99Mo/99mTc separation - Health Advance

Nuclear Medicine and Biology 40 (2013) 167–176

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99

Mo/ 99mTc separation: An assessment of technology options

Ashutosh Dash a, F.F. (Russ) Knapp Jr. b, M.R.A. Pillai a,⁎ a b

Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Mumbai 400 085, India Medical Isotopes Program, Isotope Development Group, MS 6229, Oak Ridge National Laboratory (ORNL), PO Box 2008, Oak Ridge, TN 37831, USA

a r t i c l e

i n f o

Article history: Received 17 September 2012 Received in revised form 5 October 2012 Accepted 5 October 2012 Keywords: 99 Mo/99mTc generator (n,γ)99Mo Chromatography Electrochemical separation Nanomaterial Post elution concentration Solvent extraction Supported liquid membrane (SLM) Zirconium molybdate gel generator (ZMG)

a b s t r a c t Several strategies for the effective separation of 99mTc from 99Mo have been developed and validated. Due to the success of column chromatographic separation using acidic alumina coupled with high specific activity fission 99Mo (F 99Mo) for production of 99Mo/99mTc generators, however, most technologies until recently have generated little interest. The reduced availability of F 99Mo and consequently the shortage of 99Mo/99mTc column generators in the recent past have resurrected interest in the production of 99Mo as well as 99mTc by alternate routes. Most of these alternative production processes require separation techniques capable of providing clinical grade 99mTc from low specific activity 99Mo or irradiated Mo targets. For this reason there has been renewed interest in alternate separation routes. This paper reviews the reported separation technologies which include column chromatography, solvent extraction, sublimation and gel systems that have been traditionally used for the fabrication of 99Mo/99mTc generator systems. The comparative advantage, disadvantage, and technical challenges toward adapting the emerging requirements are discussed. New developments such as solid-phase column extraction, electrochemical separation, extraction chromatography, supported liquid membrane (SLM) and thermochromatographic techniques are also being evaluated for their potential application in the changed scenario of providing 99mTc from alternate routes. Based on the analysis provided in this review, it appears that some proven separation technologies can be quickly resurrected for the separation of clinical grade 99mTc from macroscopic levels of reactor or cyclotron irradiated molybdenum targets. Furthermore, emerging technologies can be developed further to respond to the expected changing modes of 99mTc production. © 2013 Elsevier Inc. All rights reserved.

1. Introduction Technetium-99m is the common medical radionuclide estimated to be used in about 30 million medical diagnostic procedures annually throughout the world [1–4]. Considering the immense diagnostic value provided by the routinely used twenty odd 99mTc labeled imaging agents, it is expected that 99mTc will continue its central role in diagnostic nuclear medicine into the future [5]. Availability of 99m Tc for preparation of diagnostic agents is ensured in the form of the widely used 99Mo/ 99mTc alumina column generator from which 99m Tc is separated under aseptic conditions. The in vivo use of 99mTc is regulated by various governmental regulatory agencies such as FDA. The role of separation sciences in meeting the stringent requirements with respect to the purity and quality of the separated 99mTc cannot be overstated. With the ready availability of fission 99Mo (F 99Mo) of required quality and quantity relatively inexpensively in the world market along with the mature alumina column generator technology, the need to implement alternative 99mTc separation technologies did not exist until recently. The need for such technology advances changed ⁎ Corresponding author. Fax: +91 22 25505151. E-mail address: [email protected] (MRA. Pillai). 0969-8051/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.nucmedbio.2012.10.005

after 2007, when a variety of factors, well described in the literature [6,7], resulted in the reduced availability of 99Mo/ 99mTc generators in the World market. The need for phasing out highly enriched uranium (HEU) together with the uncertainty in the continued use of a few ageing reactors for the production of F 99Mo is prompting the development of alternative sources of 99mTc. The current strategy of availing 99mTc is expected to undergo significant changes in the near future; however, without exception every new technology will need separation of 99mTc from either active or inactive molybdenum. A variety of alternative options including both reactor and accelerator paths are evolving for sustainable production of 99Mo or 99m Tc directly for clinical use [8]. Hence, there is a need to develop separation technologies compatible to the new modes of 99mTc production. One of the suggested possibilities is to utilizing additional reactors for 99Mo production by (n,γ) activation of natural molybdenum targets [9,10]. There is an ongoing discussion to use 98Mo enriched targets for production to enhance the specific activity and the activity produced, although the economics of this option are yet to be demonstrated [11]. There are several alternate production routes for the production of 99Mo [8,12–25], and photon/proton activation of enriched 100Mo for production of 99Mo or direct production of 99mTc appears to emerge as a potential alternative in the near future. Recovery by suitable separation techniques for the effective

