⁶⁸Ga generator, capable of providing a ⁶⁸Ga eluate suitable for biomedical application, requires different specific technical solutions. These include a sorbent for immobilizing the parent nuclide ⁶⁸Ge, a suitable eluent used for elution of the daughter nuclide ⁶⁸Ga, and the component parts and materials used for the setup of the generator. Presently, commercial ⁶⁸Ge/⁶⁸Ga generators using tin dioxide, titanium oxide, or silica gel sorbent for ⁶⁸Ge immobilization are available. However, the 5 mL dilute HCl solution required for ⁶⁸Ga elution and the unavoidably high metallic ion contamination makes these generators’ utilization for labeling radiopharmaceuticals impossible. Moreover, the critical level of ⁶⁸Ge breakthrough and acidity of the ⁶⁸Ga eluate produced from the above-mentioned generator systems also present a disadvantage, and so further development of alternative sorbents is required for generator performance improvement.

Regarding the sorbents used in radionuclide generator technology, in addition to the high chemical separation specificity requirement, both high radiation resistance and chemical stability are equally needed. The sorbent used in a ⁶⁸Ga generator should be highly resistant to the high radiation dose delivered from the positron and gamma radiation emitted from the ⁶⁸Ge/⁶⁸Ga pair for the entire life of the generator, which is long due to the long half-life of the parent ⁶⁸Ge. For this reason, organic sorbents including ion exchange resins are likely not suitable for ⁶⁸Ga generator columns. Inorganic sorbents developed to date have hydrated amorphous structure, which has disadvantageous properties regarding chemical and physical stability. The low physical stability causes the sorbent particles to break easily, blocking the flow of fluid in the sorbent bed of the chromatographic column. The low chemical stability causes leaching of metal ions from the sorbent material into the separated solute product. Consequently, the product is contaminated with sorbent metal ions. To avoid these disadvantageous properties of amorphous inorganic sorbents, crystalline metal oxide-based sorbents should be developed to improve the performance of inorganic sorbents.

Components for generator setup should be nonmetallic to avoid metallic ion contamination of ⁶⁸Ga eluate and also be highly resistant to high radiation dose for the long lifetime relevant to the advantageously long-lived parent nuclide ⁶⁸Ge. The chromatographic column of the generator, including fritted disks located at the ends, should be made from either quartz or plastic material such as polyetheretherketone (PEEK). Components made of borosilicate glass should not be used, to avoid leaching of metallic ions into the ⁶⁸Ga solution during processing. Suprapure water and chemicals should be used for preparation and elution of the generator.

To be successfully applied for formulating ⁶⁸Ga-labeled targeted radiopharmaceuticals (molecular probes/tracers) currently used in clinical PET imaging, the ⁶⁸Ga eluate should be evaluated based on three utmost important parameters: The first, for radiation safety reasons, is that the ⁶⁸Ga solution produced from a ⁶⁸Ge/⁶⁸Ga generator should be of very high radionuclidic purity, or in other words, the ⁶⁸Ge parent nuclide contamination in the ⁶⁸Ga solution should be very low (<10⁻³%) due to the long half-life of the ⁶⁸Ge radionuclide. Besides, the chemical impurities, particularly the metallic ion content in the ⁶⁸Ga solution, should be kept as low as possible to eliminate any concurrent coordination chemistry reactions which may reduce the ⁶⁸Ga labeling yield. Moreover, ⁶⁸Ga solution of high radioactive concentration is also an important factor affecting the capability for ⁶⁸Ga labeling of the nanomole quantities of biomedical tracers/molecular probes currently used in routine molecular imaging and in targeted radiopharmaceutical development. Additional parameters are that the ⁶⁸Ga eluate should be free from either complexing agents or organic solvent which may be harmful to both biomolecules and complexation of Ga³⁺ ions.

