US20060023829A1

US20060023829A1 - Medical radioisotopes and methods for producing the same

Info

Publication number: US20060023829A1
Application number: US10/911,407
Authority: US
Inventors: Robert Schenter; Dennis Wester; Glen Hollenberg; Brian Rapko; Gregg Lumetta
Original assignee: Battelle Memorial Institute Inc
Current assignee: Battelle Memorial Institute Inc
Priority date: 2004-08-02
Filing date: 2004-08-02
Publication date: 2006-02-02
Also published as: US8126104B2; WO2006028620A8; WO2006028620A3; WO2006028620A2; US20090060812A1

Abstract

This disclosure concerns a new method for preparing technetium-99m, via its molybdenum-99 parent, by alpha particle irradiation of zirconium-96. Also disclosed are novel compositions containing one or more of technetium-99m, molybdenum-99 and zirconium species. Systems for producing molybdenum-99 and technetium-99m, including alpha particle generators and irradiation targets, also are described herein.

Description

FIELD

Disclosed are methods and apparatus for producing medical radioisotopes, particularly technetium-99m via the decay of molybdenum-99, as well as novel compositions produced according to the methods.

BACKGROUND

Technetium-99m is the primary radioisotope employed in diagnostic nuclear medicine. The importance of technetium-99m to clinical procedures is highlighted by the fact that more than 13 million diagnostic procedures using technetium-99m are performed each year in the United States alone.
Technetium-99m has a combination of desirable physical properties including its gamma decay mode and energy that are ideally suited for single photon emission computed tomography. Moreover, technetium's chemical reactivity and versatility allows it to be conveniently complexed to a variety of carrier or targeting agents, such as antibodies, peptides, and other molecules, which allows particular tissues to be selectively imaged or scanned. Because technetium-99m has a short, about 6 h half-life, this radioisotope for use in clinical practice is typically produced from its longer-lived parent nuclide, molybdenum-99 (t_1/2=66 h) through a chromatographic column generator. For an example of a molybdenum-99/technetium-99m generator, see U.S. Pat. No. 5,774,782 to Mirzadeh et al. Removing the technetium-99m daughter nuclide from the generator (i.e., separating it from molybdenum) is typically performed by “milking” the generator a few times daily by pulling normal saline through the column to elute the soluble technetium-99m for complexation in “kits” for subsequent patient injection.
Commercial quantities of molybdenum-99 have been produced in nuclear reactors over the years through the uranium fission process (for example, see U.S. Pat. No. 3,799,883 to Arino et al.) utilizing highly enriched uranium-235 that requires extensive security and non-proliferation safeguards. Unfortunately, the fission process, whether it is based on low or high enriched uranium, yields a small amount of molybdenum-99 with a large array of undesirable fission products that present significant infrastructure, health and security, liability, handling, storage, and waste issues and associated costs. Further, this mode of production requires dedicated and reliable nuclear reactors, support facilities and operation thereof to maintain a continuous supply whereby the United States currently depends solely on a limited number of foreign suppliers of molybdenum-99.
Thus it is evident that there is a need to provide technetium-99m and its precursors by alternative processes that do not depend on fission and associated nuclear reactors.