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A. Dash et al. / Nuclear Medicine and Biology 40 (2013) 167–176

separation and recycling of enriched targets is a pre-requisite for ensuring the economy of these production strategies. The emergence of professionally run central radiopharmacies has drastically reduced the number 99Mo/ 99mTc generators needed, although, higher activity levels per generator are required in such set up. Central radiopharmacies are manned with skilled staff and hence generators based on alternate separation techniques which need more manipulation would be expected to be accommodated, provided there is cost savings. Radiopharmacy operations have matured over the years thanks to the evolution of automated modules developed for [ 18 F]FDG synthesis and similar automation technologies could be easily adapted for the separation of no carrier added (NCA) 99mTc from molybdenum having different specific activities [26]. The 99Mo/ 99mTc generator is expected to undergo a paradigmatic shift from the present designs owing to changes in the source of production of 99Mo and altered user profiles. In order to sustain the diagnostic nuclear medical imaging services using 99mTc, it is of utmost importance to assure access to appropriate separation technologies that will provide clinical grade 99mTc irrespective of the source of 99Mo. In light of the necessity to provide 99mTc of pharmaceutical purity when F 99Mo is not used, proven separation technologies are expected to be quickly resurrected. At the same time, emerging technologies can be nurtured in an appropriate manner to respond to the foreseeable changes in accessing 99mTc. Exploiting alternative separation strategies will pose several challenges and will require a thorough assessment to evaluate their prospects. The choice of an effective separation process to provide 99m Tc from 99Mo is based on a number of considerations. • The physical or chemical techniques used should have high throughput capabilities. • The separation process should be rapid to reduce the decay losses of 99m Tc as well to minimize the 99gTc content in the separated product. • The yield of 99mTc should be high. • Reproducible radionuclidic, radiochemical and chemical purity of 99m Tc should be within the pharmacopeia acceptable range. • Radioactive concentration (RAC) of the separated 99mTc should be adequate to permit radiolabelling using current generation of kits. • Human intervention should be minimal. • Technetium-99 m should be obtained in a ready to use form preferably in 0.9% NaCl and compatible with the existing freeze dried kits. To a large extent, progress in the design of 99Mo/ 99mTc generator systems is dependent on the advances in separation technology described in the literature [27–38]. Since the 1982 publication of the well-known review by Boyd [29], many new technologies have

Table 1 Various methods used for the separation of the

99m

Tc from

developed which have formed the basis for evaluation of other strategies to separate 99mTc from molybdenum. The goal of this article is to provide an update of the current advances in this field to serve as a resource for scientists developing alternative strategies directed to enhance availability of 99mTc for continued clinical use. This review focuses on a broad discussion on the present status, advances achieved over the past and a perspective of different types of separation techniques on evolving 99Mo/ 99mTc separation systems. Because of the multitude of techniques available to separation scientists, speculative options mainly of academic interest are not included. We focus instead on existing and emerging concepts which are currently in use or which have made substantial progress or likely to be materialized in the foreseeable future. There are many methods available for the separation of 99mTc from molybdenum and in most cases choice of the separation method is dictated by the mode of 99Mo production. Several separation processes summarized in Table 1 are based on differences in physical and chemical properties that have been studied and have the potential for routine current codes of good manufacturing practices (cGMP) separation of the 99mTc from 99Mo. In the following sections, an overview on the different types of 99m Tc separation techniques, their utility, relative strengths and weakness are summarized; and possibilities for their application in separation of 99mTc from 99Mo are evaluated. Selection of a separation process is primarily aimed at simplification of the overall 99mTc separation and maximizing the yield. Amenability for safe operation on the small scale as individual units at central pharmacies or nuclear medicine departments is also an important criterion for choosing a particular separation processes. Many new separation techniques have considerable potential and may pave the way for developing state-of-the-art 99Mo/ 99mTc separation systems adaptable to existing and future demands. 2. Column chromatography The principle of column chromatography is based on the differences in adsorption of 99Mo and 99mTc in response to an adsorbent. The goal is to have a high binding (high KD) of the parent ( 99Mo) to the adsorbent with a low KD for the decay product ‘daughter’ ( 99mTc), which can then be readily and reproducibly removed on demand by using a suitable eluent. When performing 99 Mo/ 99mTc separation, there are many aspects that must be considered which include the separation scheme, column type, column dimension, quality of column bed, chemical nature of the adsorbent, pre-treatment of column bed, adsorbent loading technique, species of interest to be separated, sample throughput, and reagent usage for elution of the daughter radionuclide. In the quest for

99

Mo.

Separation method

Physical/chemical property for parent daughter separation Basis

Relevant references

Column chromatography

Charge

[39–41]

Electrochemical

Standard electrode potential (Eo)

Extraction chromatography

Specific chemical interaction

Precipitation Solvent extraction

Solubility Hydrophobicity

Solid-phase column extraction

Hydrophobicity

Sublimation Vapor pressure Supported liquid membrane (SLM) Chemical energy

Thermochromatography

Vapor pressure

Selective adsorption on an adsorbent by the target species Selective electrodeposition of the target species on an inert electrode. Selective extraction of the target species by an extractant immobilized on an inert support. Precipitation of target metal with an added reagent. Selective transfer of target species to a second immiscible solvent. Adsorption on an adsorbent followed by selective desorption of the target species by an organic reagent. Selective sublimation of target metal Selective extraction of the target species in a porous hydrophobic membrane support, and further movement to an aqueous phase. Fractionation of sublimed materials through a column having temperature gradient.

[42,43] [44,45] [46,47] [48,49] [50,51] [52,53] [54,55]

[56,57]

A. Dash et al. / Nuclear Medicine and Biology 40 (2013) 167–176 Table 2 Comparison of alumina column chromatographic generators fabricated from fission

99

Mo and (n, γ)

99

Mo.