To be used in biomedical applications, especially for labeling of targeting radiopharmaceuticals useful in PET imaging as mentioned above, the ⁶⁸Ga eluate from the generator (generator column) should typically be purified to remove the trace amount of ⁶⁸Ge breakthrough and metallic ion impurities, then concentrated to increase the radioactive concentration. Although the solvent extraction technique for concentration–purification of ⁶⁸Ga eluate using the extractant methyl ethyl ketone has recently been studied (Bokhari et al. 2009), processes for purification and concentration of ⁶⁸Ga eluate are still preferably applied using a single column of either cationic or anionic ion exchange resins. A strong anionic exchanger resin column-based process and automated system were recently patented and published. ⁶⁸Ga eluate in 4 M HCl solution was passed through a strong anionic ion exchange resin column. ⁶⁸Ga retained on this column was then eluted with a small volume of distilled water (Mourtada et al. 2009; Velikyan et al. 2004b). This method is not capable of removing some important metallic ion impurities, such as Fe³⁺ or Zn²⁺. The above-mentioned patent presents a complex and sophisticated apparatus, unfriendly to nonprofessional users. A strong cationic ion exchange resin-based method has also been reported and is currently in use. This technique is based on retaining ⁶⁸Ga³⁺ ions from the ⁶⁸Ga eluate onto a strong cationic ion exchange resin column; then, the co-adsorbed impurity metal ions are removed by washing the column with 0.15 M HCl solution containing 80% acetone. Finally, ⁶⁸Ga ions are eluted from the resin column with a small volume (around 0.5 mL) of 0.015 M HCl solution containing 98% acetone (Rösch et al. 2008; Zhernosekov et al. 2007). This method successfully removes the majority of impure metallic ions, including Fe³⁺ and Zn²⁺; however, the acetone solvent can react with the HCl solution to form a polymer product. Consequently, the purification process will fail if the history of the acetone/HCl solution is unknown. It is also worth mentioning that polymeric residue in the ⁶⁸GaCl₃ preparation after evaporation of acetone will affect the radiolabeling of radiopharmaceuticals, which are usually biomedical substances. In a similar manner, 98% acetone/2% acetylacetone mixture has also been used to elute ⁶⁸Ga from the cation exchange resin column for ⁶⁸Ga-labeling under anhydrous conditions (Zoller et al. 2010). All steps of these purification processes were performed manually.

Dual-column methods for ⁶⁸Ga purification–concentration were recently reported. Compared with the single-column method mentioned above, two columns of different resins connected in series with separate outlets and inlets for eluents were used. In the first option, a strong cationic resin column (column 1) followed by a strong anionic resin (column 2) (Pawlak et al. 2011) and in the second a strong cationic resin (column 1) and TODGA (N, N, N’, N’-tetraoctyl-diglycolamide) extraction resin (column 2) (Loktionova et al. 2011) were used. The dual-column technique, although resulting in ⁶⁸Ga solution of very high purity, is not practical due to its complicated tubing connection and thus elution processing. Therefore, there is a need in the art for a new method and fully automated apparatus that purifies and concentrates generator-produced ⁶⁸Ga eluate. The required apparatus should be easily adaptable for use with ⁶⁸Ga eluate produced from different ⁶⁸Ge/⁶⁸Ga generators which are commercially available and expecting further development.

A comprehensive project for ⁶⁸Ga generator development has been implemented in ANSTO, starting with synthesis of inorganic sorbents which offer suitable sorption/elution performance for useful ⁶⁸Ga generator system (high ⁶⁸Ga elution yield, low breakthrough of ⁶⁸Ge parent nuclide, and high chemical and radiation stability), followed by generator design and setup. A newly developed purification–concentration process using mild aqueous solutions was also developed to provide effective and safe ⁶⁸Ga production. As a result of our project, a radioisotope generator coupled/integrated with post-elution purification concentration (PC) processing apparatus [radioisotope generator integrated system (RADIGIS)], specially designed for ⁶⁸Ga solution processing (RADIGIS-⁶⁸Ga), has been developed. This system is a benchtop ⁶⁸Ga generator coupled with a programmable and automated purification–concentration processing unit. The first version of RADIGIS-⁶⁸Ga system (Model GAG-1-Plus), operated with the single PC column process and manual neutralization of purified ⁶⁸Ga solution, was developed in ANSTO. The second version (MEDI-Ga-2) with additional improved functions, including automatic neutralizing/conditioning process and alternative dual-PC column purification–concentration operation, is recently developed by MEDISOTEC. An automatic elution process ensures a low radiation dose exposure and reliable long-time operation for safe and cost-effective production of reproducible high-quality ⁶⁸Ga solution product. This system makes the ⁶⁸Ga production process safer and friendly to moderately skilled operators available in a daily hospital environment.