SUMMARY

Disclosed herein are radiopharmaceutical compositions, particularly technetium-99m compositions and their precursors, as well as novel methods, apparatus and systems for producing such compositions.
In general, presently disclosed methods for producing the disclosed radiopharmaceutical compositions include the provision of zirconium-96-containing material, and in certain embodiments a material enriched in zirconium-96. The zirconium-96-containing starting material, in certain embodiments, is then manufactured or otherwise formed into a target. The target is irradiated with charged particles to transmute material in the target into molybdenum-99. The molybdenum-99 is then separated from the target material. Alternatively, the zirconium-96-containing starting material itself may be irradiated rather than forming a target prior to irradiation.
Certain embodiments of the disclosed methods include harvesting the irradiated material by partially or completely dissolving the irradiated material to produce an irradiated target solution. Certain embodiments of the disclosed methods may include removing the irradiated material from the target by, e.g., ionization, ablation, spallation, sputtering, and mechanical removal, such as milling. Such harvesting can be performed during irradiation, following irradiation or both. Separation of the desired molybdenum-containing species in the irradiated material can be accomplished by any suitable process such as chemical separation, mass difference, plasma separation, (e.g., diffusion, centrifuge, and mass spectrometry) and combinations thereof. In another embodiment of the disclosed methods, harvesting the desired product includes contacting an irradiated target or material from the irradiated target with a solvent, such as aqua regia, to produce an irradiated target solution. The irradiated target solution contains the desired product, molybdenum-99, as well as zirconium. The molybdenum-99 can then be separated from other species in solution, such as zirconium species and incidental impurities or transmutation products. Another embodiment of the methods includes purification by ion exchange chromatography. For example, molybdenum-99 can be separated from zirconium present in an irradiated target by anion exchange chromatography.
Another embodiment of the process for making and purifying molybdenum-99 includes contacting the irradiated target or material from the irradiated target with a fluoridating agent, such as NF₃and/or HF. Fluoridation of such materials can produce MoF₅, MoF₆or both, as well as zirconium fluoride species. The molybdenum fluoride products MoF₅and MoF₆are relatively volatile at about ambient temperatures. On the other hand, zirconium fluoride compounds produced by the process are non-volatile under the analogous conditions. Thus, the desired molybdenum-99 material can be isolated by evaporation and condensation. Upon separation from the zirconium species, molybdenum fluorides optionally can be hydrolyzed to produce molybdate, which is typically the molybdenum species used to produce technetium-99m.
Also disclosed are targets for producing the disclosed radiopharmaceutical compositions. In certain embodiments the target is enriched in zirconium-96. The target may take any suitable form to meet operational and production requirements, as known to those persons of ordinary skill in the art. Certain target embodiments include target shapes and dimensions selected so that molybdenum-99 yield and/or purification efficiency are optimized. In certain embodiments the target comprises a disk, a ribbon, a wire or combinations of these forms. Because of the value associated with the target material, other embodiments include target designs that enable molybdenum-99 to be harvested and the target to be subsequently re-irradiated for further molybdenum-99 formation and harvesting.
One embodiment of a system for producing the molybdenum-99 includes an alpha particle source for producing an alpha particle beam and a target comprising zirconium-96 arranged such that at least a portion of the alpha particle beam intersects the target. Any suitable charged-particle beam source can be used in the presently disclosed system, including without limitation, an alpha particle source comprising a table-top generator, a cyclotron or a linear accelerator. In certain embodiments of the system, a bath is provided for harvesting irradiated material from the target by chemical means. In certain embodiments of the system, mass difference means is used to harvest irradiated material from the target. Both of these harvesting methods, as are others, are suitable for continuous or near-continuous processing during irradiation, following irradiation, or both. For increased efficiency, the disclosed systems can include means for conducting the irradiation processes in a continuous mode or near-continuous mode by continuously exposing non-irradiated portions of the target (or starting material) to the charged-particle beam, which may be continuous or pulsed with a duty factor. In systems where the target is in a form of a disk or other rotatable form, the process may be facilitated by rotating the target relative to the beam so that fresh material is thereby exposed. In one embodiment, the process includes harvesting irradiated target material at one location on the target while another portion of the target is being irradiated.
Also disclosed are compositions including molybdenum comprising molybdenum-99. For example, certain embodiments of the compositions can include 80% or greater abundances of molybdenum-99, and in some embodiments the compositions include at least about 90% molybdenum-99. In one embodiment, such compositions also include a carrier, such as a carrier gas. The carrier gas may comprise, e.g., helium, argon, combinations thereof and other suitable carriers.
Other embodiments of the compositions disclosed herein include radiopharmaceutical compositions containing one or more of zirconium-96, molybdenum-99 and technetium-99m. In certain embodiments, the compositions include molybdenum-99 produced by the process described above.
The molybdenum-99 produced as described herein can be used to prepare a technetium-99m generator. Such generators are suitable for clinical use, for example, for use at a hospital to produce the disclosed radiopharmaceutical solutions. The preparation of the technetium-99m generator typically involves loading the purified molybdenum-99 onto an adsorbent column. After an appreciable amount of molybdenum-99 has decayed into technetium-99m, the technetium can be eluted from the column, thereby separating the molybdenum species from the technetium species.
Certain embodiments of the molybdenum and technetium compositions disclosed herein are substantially free of radioactive impurities. Certain compositions include less than about 5×10⁻²% percent radioactive impurities (by weight). Specifically, particular compositions are substantially free of actinides. Similarly, certain compositions are substantially free of radioactive isotopes of strontium, ruthenium, tellurium and iodine. One embodiment of the present compositions consists essentially of zirconium and molybdenum-99. Some embodiments of the compositions disclosed herein include at least one carrier. For example, radiopharmaceutical compositions and many of their precursor compositions include a pharmaceutically compatible carrier.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a flowchart illustrating certain embodiments of disclosed processes for preparing molybdenum-99.
FIG. 2 is a block diagram illustrating an embodiment of a system for producing radioisotopes.
FIG. 3A is perspective view of an embodiment of a target for the production of radioisotopes.
FIG. 3B is a side view of the target depicted in FIG. 3A.