99

Description

(n, γ)

Time required for preparation of column chromatographic generator. 99 Mo specific activity Minimum size of the generator % 99mTc recovery 99 Mo breakthrough⁎

N2 hours b111 GBq (3 curies)/g 2 cm(ϕ) × 4 cm (h) 40-90 % in 10 mL of isotonic saline ~10-3

⁎ Expressed as % of available

169

Mo

Fission

99

Mo

b5 minutes N37 TBq (1,000 Ci)/g b0.3 cm (ϕ) × l cm (h) ~95 % in b 4 mL of isotonic saline ~10-4

99

Mo product.

an effective adsorbent to realize the scope of separation of 99mTc from 99 Mo, a variety of sorbents such as hydrous zirconium oxide [58], hydrous titanium oxide [59], manganese dioxide [60,61], silica gel [62], hydrotalcites [63], etc., have been investigated over the years. Given the simplicity of adsorbing F 99Mo of required quantity and the ease of availing 99mTc with 0.9% NaCl, the alumina column chromatographic generator using F 99Mo emerged as the most practical separation system used in 99Mo/ 99mTc generators [3,39,40,41,64–67]. While use of F 99Mo based alumina chromatographic generator constitutes a major step on the availability of 99mTc for routine clinical applications, the limited capacity of alumina for adsorbing molybdate ions (2–20 mg Mo per g of alumina) is the major impediment that continues to discourage efforts of using this procedure with (n,γ) 99Mo, which is of low specific activity as compared to F 99Mo. The specific activity of (n,γ) 99Mo is b 111 GBq(3 Ci)/g even when produced in high flux research reactor as compared to N 37 TBq (1,000 Ci)/g for F 99Mo. A point to be noted is that irrespective of the specific activity of 99Mo, the 99mTc eluted will be no carrier added. Comparison of the column chromatographic 99Mo/ 99mTc generator based on F 99Mo and (n,γ) 99Mo [41,68] is depicted in Table 2. Owing to the relatively low specific activity, use of (n, γ) 99Mo requires a very large alumina column to adsorb useful quantities of 99Mo for fabrication of clinical-scale 99Mo/ 99mTc generators. The larger size of the chromatographic column not only becomes bulky but also requires larger eluate volumes to recover the 99mTc. Subsequently, the radioactive concentration (RAC) of the eluate can become unacceptably low for direct formulation of radiopharmaceuticals using ‘freeze-dried’ kits. In order to circumvent such limitations, researchers have focused on developing a wide range of alternative chromatographic techniques adaptable with (n,γ) 99Mo, some of which are discussed below. 2.1. Column chromatography using high capacity sorbents Development of high capacity sorbents capable of adsorbing much larger quantities of Mo such as the poly zirconium compound (PZC) [69], poly titanium oxychloride [70] and synthetic alumina functionalized with a sulfate moiety [71,72], is a promising strategy to prepare column-based generators using the (n,γ) 99Mo. While the capacity of alumina is confined to 2–20 mg/g, the capacity of these sorbent materials can be as high as 200–500 mg/g. Although the development of high capacity sorbents seems to be an effective strategy for achieving the objectives, the inherent drawbacks of these sorbents include loading of radioactive 99Mo solution into the sorbent by batch process, difficulties in realizing optimum capacity owing to slow kinetics of sorption and requirement of a post purification column to achieve requisite 99mTc purity and RAC. These sorbents could still be of interest and utility in the future if adequate consideration is given to ensure that these constraints can be effectively addressed. 2.2. Column chromatography using nanomaterial based sorbents In recent years, the field of nano sized materials has stimulated the attention of scientists in diverse fields. Owing to the high surface area

and intrinsic surface reactivity, nanomaterial based sorbents possess much higher sorption capacity compared to the conventional sorbents. In order to tap the potential of nanomaterials as a sorbent in the relatively unexplored field, several nanomaterial based sorbents have been reported for the preparation of chromatographic radionuclide generators using (n,γ) 99Mo [73–75]. By careful optimization of the synthesis procedure, it is estimated to be possible to prepare novel materials that could provide sorption capacity up to 500 mg of 99Mo/g. Preparation of a 13 GBq (350 mCi) generator using 99Mo of specific activity of 14.8 GBq (400 mCi)/g using nanocrystalline γ-Al2O3 has recently been demonstrated [75]. This strategy of using nanocrystalline γ-Al2O3 as column matrix is especially useful for manufacturers having accessibility to medium-high flux research reactors (N3 × 10 14 n/cm 2/sec) where in 99Mo of specific activity N 2 Ci (74 GBq) can be obtained with natural 99Mo targets. High activity (0.5 to 2 Ci, 18.5 to 74 GBq) generators can be prepared easily using the above nanomaterials and 99Mo obtained from medium-high flux reactors. The shielded generator assembly as well as elution procedure can be identical in design to the existing alumina based generators. 2.3. Multicolumn selectivity inversion (MSIG) generator An alternative to the conventional radionuclide generator system is the multicolumn selectivity inversion (MSIG) generator [76–78] in which 99Mo is stored in solution and passed through a chromatographic column (primary separation column, PSC) specific for 99mTc wherein 99mTc is selectively retained, stripped, and passed through a second guard column that retains any 99Mo or other 99mTc interfering ions. 99mTc is then recovered in a small volume of eluate (0.9% NaCl) solution. Since the MSIG selectively retains eventually carrier-free 99m Tc, the column size and the elution volume are essentially independent of the parent nuclide specific activity. Such a possibility has been demonstrated in the laboratory scale and extended for making automated module [26,79]. NorthStar Medical Radioisotopes, LLC has developed an automated 99mTc separation unit, ‘TechneGen™’ [80] that uses low-specific activity 99Mo and consists of a primary separation column containing ABEC resin with an alumina (Al2O3) guard column. Technetium-99m obtained from, TechneGen, meets the United States Pharmacopeia (USP) requirements. This new generator system is currently in the process of being validated for nuclear pharmacy use through a New Drug Application (NDA) filed with the U.S. Food and Drug Administration. 2.4. Post elution concentration technique One of the possible pathways to enhance the radioactive concentration (RAC) of the pertechnetate availed from an alumina based column chromatographic generator using (n,γ) 99Mo is the use of a ‘post elution concentration’ technique. This method consists of passage of the generator eluent through an ion exchange column to trap ‘no-carrier-added (NCA)’ levels of 99mTc, followed by elution in a small volume of normal saline. This strategy has been evaluated and was originally developed for concentrating 188Re obtained from alumina-based 188 W/ 188Re generators [81] but can be also successfully adapted for 99Mo/ 99mTc generators [82–85].