2 Nuclear Characteristics and Radioactive Transformation Equilibrium

The nuclear characteristics and principal decay scheme of ⁶⁸Ge and ⁶⁸Ga are shown in Fig. 1. The radioactive transformation equilibrium of the radionuclide pair ⁶⁸Ge/⁶⁸Ga is presented in Fig. 2. The half-life of the parent nuclide ⁶⁸Ge is much longer than that of the daughter ⁶⁸Ga, so this equilibrium is considered as a transient/secular process for which the maximum ⁶⁸Ga build-up time t _{100% Build-up} is calculated using the equation $t_{{100\% \,{\text{Build}}-{\text{up}}}} = [\ln (\lambda_{{{\text{Ga}} - 68}} /\lambda_{{{\text{Ge}} - 68}} )]/(\lambda_{{{\text{Ga}} - 68}} - \lambda_{{{\text{Ge}} - 68}} )$ , and the approximate time required to reach 50% of the maximum ⁶⁸Ga build-up is $t_{{50\% \,{\text{Build}}-{\text{up}}}} = [\ln (2 \cdot \lambda_{{{\text{Ga}} - 68}} /(\lambda_{{{\text{Ga}} - 68}} + \lambda_{{{\text{Ge}} - 68}} ))]/(\lambda_{{{\text{Ga}} - 68}} - \lambda_{{{\text{Ge}} - 68}} )$ .

Fig. 1

Nuclear characteristics and principal decay scheme of ⁶⁸Ge and ⁶⁸Ga (Eckerman and Endo 2011; Browne and Firestone 1986)

Fig. 2

Transient/secular equilibrium and radionuclide generator kinetics for the system ⁶⁸Ge/⁶⁸Ga

3 ⁶⁸Ge/⁶⁸Ga Separation and ⁶⁸Ga Generator

3.1 Nanocrystalline Ceramic Structure Sorbent Used for Chromatographic ⁶⁸Ge/⁶⁸Ga Separation

Sorbent synthesis: The synthesis methods were detailed in our previous work (Le et al. 2007, 2009a, b; Le 2011a, b). Briefly, the sorbent comprises a porous nanocrystalline powder of a metal oxide or mixed metal oxide. A process for making the sorbent comprises several steps: reacting a metal halide or a mixture of metal halides and an alcohol to form a gel, heating the gel to activate the condensation and/or polymerization reaction for the formation of a particulate material, exposing the particulate material to an oxidant to completely convert the metals to tetravalent state, and heating the powder to a temperature sufficient to at least partially melt or sinter particles of the powder so as to form the sorbent. In an example of the reaction, the following reactant mixtures, with different reactant ratios, have been used to prepare a range of different sorbents:
- 0.5 mol ZrCl₄ + 0.5 mol TiCl₄ + iPrOH for the sorbent ZT-11
- 0.75 mol ZrCl₄ + 0.25 mol TiCl₄ + iPrOH for the sorbent ZT-31
- 1.0 mol ZrCl₄ + iPrOH for the sorbent ZiSORB
- 1.0 mol TiCl₄ + iPrOH for the sorbent TiSORB

An exothermal chemical reaction starts immediately, raising the temperature of the reaction mixture at the end of reactant addition. The condensation reaction of the reactants is allowed to proceed under heating of the reaction mixture with thermostat control. The solid polymer gel material in powder form with particle sizes from 0.10 to 0.01 mm is then left to cool at room temperature overnight before starting further chemical treatment.