DETAILED DESCRIPTION

Disclosed herein are methods, apparatus and systems for the production of technetium-99m. Also provided are novel medical radioisotope compositions and their precursors including compositions comprising technetium-99m, molybdenum-99 or both.
It should be understood that when a particular isotope, such as molybdenum-99 or technetium-99m is referred to herein, compounds containing the particular isotope also are intended. With respect to molybdenum-99 and technetium-99m, such compounds can include, without limitation, molybdate (MoO₄ ²⁻) salts, pertechnetate (TcO₄ ¹⁻) salts, chlorocomplexes of both and other chemical species.
Unless otherwise indicated, all numbers expressing quantities of ingredients, properties, thicknesses, power levels, and so forth used in the specification and claims are to be understood as being modified by the term “about” whether explicitly stated or not. Accordingly, unless indicated clearly to the contrary, the numerical parameters set forth are approximations.

I. INTRODUCTION

The disclosed methods for making molybdenum-99 and technetium-99m may include a zirconium-96 containing starting material. One embodiment of such a process for preparing molybdenum-99 disclosed herein is illustrated in FIG. 1. With reference to FIG. 1, an embodiment of the process begins with a target containing zirconium-96. Irradiation of the target with alpha particles yields, via an alpha particle capture/neutron emission process, an irradiated target containing molybdenum-99. The irradiated target is then processed to harvest the irradiated material and to purify molybdenum-99. Alternatively, the starting material containing zirconium-96 may be irradiated without forming a target. As illustrated in FIG. 1, the starting material may be irradiated directly to produce molybdenum-99. The irradiated starting material also can be processed to purify molybdenum-99 from the remaining components of the starting material.
After molybdenum-99 is harvested from the target material or the starting material it typically is loaded onto a technetium generator from which technetium-99m can be directly extracted by the end user. Typically, the molybdenum-99 product is purified to separate it from zirconium isotopes present in the irradiated target or irradiated starting material, prior to loading onto the technetium generator. As is known in the art, technetium-99m can be separated as pertechnetate (^99mTcO₄ ¹⁻) from its parent hydrated molybdenum trioxide (MoO₃) or molybdate ion (⁹⁹MoO₄ ²⁻) via column chromatography. Examples of technetium “generators” for purifying radiopharmaceutical quality technetium-99m produced from molybdenum-99 decay are described in U.S. Pat. No. 5,774,782 and in U.S. Pat. Pub. No. 2003/0219366, both of which are incorporated herein by reference. Further variations of the processes, as well as other specific embodiments are set forth below.