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3. Solvent extraction The process of selective extraction of technetium from an equilibrium mixture of 99Mo/ 99mTc exploits the differences in their solubility in two immiscible liquid phases and is the basis of the solvent extraction technique. There are two main categories for solvent extraction, which include conventional solvent extraction utilizing two immiscible liquids and the aqueous biphasic system (ABS) making use of two immiscible water soluble polymers. 3.1. Conventional solvent extraction Conventional solvent extraction separation is based on the partitioning of the 99mTc between the aqueous phase and an organic solvent immiscible with water. The solvent extraction technique for the separation of 99mTc was originally demonstrated using methyl ethyl ketone (MEK) [48,86–91]. More recently solvent extraction has gained further attention and a wide variety of systems have been proposed. These systems include cetyl trimethylammonium bromide (CTAB) [49], methylene blue/nitrobenzene [92], trioctylamine [93], 4-(5-nonyl)pyridine [94] and crown ether 2,3,11,12dibenzo1,4,7,10,13,16-hexaoxacyclooctadeca-2,11-diene/DB18C6/ diluted with nitrobenzene [95]. Among these MEK, popularly known as the MEK extraction method, has been the most widely evaluated. The MEK extraction processes seemed very attractive as it would allow the convenience of using (n,γ) 99Mo by reactor activation of MoO3 targets and at the same time offer the production of 99mТс with high radioactive concentration. The MEK extraction process had been validated to provide 99mTc for human use [96–98] and offers the following advantages. • Technique permits the use of low-specific activity (n,γ) 99Mo produced by reactor activation of MoO3 targets having 98Mo of natural isotope abundance. • High separation efficiency of 99mTc is attainable. • System and 99mTc produced are inexpensive compared to chromatographic column generators. • Has the flexibility to scale up or down to its level of operation in response to requirements. • The 99mTc obtained by this MEK extraction method has been reported to be of good quality in terms of radionuclidic, radiochemical and chemical purity. • Process provides 99mTc of high radioactive concentration. • Separation efficiency and product purity remain unchanged with repeated extraction of 99Mo stock solution. • Can be easily automated. Some concerns that have been raised on the use of this technique include • Use of the flammable solvent MEK requires very high degree of robustness of the operational systems for addressing safety issues. • Apparatus currently used to perform extraction is complex, bulky and requires a high degree of manual control. • Process of extracting 99mTc is a tedious, time-consuming and multiple steps of careful operation are needed. • MEK is susceptible to radiation degradation. • Operational problems may be frequently caused by poor phase separation and would not only lead to poor 99mTc yield but also add 99Mo contaminants. • Evaporation of the flammable solvent MEK by heating needs adequate safety measures owing to the low flash point (− 9 °C) of MEK. • Possible chances of polymeric organic contamination along with aldol impurities in the 99mTc product which has detrimental effects during subsequent radiolabelling reactions.