The solid polymer gel powder is treated in an alkali solution which contains oxidizing agent NaOCl: about 10 mL 0.5 M NaOH solution containing 1% by weight NaOCl is used per gram of solid polymer gel powder. The solid powder/oxidant solution mixture is gently shaken using a mechanical shaker for at least 4 h so as to convert the gel structure solid powder into a macroporous solid powder and to convert any lower-valence metallic ions to their original 4+ valence. The volume of solution required per gram of solid gel powder is determined so that the pH of solution at the process end is between 2 and 5. The solid matter is then separated by filtering through a sintered glass filter, washed several times with double-distilled water to remove all dissolved sodium and chloride ions, and dried at 80°C for 3 h to dryness to obtain a white solid powder. The resulting white solid powder is heated at a temperature in the range from about 500°C to about 900°C (the actual temperature depending on the particular sorbent being prepared). This may be conveniently performed in a furnace. A suitable heating time is about 3 h. The heating allows the nanoparticles of the powder to recrystallize and melt, and partially fuse so as to produce a solid powder of crystalline structure. The partial fusion and surface coordinative connection are thought to cross-link the particles to create a hard porous matrix of solid material. The initially formed solid is commonly in the form of white solid powder particles composed of different clusters of greater than about 100 nm in size. The clusters are aggregates of amorphous and semicrystalline nanoparticles (less than about 5 nm). The clusters appear to be held together by weak hydrogen bonds and van der Waals bonds. Consequently, the aggregate particles are macroporous and soft. During high-temperature heating (sintering) the amorphous and semicrystalline nanoparticles (less than about 5 nm) crystallize to form crystalline nanoparticles inside clusters. Simultaneously, these crystalline nanoparticles partially melt and combine with other nanoparticles inside the same cluster with interfacial coordinatively-bond/ordered structure to form larger porous crystalline particles. Because there is longer distance between the clusters than between nanoparticles within a single cluster, the nanoparticles belonging to different clusters do not combine with each other to form a single mass. Adjacent nanoparticles on the surface of clusters fuse to a limited area of the cluster surface to form a bridge to crosslink the clusters (at this stage, the clusters have already become larger crystalline particles) to form sorbent particles. In this way, meso/macroporosity formed between the former clusters can be maintained.

The high chemical and mechanical stability of the product is thought to result at least in part from the formation of stable crystalline monophase in the solid material. The crystalline structure of the product is stable when exposed to high radiation doses from radioactive materials. Doping by different amounts of metal ions (for example, Ti, Sn, or Ge) added to the zirconium chloride solution in the synthesis is thought to be responsible for a stabilized crystalline phase which makes the product chemically and mechanically stable. The doping of smaller ions, Ge⁴⁺(radius 0.53 Å), Ti⁴⁺ (radius 0.605 Å) and Sn⁴⁺(radius 0.69 Å), onto the matrix of larger ions Zr⁴⁺(radius 0.8 Å) facilitates isomorphism-based adsorption of ⁶⁸Ge⁴⁺ ions from its acidic solution. The powders obtained using the above process have high stability and high porosity and may be used as a state-of-the-art sorbent for different chemical separation processes, for example, for separation of highly radioactive materials.

At the end of this heating process, the resulting powder is sieved. In particular, the fraction of particle size between about 50 and about 100 μm may be collected to be used as a sorbent for chromatographic column packing applied to chemical separation processes.

Structure and adsorption characteristics: The sorbents of a Ti-Zr ceramic structure (Le et al. 2011a, b) were used as a generator column packing material. Scanning electron microscopy (SEM) images showing the micro- and mesoporosity of the sorbent materials synthesized above are shown in Fig. 3. A tetragonal nanocrystalline Ti-Zr ceramic structure is present. A typical X-ray diffraction pattern of these sorbents is shown in Fig. 4.

Fig. 3

SEM image of the Ti-Zr ceramic sorbent used for loading ⁶⁸Ge/⁶⁸Ga generator column. Sorbents: a ZT-11, b ZT-31, c ZiSORB, and d TiSORB

Fig. 4

Tetragonal structure X-ray diffraction pattern of nanocrystalline ceramic sorbent ZT-31

The adsorption capacity for Ge⁴⁺ ions is approximately 120 mg Ge per gram sorbent in 0.1 M HCl solution. The distribution coefficient K _d >10,000 mL/g for carrier-free ⁶⁸Ge⁴⁺ ions and 2 mL/g for ⁶⁸Ga³⁺, when evaluated in 0.1 M HCl solution.