II. TARGETS AND STARTING MATERIALS

Different compounds and compositions comprising zirconium-96 are suitable for producing molybdenum-99. Zirconium has a natural abundance of about 2.8% zirconium-96 and zirconium-containing materials can be used in embodiments of the present method without enrichment. Zirconium can be enriched to higher abundances of zirconium-96 to improve the yield of molybdenum-99 production. For example, in some embodiments the concentration of zirconium-96 can range from about 10% to greater than about 95%. Typically, when a target enriched in zirconium-96 is used, the zirconium includes at least about 50% of the zirconium-96 isotope, and in some embodiments, at least about 90%. Methods for preparing compounds enriched in zirconium-96 are known to those of ordinary skill in the art. For example, plasma separation is one technique that can be used to separate zirconium-96 from other zirconium isotopes. Plasma separation methods and apparatus are well known to those of ordinary skill in the art. For examples, see, Rosenthal et al. Localized Density Clumps Generated in a Magnetized Nonneutral Plasma. Phys. Lett. A 1992, 170, 443-447; Bauer et al. Experimental-Observation of Superstrong Electron-Plasma Waves and Wave Breaking. Phys. Rev. Lett. 1992, 68, 3706-3709; and U.S. Pat. No. 5,981,955 to Wong and Rosenthal. Zirconium compounds enriched in zirconium-96 also are commercially available. For example, zirconium oxide enriched in zirconium-96 is commercially available at various enrichment levels. Zirconium oxide having 58.5% zirconium-96 is commercially available from STB Isotope, Hamburg, Germany, and zirconium oxide having over about 95% zirconium-96 is available from International Isotopes Clearing House Inc., Leawood, Kans., and from Chemotrade, Düisseldorf, Germany.
Any zirconium-containing starting material can be irradiated to produce molybdenum-99. Suitable starting materials are known to those of ordinary skill in the art and include, without limitation, zirconium metal, zirconium nitride and zirconium oxide. Zirconium oxide is useful due to its ready availability, low cost and chemical stability. Zirconium metal also is readily available and due to its ductility and malleability is useful for fabricating into a desired target form. The starting material optionally can include other elements or compounds, such as other metals in addition to zirconium, to facilitate target construction.
The starting material can be fabricated into various target configurations to enhance the production and recovery of the desired molybdenum-99 species. Typically the target is adapted to dissipate both excess heat and charge that builds up during irradiation. For example, the target can have a relatively large surface area to volume ratio to favor heat dissipation. To dissipate charge the target can be, e.g., electrically coupled to ground.
The beam energy and target thickness may be selected such that the efficiency of the overall process is optimal. For example, the path length of alpha particles within zirconium-96 containing materials is dependent upon the beam energy. Specifically, the path length of a 15 MeV beam of alpha particles within such materials is about 200 μm. In certain embodiments the target is designed to have a thickness of about the alpha particle path length or less such that the target is irradiated to its full thickness. In some such embodiments the purification of the desired molybdenum-99 product is more efficient because less zirconium-96 remains in the target. In some embodiments, however, only the irradiated material is removed from the target for purification, which also simplifies purification of the desired molybdenum-99 product.
In certain embodiments the target has a thickness, positioned substantially parallel relative to the beam vector or axis, of less than about 1 mm and more typically has a thickness of from about 0.05 mm to about 0.5 mm. In particular embodiments the target thickness is from about 0.2 to about 0.4 mm or from about 0.1 to about 0.2 mm. The desired thickness depends in part upon the energy level of the particle beam, as is known to those of ordinary skill in the art. Similarly, in some embodiments, the target has a width as positioned substantially perpendicular to the beam axis of less than about the beam diameter. Such dimensions are design to result in a greater percentage of the target material being irradiated in effort to simplify purification (due to a lower percentage of starting material remaining in the sample to be further treated for separation following irradiation). In one embodiment of a system for producing molybdenum-99, the alpha particle beam diameter is less than about 1 mm.