• The MEK process is conducted in an open system and necessitates use of a terminal sterilization of extracted 99mTc prior to clinical application. While the MEK extraction method was extensively used in the late 1960s [99], this method had been abandoned in favor of the alumina column generator technology with F 99Mo for its ease of use and relative safety. However, this method would be expected to be quickly revived. The developments in automated modules and better understanding of the process have led to the resurgence in interest of this technology [100,101]. This concept has been successfully implemented in Russian Federation, where it is currently used for the production of 4.44 TBq (120 Ci) of 99mTc for distribution to 21 diagnostics centers of St. Petersburg [102]. Using similar technology, ‘Medradiopreparat’ plant in Moscow regularly produces 99mTc and supplies to various clinics in the city. M/s Center ‘Atommed’, Moscow, Russia has developed a computer controlled semi-automatic 99mTc delivery system based on the MEK extraction of 99mTc followed by ion-exchange purification. The system is capable of handling 296 GBq (8 Ci) of 99Mo [103]. This automated system as small scale individual units can be safely operated with care at central pharmacies. 3.2. Aqueous biphasic system (ABS) Rogers et al. [104–107] have introduced another dimension to the applications of solvent extraction technology by using polyethylene glycol-based aqueous biphasic systems (ABS) to obtain concentrated solution of 99mTc from (n,γ) 99Mo. An advantage of using ABS would be that the pertechnetate is eluted using aqueous salt solution, rather than an organic solvent, which significantly simplifies the downstream purification and reduces the risks of organic solvent contamination. One of the major drawbacks of ABS is the necessity to strip the two-phase system between runs that not only makes the extraction complicated but is also associated with all the disadvantages of solvent extraction generators. In order to obviate such shortcomings, an Aqueous Biphasic Extraction Chromatography resins (ABEC resin) was developed jointly at Argonne National Laboratory and Northern Illinois University that can be adapted in chromatographic mode for selective extraction of pertechnetate from alkaline solution. Eichrom Industries, Inc. has licensed this technology to produce ABEC resin [108]. The concept of using ABEC resin seems attractive as it would offer the convenience of column based separation system. ABEC resins are successfully used in the preparation of 99Mo/ 99mTc generators [109–114]. 4. Thermo separation 4.1. Sublimation The strategy to obtain pure 99mTc from bulky masses of (n,γ) 99Mo by sublimation by making use of the differences in the volatilization properties of oxides of molybdenum and technetium has been widely explored by various institutions [29,52,53,115–126]. Sublimation generators were previously used in Australia for centralized production [29] which can produce multi-Curie quantities of 99mTc activity, but with only 20–25% yields. Subsequent refinement efforts in Hungary led to an increase in 99mTc yields up to ~ 50% [125]. Sublimation technology is more suited for centralized production of 99m Tc and has the following advantages: • Technique offers the scope of using low-specific activity (n, γ) 99 Mo produced by reactor activation of MoO3 targets of natural isotope abundance. • Neutron irradiated MoO3 targets can be directly used without chemical processing. • Physical process, precludes use of external chemical reagent.


• Process is capable of being scaled up from small batch sizes to multi curies quantities in a simple manner. • Provides 99mTc of high radionuclidic purity. • Generates relatively low level of radioactive waste. • Amenable for repeated 99mTc distillation. This process has the following shortcomings that would be expected to obstruct the path toward wide scale utility. • Distillation apparatus is bulky, expensive and complex and requires a high degree of safety measures. • Need to perform high temperature operations, typically several hundred degree centigrade on a very regular basis is a major disincentive. • Requires skilled workforce and the observance of strict safety measures of highest standards. • Any system failure will not only reduce the 99mTc yield but also cause associated radiation hazard in the operational area. • Separation efficiency only up to 50% is attainable. • Open system and necessitating a terminal sterilization of distilled 99mTc prior to clinical application. 4.2. Thermochromatography As the name suggests, thermochromatography (TC) is a high temperature gas-phase separation method akin to the sublimation method in which volatilized species are transported along a column maintained in a temperature gradient. As the sublimed and vaporized materials pass through the column, they are progressively condensed and collected at successive locations in the cooling zone and thus separated from one another in the form of deposits [56,126–131]. A schematic representation of the thermochromatography separation concept is shown in Fig. 1. More recently, the thermochromatographic approach has been successfully utilized for the separation of 94mTc from 94MoO3 [57,132]. This recent method could be readily adapted Thermochromatographic column

Outer column

Air (oxygen)

Low temperature zone

High temperature zone

Material Oven

Fig. 1. Thermochromatography separation concept. In the presence of moist air as carrier gas and at an oven temperature of 1,090 °C, both MoO3 and HTcO4 are sublimated. In this thermochromatography column MoO3 condenses in the temperature zone of 600–800 °C and HTcO4 migrates further and is condensed at a temperature zone of 250–350 °C.

171

for separation of 99mTc from 99Mo. Advantages of thermochromatography technique are the following: • Technique not only provides opportunity to use low-specific activity (n, γ) 99Mo but also offer the scope of using metallic target. • Precludes the necessity of chemical processing of neutron irradiated target. • Process is well suited for small to medium batch size and could be easily scaled up to larger batch sizes to match demand. • High radionuclidic purity of 99mTc is attainable. • Distillation can be performed repeatedly using the same set up. • Enables recycling of target materials. Despite the above advantages, the process has the following weakness. • Challenges associated with the sustained operation of high temperatures process on a reliable and continuous basis. • Requires additional safety measures to preclude the probability and consequences of radioactive vapor release. • Complex process equipment requiring frequent maintenance. • Requires skilled workforce to perform the thermochromatography separation of 99mTc on a reliable basis. • Version suitable for separation of clinical scale 99mTc activity is yet to be realized and tested. Despite the above shortcomings, the scope of using thermochromatographic concept still is of interest and utility if adequate technological attentions are given to make a compact automated module to ensure product consistency both in terms of purity and yield. 5. Chemical precipitation/gel generator Chemical precipitation is a conventional separation technology and involves the addition of chemical reagents, followed by the separation of the precipitated solids from the mixture. Since 99Mo is mostly present as an anion in aqueous solution, a specific precipitating reagent containing a cation is added to the mixture. A somewhat different path exploiting the differences in the solubility of zirconium salt of 99Mo and 99mTc has been followed to develop an approach popularly known as zirconium [ 99Mo]molybdate gel (ZMG) strategy in which low specific activity (n,γ) 99Mo can be used. In view of the foreseeable convenience of column chromatographic technique, ZMG granules are packed in a fixed-bed column on which the 99mTc formed from 99Mo decay is collected by passing 0.9% NaCl solution through the column. This option was originally developed by Australian scientist R.E. Boyd through a research program conducted during the 1978–1988 periods [46]. This strategy involves many intricate steps including the dissolution of (n,γ) 99Mo, precipitation into a gel form as zirconium molybdate, gel filtration, drying, gel fragmentation and column packing that necessitates significant handling of radioactivity. The above series of operations have to be performed in adequately shielded processing facility equipped with remote handling equipment by skilled personnel [47,133–135]. This strategy was subsequently pursued under an International Atomic Energy Agency (IAEA) Coordinated Research Project (CRP) [136]. The gel generator concept possesses the following advantages: • Technique offers the scope of using (n, γ) 99Mo produced by reactor activation of MoO3 targets of natural isotope abundance and at the same time offer the advantages of column operation. • Provides 99mTc of acceptable purity in 0.9 % NaCl solution amenable for radiolabelling of current generation of ‘kits’. Despite the above positive features, the concept has the following limitations: • Requirement of a capital intensive shielded facility for chemical processing of radioactive gel.