Strong adsorption of ⁶⁸Ge⁴⁺ ions is supposed to result from chemically coordinative bonds formed between germanium and oxygen atoms in the solid matrix of the sorbent material. The similar ionic radius of Ge⁴⁺ and Ti⁴⁺ ions (0.53 and 0.605 Å, respectively) facilitates isomorphism-based adsorption (doping) of ⁶⁸GeO₄ groups onto the (ZrTiO₄)_nmatrix of the sorbent. The larger radius of the main component Zr⁴⁺ ions (0.8 Å), playing the role of the backbone of the solid matrix in the sorbent, reduces the bonding power of TiO₄ groups doped into the (ZrTiO₄)_nmatrix, and hence the rate of isomorphic doping/sorption of ⁶⁸GeO₄ groups will be enhanced. So, the strong adsorption of ⁶⁸Ge⁴⁺ ions onto the Zr-Ti matrix-based ceramic sorbents is supported by an isomorphic incorporation mechanism. In contrast, the weak adsorption of Ga³⁺ ions is attributed to an amorphism process. The strong adsorption of Ge⁴⁺ ions supposed above is valued for other sorbents of similar structure, (ZrSnO₄)_n and (ZrGeO₄)_n, which are recently investigated in our laboratories (Le 2011a, b).

3.2 ⁶⁸Ga Generator Setup

Generator design: As discussed above, the sorbents synthesized above may be used to produce a ⁶⁸Ga generator (Figs. 13 and 14a). A chromatographic column is packed with the sorbent. A stock acidic ⁶⁸Ge solution is applied to the column to immobilize the ⁶⁸Ge parent nuclide on the sorbent. As the ⁶⁸Ge decays to generate the daughter nuclide ⁶⁸Ga, ⁶⁸Ga³⁺ ions are formed and weakly adsorbed on the column. Eluting the column with a dilute acidic solution will therefore generate a ⁶⁸Ga-containing eluate. Because the sorbent has much higher adsorption affinity for ⁶⁸Ge than for ⁶⁸Ga, the acidic eluate contains mainly ⁶⁸Ga³⁺ ions and a significantly lower amount of ⁶⁸Ge (⁶⁸Ge breakthrough). An apparatus or generator for separating ⁶⁸Ga from ⁶⁸Ge ions may therefore comprise: a column made from radiation-resistant material such as quartz glass and thermoplastic and having a column inlet and outlet, provided with filter fritted diskettes on both ends and closed by a plastic septum together with silicon rubber gaskets and being capped by aluminum clamping lids; a radiation protection shielding lead housing surrounding the column, provided with two ports for tubing to the column outlet and inlet; an acidic eluent supply system coupled to the sorbent column inlet; a pump to pass eluent or other liquid through the column as required, located downstream of the column and operating by suction; an outlet valve coupled to the column outlet, to stop the eluent or direct it to a product container; and an electronic controller for generator operation, designed to make the process reproducible and radiation safe.

To avoid any possible contamination by metallic ions of the ⁶⁸Ga solution produced by the ⁶⁸Ga generator, all components of the generator, including the chromatographic column and tubing lines, should be made of nonmetallic materials.

Due to the long half-life of the parent nuclide ⁶⁸Ge, the radiation stability of the nonmetallic materials used in the ⁶⁸Ge/⁶⁸Ga generator design should be evaluated to ensure an advantageously long operating lifetime of the ⁶⁸Ga generator. The radiation exposure dose of the materials used for the generator column and its fritted diskettes were therefore estimated for the generator design. The PEEK material intended to be used in the design of the generator column can withstand any radiation doses likely to be sustained during service. PEEK 450G can withstand over 1,000 Mrads (10 MGy) without any loss of mechanical properties. Radiation exposure from a single loading of 100 mCi of ⁶⁸Ge into the column is less than this 1,000 Mrads value (as shown below), and therefore radiation exposure is not a problem for the PEEK column. Using MicroShield software, the initial dose rate from the unshielded 100 mCi ⁶⁸Ge source is calculated to be 25 mGy/h at contact. It is assumed that the dose from the isotope is negligible after 10 half-lives (i.e., 68,880 h) and then the total dose can be calculated as follows: $D = \int_{0}^{68,880} {25\text{e}^{ - 0.0001t} } {\text{d}t} = 249.7\,{\text{Gy}}.$ The exposure limits of 2,600 Gy and 3,321 Gy for the 2-mm column segments of the PEEK column and its quartz frits, respectively, show that these generator parts are capable of withstanding the dose from the ⁶⁸Ge/⁶⁸Ga radioisotopes for the entire life of the isotope (10 half-lives). This is based on the conservative assumption that the entire dose is absorbed by the column for a single-use package.