One embodiment of a target is depicted in FIG. 3A, which depicts a target assembly 50, the target formed into the shape of or onto disk 70, which in turn can be mounted on spindle 60. With reference to FIGS. 3A and 3B, disk 70 includes an irradiation surface 80 arranged in alpha beam path 90. Rotation of disk 70 about spindle 60 may place fresh portions of irradiation surface 80 in beam path 90. Spindle 60 optionally includes a ground connection (not shown) thus providing electrical coupling of disk 70 to ground to dissipate charge accumulated during irradiation. Typically disk 70 has a diameter of from about 1 cm to about 30 cm, and in one embodiment, disk 70 has a diameter of about 30 cm. Of course, the dimensions of the disk are based on the other various parameters and apparatus, as would be known to those persons of ordinary skill in the art.
In another embodiment of the disclosed target can take the shape of or be formed upon a ribbon, the ribbon being similar in shape to the shape of a piece of photographic film. The ribbon can be passed through an alpha particle beam at a rate suitable for producing useful amounts of molybdenum-99. In this embodiment, the ribbon can for example be wound from one spool to another. As with the disk-shaped target discussed above, the target ribbon is well-suited to a continuous process, wherein irradiated target material is harvested from an irradiated portion of the target ribbon while a second portion of the target ribbon is being irradiated. The ribbon can have thicknesses similar to that discussed above in relation to a disk-shaped target, for example, 200 μm. The width of the ribbon may be comparable to the width of the alpha beam.
In certain embodiments, the target includes a substrate of a first material and is coated or in some manner combined with a layer of zirconium-containing material. The substrate may comprise a flexible or rigid material depending upon the form the target is to take. The substrate material is selected to have sufficient thermal conductivity to withstand the heat produced during alpha particle irradiation and a material that can readily dissipate heat. The substrate also may be selected so that it does not produce undesirable transmutation products during irradiation. The layer of zirconium-containing material can have thicknesses similar to that discussed above in relation to a disk-shaped target. Alternatively, the substrate can be coated with at least about 200 μm of a zirconium-containing material, in effort to prevent alpha particles from reaching the substrate (when the particle beam energy (and other parameters) is set accordingly, e.g., 15 MeV, as known to those of ordinary skill in the art). In certain embodiments, such as where the target is a ribbon, the substrate is selected such that the substrate and coating form a ribbon that is sufficiently flexible to be wound about a spool. The substrate can be an inorganic material or materials, such as a metal, and/or can be an organic material or materials, particularly a synthetic material, such as a synthetic polymer.
Embodiments containing a substrate and a coating optionally can include an interlayer positioned between the substrate and the coating. In one embodiment the interlayer is selected to improve adhesion between the substrate and the coating. Thus, such interlayers may be employed for example when the substrate and the coating do not adhere with sufficient affinity. In such cases interlayer materials can be selected by a person of ordinary skill in the art such that the interlayer adheres to the substrate and the coating, thus effectively bonding the substrate and the coating. Combinations of coatings, substrates and interlayer materials can be selected for compatibility and appropriate physical properties by a person of ordinary skill in the art.