172


• Most intricate multistep complex processing procedure due to several factors influencing the gel characteristics and in turn its final performance. It is not only manufacturer unfriendly, but also could lead to inter batch variation. • The need to obtain adequate radioactive concentration of 99mTc from the generator puts a limit on the minimum specific activity of 99Mo that can be useful. • Expensive mode of providing 99mTc.

electrochemical cell by applying a potential of 5 V over a period of 1 h in NaOH electrobath maintained at pH 13 and stripped back again into the 0.9% saline solution. A schematic diagram of a proposed simple electrochemical 99Mo/ 99mTc generator is shown in Fig. 2. The generator assembly can be permanently housed in the radiopharmacy; and 99Mo solution supplemented/replaced at regular intervals. The electrochemical separation strategy possesses the following advantages:

Despite the inherent shortcomings, interestingly and surprisingly enough enthusiasm to use (n,γ) 99Mo encouraged some institutions to evaluate this pathway [137]. However, developments over the last few decades have shown that it has not yet been embraced by generator manufacturers and is being progressively phased out.

• The electrochemical route has the unique features of utilizing 99 Mo of any specific activity. • Capacity is not limited by the amount of adsorbent or extractants. • Flexibility to scale up or down the level of operation as per demand and supply. • The 99mTc obtained by this method is expected to be of better quality than that obtained from a column generator owing to the absence of radiolytic impurities that may be normally encountered in 99Mo alumina column eluants. • Process not only provides an effective way of separating 99mTc from 99Mo but also offers a means of availing 99mTc of high radioactive concentration. • Separation efficiency and product purity remain unchanged on repeated extraction. • Generation of radioactive waste is very low. • Electrochemical generator assembly/hardware has a long shelf life compared to other generators; periodic addition/replacement of 99Mo will be needed. • Amenable for automation.

6. Solid-phase extraction An alternative to solvent extraction is the separation of metal ion by direct contact of the aqueous sample with a sorbent usually using a column chromatographic technique. Desorption of the metal ion of interest can be carried out by elution with a suitable solvent or solvent mixture. Such a combination of ion exchange and solvent extraction (CIESE) technique has attracted attention [138,139]. The CIESE concept has gained interest and is directed towards the development of alternative technique for the separation of 99mTc from 99Mo [50,51,140]. In this procedure, the aqueous 99Mo solution is adsorbed as it passes through a column packed with granular support material. Technetium-99 m is then selectively desorbed from the adsorbent with MEK or another appropriate extractant. This concept offers the following advantages. • Easy operation under laboratory conditions compared to solvent extractions. • Capable of separating 99mTc with a sharp elution profiles and thus offer a means of availing 99mTc of high radioactive concentration. • 99mTc purity is superior to both column chromatography and solvent extraction technique. • Repeated extraction of 99mTc from the same column is possible. • Method minimizes the radiation exposure of operators. • Amenable for automation. Limitations of this technique include:

However, there are also shortcomings with this concept which include: • Requires skilled manpower well versed in both electrochemistry and radiochemistry.

+

_ POWER SUPPLY

V A

• Tedious multistep separation protocols. • Need to dry the column after 99Mo adsorption which is a deterrent. • Significant amount of radioactive waste is generated. This strategy thus far has been confined to laboratory-scale investigation but could still be of interest and utility if adequate technological attention is imparted. A continuing increase in the automation of this technology can be expected in near future. 7. Electrochemical separation A mixture of metal ions having adequate difference in their formal potential values in an electrolytic medium can be mutually separated by selective electrodeposition of one metal on an electrode surface under the application of the applied potential. The potential of electrochemical technique for the separation of metal ions has been exploited for various purposes [141–145]. Electrochemical separation technologies have many advantages to be used for separation of parent daughter pairs and was first reported for making a 90Sr/ 90Y generator and then extended to the 188 W/ 188Re generator yielding clinically useful 90Y and 188Re, respectively [146–148]. In an endeavor to electrodeposit 99mTc selectively from an aqueous electrobath containing (n,γ) 99Mo, this concept was more recently adapted for the development of a 99Mo/ 99mTc generator [42,43,149]. In this process, the separation of 99mTc from 99Mo/ 99mTc is realized in an

Electrode for 99m

Electrochemical cell

99

Tc deposition

Mo/

99m

Tc solution

100mm Thick lead shield

Fig. 2. Electrochemical 99Mo/99mTc generator. Technetium-99 m from an equilibrium mixture of 99Mo/99mTc is selectively deposited on a platinum cathode in an electrochemical cell by applying optimal potential of 5 V over a period of 1 hour in NaOH electrobath and stripped back again into the 0.9% saline solution by reversing the polarity.