III. TARGET IRRADIATION

The zirconium target can be irradiated with alpha particles using any alpha particle source to produce molybdenum-99. For example, a cyclotron, linear accelerator or table-top generator can be used in embodiments of the method. Examples of suitable cyclotrons for use in embodiments of the present method include the Duke University Medical Center Cyclotron and the University of Washington's Scandatronix MC-50 cyclotron. In certain embodiments an alpha particle generator, such as a table-top generator is used to produce an alpha particle beam. Such alpha particle generators are known to those of ordinary skill in the art. For examples of such table-top alpha particle generators, see, Ji et al., Production of Various Species of Focused Ion Beam, Rev. Sci. Instrum., 2002, 73, No. 2, pp. 822-824, and Schneider, Operation of the Low-Energy Demonstration Accelerator: the Proton Injector for ATP, Proc. 1999 IEEE Particle Accelerator Conf., pp. 503-507 (IEEE Catalog No. CH36366, 1999), both of which are incorporated herein by reference. An example, suitable table-top generator, a multicusp plasma generator employing a multicusp ion source, has been developed at Lawrence Berkeley National Laboratory, in Berkeley, Calif.
In principle, as known to those of ordinary skill in the art, virtually any flux is acceptable for producing molybdenum-99, however for commercial usage the alpha particle beam flux typically is at least about 10¹⁶α/(cm²)s. The alpha particle beam flux also may be less than about 10¹⁸α/(cm²)s. For efficient transmutation of zirconium-96, in certain embodiments of the disclosed methods, the alpha particle beam has an energy of from about 10 to about 50 MeV. In certain embodiments, the alpha particle beam has an energy distribution centered at from about 10 to about 30 MeV, for example at about 15 MeV. In some cases the beam can be substantially monoenergetic having beam energy of about 15 MeV. A lower energy may be useful in production costs reductions.
Although other flux levels may be used, when an alpha particle beam has a flux of about 10¹⁶α/(cm²)s, a beam energy of about 15 MeV, the target may be irradiated for a period of from about 2 hours to about 20 hours. Such a target may have a Zr-containing material thickness relative to a beam vector of about 100 μm in such a method. However, specific irradiation times, energy levels and flux levels can be readily selected by a person of ordinary skill in the art upon consideration of target system parameters, the target thickness as well as desired product specifications.
Because alpha particles have a relatively short path length (on the order of about 200 μm) within the target material, the target can be relatively thin. With reference to FIGS. 3A and 3B, disk 70 may have a thickness of Zr-containing material of less than about 0.5 mm, and in some embodiments a thickness of less than about 200 μm or even 100 μm. Such relatively thin targets generally effectively dissipate heat. Because only the outer few microns of the target may be effectively irradiated with alpha particles in certain embodiments of the disclosed method, only the first few atomic layers of the target need to be removed following irradiation.
Sputtering processes, such as focused ion beam mediated sputtering are particularly useful for harvesting such small amounts of irradiated material from the target. Irradiated material also can be removed by dissolving or contacting the irradiated material with a reagent. For example, in one embodiment the irradiated area can be contacted with a reagent, such as aqua regia, to remove a portion of the target. Simple mechanical techniques also can be used to remove irradiated material from the target as is known to those of ordinary skill in the art. For example, abrasion and/or mechanical skimming can be used to remove a portion of target material. Following removal of the irradiated material, the newly exposed target surface can be subjected to alpha particle irradiation and the process repeated to provide a continuous process.

IV. PRODUCT ISOLATION FROM IRRADIATED MATERIALS

Methods for isolating molybdenum-99 from irradiated target materials are described herein. These methods can be used alone or in combination to provide the desired composition including molybdenum-99.
In certain embodiments of the disclosed methods, molybdenum-99 produced as described herein need only be purified from the zirconium-containing target material, because the irradiation process generally does not produce other products. Thus, the crude mixture produced by irradiation primarily includes zirconium and molybdenum-99, and is relatively tractable compared to the mixture produced by the fission-based process.
One embodiment of the disclosed methods for purifying molybdenum-99 exploits the different solubilities of molybdenum and zirconium species in alkaline solution. This solubility-based method is compatible with the zirconium-based starting materials described above with respect to the target. One embodiment of this method includes the following basic steps: Contact of the irradiated target with aqua regia; evaporation of the aqua regia solution to dryness to yield a residue including molybdenum and zirconium species; contact of the residue with an alkaline solution; and separation of the alkaline solution from the insoluble material. The molybdate salts are highly soluble at elevated pH, whereas zirconium oxides and hydroxides are not. In general, any pH above about 2 provides sufficient solubility differences to separate molybdenum compounds from zirconium compounds. In one embodiment solutions having a pH of greater than about 6 can be used to separate molybdenum from zirconium. In such embodiments, sodium hydroxide solutions having a molarity of from about 0.2 to about 0.3 (or pH values of about 0.7-0.5) can be used for solubility-based separation. This method provides a purified solution containing molybdenum-99. The method also can be repeated one or more times, such as from one to five times, to increase the molybdenum purity. Typically, a single purification according to this protocol provides a composition including molybdenum-99 and containing less than about 1% zirconium. In certain embodiments a single solubility-based purification procedure provides molybdenum-99 of analytical purity.
Another embodiment of the disclosed methods for purifying molybdenum-99 from irradiated target material involves ion-exchange chromatography. Molybdenum and zirconium species can be resolved according to embodiments of this method using either strongly basic or weakly basic ion-exchange resin. Suitable ion-exchange resins are well known to those of ordinary skill in the art and are commercially available. In general, the zirconium species exhibit a low affinity for anion-exchange resins until the acid concentration is greater than about 8 M. In contrast, molybdate exhibits a strong affinity for anion-exchange resin above an acid concentration of about 4 M, but a much lower affinity below this concentration. This acid concentration dependent difference in affinity provides the basis for successful resolution of zirconium/molybdenum mixtures.
The ion exchange purification can be repeated to afford molybdenum-99 of increased purity. However, in certain embodiments a single ion-exchange purification provides a decrease of from about two to about three orders of magnitude in zirconium. Typically, from one to five repetitions of the ion exchange protocol results in molybdenum-99 of analytical purity. In one embodiment of a purification method, the ion exchange protocol is performed in combination with the solubility-based protocol described above to provide purified molybdenum-99. In this tandem protocol, the solubility-based purification described above is typically performed prior to the anion-exchange protocol.
Another embodiment of the disclosed methods includes purifying molybdenum-99 from targets including zirconium species exploits the different vapor pressures of molybdenum fluoride and zirconium fluoride species. For example, molybdenum pentafluoride (MoF₅) has a boiling point of 213° C. and molybdenum hexafluoride (MoF₆) has a boiling point of 34° C., whereas zirconium fluorides are non-volatile. The irradiated target is subjected to exhaustive fluoridation using a fluoridating agent. Any fluoridating agent can be used, including, without limitation hydrogen fluoride, nitrogen trifluoride, fluorine gas or combinations thereof. Other fluoridating agents can be substituted for hydrogen fluoride, nitrogen fluoride and fluorine as is well known to those of ordinary skill in the art. The fluoridating agent can optionally be delivered in combination with a carrier, for example carrier gases, such as helium, argon and the like, or for example a carrier solvent, such as water, fluorinated hydrocarbons or the like. As is known to those of ordinary skill in the art, solvents, including water and acetonitrile can be used to modify the reactivity of the fluoridating agent.
In another embodiment of the disclosed methods the fluoridating agent is activated either in situ or prior to contact with the irradiated target material. Any suitable activation method can be used, such as microwave activation, which generates free radicals via photon-induced homolysis of a bond.