• Strict adherence to operating protocol will be essential owing to the sensitive nature of electrochemical process. A fully integrated computer controlled operation system with suitable features is an achievable objective as the basic automation technology already developed for 90Sr/ 90Y generator can be easily incorporated into the 99Mo/ 99mTc generator [150]. The prospects of adopting such a scheme, especially in a centralized radiopharmacy, appear promising in the foreseeable future. 8. Extraction chromatography The possibility to incorporate an extractant or a solution of an extractant into an inert substrate is the basis of extraction chromatography (EXC). This method is now widely recognized as an effective means of separation and pre-concentration of a variety of metal ions [44,45,151]. The concept of extraction chromatography separation seemed very attractive since it would exploit the selectivity of liquidliquid extraction and at the same time offer the ease of operation of column based separation system. Although extraction chromatography has been shown to provide a means of performing separations of 99m Tc from 99Mo [152–154], potential application of this technique in the development of 99Mo/ 99mTc system has thus far not been realized, but the foundation needed to build to the next level has been well established. Recent progress in extractant design, together with the introduction of new supports capable of enhancing the physical stability or improving the metal ion retention properties of extraction chromatographic resins, however, promises to offer the utility of this technique in the preparation of 99Mo/ 99mTc generator. 9. Supported liquid membrane (SLM) The supported liquid membrane (SLM) method for radiochemical separation is a modified version of extraction chromatography in which an ion-selective organic extractant is impregnated on an inert semi-permeable membrane and separation of metal ion is achieved by its selective transport through the pores of the impregnated membrane. A conceptual diagram of supported liquid membrane (SLM) separation technique is shown in Fig. 3. A wide variety of supported liquid membranes (SLM) have been studied for the separation of Tc on laboratory scale. These systems are based on trin-octylamine material [54], TOPO-kerosene [55], 2-nitrophenyl octyl ether (NPOE) [155], tetraalkyl phosphonium bis [(trifluoromethyl) sulfonyl]imide and a crown ether [156], amberlite LA-2 (secondary) and trilaurylamine (TLA, tertiary) [157]. It is apparent that SLM technology is still in its infancy and presently stands as a potential Outlet

Inlet Supported Liquid Membrane (Organic phase)

Feed Aqueous phase Parent/Daughter solution

Product Aqueous phase Daughter radionuclide solution

Fig. 3. The supported liquid membrane (SLM) separation concept. Supported liquid membranes (SLMs) are composed of an organic solution of a carrier immobilized in a porous material. The ion transport involves complexation at the feed side of the membrane and release at the receiving (product) side.

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separation technique. Much work needs to be done in order to explore its promising utility in a 99Mo/ 99mTc generator setting. 10. Conclusion A review of existing separation methodologies along with the recent developments on the separation of 99mTc from 99Mo indicates that this field is rapidly evolving, but that the best alternative to the use of F 99Mo based alumina column generator has not yet been identified for widespread use. Nuclear non-proliferation and security concerns have led to advanced discussions around the world in evolving possible alternative strategies to produce 99Mo without HEU. A variety of alternative non-HEU based options are emerging far more quickly than they did over the past decade for sustainable 99Mo or 99m Tc production. Because of the pace in which 99mTc production scene is changing, molybdenum/technetium separation strategies need a vision for the future. While the EXC, SLM and thermochromatographic concepts are fascinating field of research for the separation scientists, they are yet to be tested at high activity level operations and other harsh conditions typically encountered in fabrication and use of clinical scale generators. These technologies are still in their infancy and the utility for 99Mo/ 99mTc generator is not yet a reality. An examination of the separations technologies indicates that in the lively debate between the use of F 99Mo and (n,γ) 99Mo, the need for the separation of 99mTc from accelerator produced 99Mo has been often overlooked. This strategy deserves greater attention not only because a greater range of separation options will be needed, but also for the adaptability to use 99Mo/ 99mTc produced from different cyclotrons having different beam current and energies and consequently with a wide range of specific activities. The 99mTc produced is also likely to contaminated with several other isotopes of technetium other than 99gTc which is the only contaminant while using 99Mo of either fission or activation source [10,22]. The separation of 99mTc from F 99Mo essentially consists of the separation of μg quantities of Tc from mg quantities of 99Mo. On the other hand, separation of 99mTc from proton or photon irradiated target using accelerator could involve separation of μg quantity of Tc from gram quantities of 99Mo which is more akin to the use of (n,γ) 99Mo. Among the various available separation technology options, the thermochromatographic technology and electrochemical separation might be attractive to obtain 99mTc from proton irradiated 100Mo as it would allow separation of 99mTc together with the convenience of recovering the 100 Mo target for recycling. The electrochemical separation strategy can also be nurtured in an effective way to obtain 99mTc from 99Mo produced from 100Mo(γ,n) 99Mo nuclear reaction. Also needed is the development of automated modules capable of separating 99Mo or 99m Tc from the irradiated target in a rapid and efficient manner. This would represent a step in the right direction as automation of the separation procedure offers several advantages, including, reducing the radiation exposure to personnel, reduce the probability of human errors, offer consistent separation performance, and provide a log of the steps performed. This strategy has already made some progress [26,79,80] and must be hastened further to expand its scope. The existing modality of using 99Mo/ 99mTc generators in nuclear medicine centers will diverge, making it likely that future supply in many countries will take place through centralized radiopharmacies set up to achieve cGMP compliance. Any new method will require a demonstrated pharmaceutical equivalence of 99mTcO4- to that obtained from an alumina column chromatographic generator containing F 99Mo. It is envisaged that some of the non-conventional separation technologies such as electrochemical separation, solidphase column extraction, MSIG and ABS, discussed earlier in this article can be adapted in centralized radiopharmacies in an efficient, seamless and effective way owing to the availability of qualified skilled manpower.

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As technology transformation is pursued, it must be balanced with continuity so that existing, still-important technology options are retained. The progressive fusion of existing and emerging technologies is challenging but would make an exciting area for research and development. Some of the existing proven technologies such as the MEK extraction method must be consciously modified with more automation and nurtured in ways that respond to changing times. Of the several separation technology options discussed, the prospect of using MEK solvent extraction method, electrochemical separation process and column chromatographic generator using nanomaterial based sorbents is relatively more appealing in terms of utility if adequate technological attention is given and upgraded with the required automation. These three approaches are inexpensive, realistic, would be expected to be implementable in a very short period of time and capable of producing pharmaceutical grade 99mTc to a reasonable extent. Nonetheless, to be effective in addressing the particular regulatory barriers, new technologies must be customized to local legislative, regulatory and institutional conditions. The use of MEK extraction or electrochemical method at hospital radiopharmacy will also help in improving 99Mo economy, as the time required for making column generators can be saved and hence avoiding the decay loss. Acknowledgments Research at the Bhabha Atomic Research Centre is part of the ongoing activities of the Department of Atomic Energy, India and fully supported by government funding. Research at the Oak Ridge National Laboratory is supported by the US Department of Energy under contract DE-AC05-00OR22725 with UT-Battelle, LLC. Disclaimer This manuscript has been authored by UT-Battelle, LLC, under contract DE-AC05-00OR22725 with the U.S. Department of Energy. The United States Government retains and the publisher, by accepting the article for publication, acknowledges that the United States Government retains a non-exclusive, paid-up, irrevocable, world-wide license to publish or reproduce the published form of this manuscript, or allow others to do so, for United States Government purposes. References [1] Verbeek P. Report on molybdenum-99 production for nuclear medicine 2010– 2020. State of the art, Association of Imaging Producers & Equipment Suppliers (AIPES) Report, November 2008. Available at http://www.oecd-nea.org/medradio/docs/200902_AIPESMolySupplyReport.pdf. [2] Technopolis Group. Radioisotopes in medicine. Foresight of the use of reactor isotopes until 2025. Technopolis Report, December 2008. Available at http:// www.technopolis-group.com/resources/downloads/life_sciences/EN Radioisotopes in_Medicine_final.pdf. [3] Eckelman WC. Unparalleled contribution of technetium-99m to medicine over 5 decades. J Am Coll Cardiol Img 2009;2:364-8. [4] Srivastava SC. Is there life after technetium: what is the potential for developing new broad-based radionuclides? Semin Nucl Med 1996;26(2):119-31. [5] International Atomic Energy Agency(IAEA). Technical Report Series 466: technetium-99m radiopharmaceuticals: manufacture of kits. IAEA 2008. Available at http://www-pub.iaea.org/MTCD/publications/PubDetails.asp?pubId =7867. [6] Lantheus Medical Imaging Inc. 99Mo and 99mTc: radioisotopes critical to nuclear medicine. Available at http://www.lantheus.com/SupplyUpdate/pdf/MolyFactSheet-v3_07Oct10.pdf. [7] IAEA Staff Report. IAEA helps to close radioisotope production gap. Available at http://www.iaea.org/newscenter/news/2011/prodgap.html. [8] Pillai M R A, Dash A, Knapp F F (Russ) Jr. Sustained availability of technetium99m-possible paths forward. J Nucl Med In press. [9] Pillai M R A, Knapp F F (Russ) Jr. Overcoming the Tc-99m shortage: are options being overlooked? J Nucl Med 2011; 52: 15N-16N and 28 N. [10] Pillai MRA, Knapp Jr FF(Russ). Molybdenum-99 production from reactor irradiation of molybdenum targets — a viable strategy for enhanced availability of technetium-99m. Q J Nucl Med Mol Imaging 2012;56(4):385-99. [11] Mushtaq A. Can enriched molybdenum-98 replace enriched uranium? Nonprolif Rev 2009;16(2):285-92. [12] Guérin B, Tremblay S, Rodrigue S, Rousseau JA, Dumulon-Perreault V, Lecomte R, et al. Cyclotron production of 99mTc: an approach to the medical isotope crisis. J Nucl Med 2010;51:13N-6N.

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