Because molybdenum fluoride materials are relatively volatile as compared to zirconium fluoride materials are not, the desired molybdenum fluoride species can be isolated from the zirconium-based materials. An inert carrier gas, such as helium, a fluorocarbon (e.g., Freon) and/or argon may be used to flush away a molybdenum fluoride compound or compounds that are collected via, for example, a low-temperature trap.
Suitable apparatus for performing this procedure are well known to those of ordinary skill in the art. Optionally, a system for performing a fluoridation process may include a filter positioned between a fluoridation chamber and the low temperature trap, e.g., below ambient temperature. This filter can be used to prevent solid materials, such as non-volatile zirconium species, from being swept into the low temperature trap. When the molybdenum fluoride or fluorides have been isolated, they can be converted to molybdate salts via hydrolysis with an alkaline solution, such as a sodium hydroxide solution. The resulting material, a molybdate solution, can optionally be subjected to further purification, such as by ion exchange.
Embodiments of molybdenum-99 compositions produced according to certain variations of the presently disclosed method may be substantially free of impurities that accompany fission-produced molybdenum-99 compositions. For example, fission-produced molybdenum-99 compositions can include one or more gamma particle emitters, such as iodine-131 (e.g., 1.46×10⁻⁷), iodine-132 (at levels of about 3.0×10⁻⁵), ruthenium-103 (at levels of about 3.0×10⁻⁵or about 1.6×10⁻⁷) and/or tellurium-132. Beta emitters, such as strontium-89 and strontium-90 also can be included in molybdenum-99 compositions produced by a fission process (in amounts as high as 5×10⁻⁶). In certain embodiments the present molybdenum-99 compositions include other isotopes, such as molybdenum-93m, niobium-96, niobium-95, niobium-92, and/or strontium-89.
In certain embodiments of the molybdenum-99 compositions disclosed herein, the compositions have a higher activity concentration than molybdenum-99 compositions produced using a fission-based process. Pure molybdenum-99 has an SPA of 4.8×10⁵Ci/gm. A fission reactor molybdenum-99 composition has a maximum SPA of 9.6×10⁴Ci/gm at discharge and rapidly reduces to 1.6×10⁴Ci/grn for a “7 day” molybdenum-99 composition. When 100% Zr-96 material or even 70% Zr-96 containing material of the present disclosure methods is irradiated as described in the above methods the resulting molybdenum-99 composition as disclosed in certain embodiments herein is as much as a factor of four times greater than a fission reactor molybdenum-99 composition. Certain embodiments of the disclosed molybdenum-99 composition have a activity concentration or an SPA value of at least about 19.2×10⁴Ci/gm at discharge and other embodiments of the disclosed molybdenum-99 composition have a activity concentration or an SPA value of at least about 38.4×10⁴Ci/gm at discharge.
The SPA values of a molybdenum-99 composition can be determined by calculating isotope cross sections using the Empire II Computer software code, available from, e.g., The Nuclear Energy Agency, EMPIRE-II 2.18, Comprehensive Nuclear Model Code, Nucleons, Ions Induced Cross-Sections, at, for example, http://vww.nea.fr/abs/html/iaea1169.html (Aug. 2, 2004), which is incorporated herein by reference. Using the values of initial enrichment amounts (e.g., 70% Zr-96) for a given starting material, the isotope production value is calculated using an isotope generation and depletion code system, such as ORIGEN (a well-published code) developed for the Nuclear Regulatory Commission and the Department of Energy to satisfy a need for an easy-to-use standardized method of isotope depletion/decay analysis for spent fuel, fissile material, and radioactive material. ORIGEN computer software code solves equations of radioactive growth and decay allowing continuous first order chemical processing and a neutron flux described by a three-region spectrum. Complex decay and transmutation schemes can be treated. ORIGEN code is available from, for example, The Nuclear Energy Agency at http://www.nea.fr/welcome.html, or from the Radiation Safety Information Computational Center (RSICC), at http://www-rsicc.ornl.gov/rsicc.html or http://www.ornl.gov/sci/origen-apr/origen-apr.html, all of which are incorporated herein by reference. The output from the isotope production code provides the mass (in grams) of all of the molybdenum isotopes produced. From this the SPA is calculated by multiplying 4.8×10⁵Ci/gm by the mass of the molybdenum-99 divided by the mass of all the molybdenum isotopes including molybdenum-99.
Molybdenum-99 compositions produced as described above, can be used to generate technetium-99m. In one embodiment of a method for producing technetium-99m, a chromatographic generator column is charged with an alumina adsorbent. The adsorbent is then equilibrated using a salt solution, such as an ammonium nitrate or saline solution. Particular examples use 0.1 M NH₄NO₃for column equilibration. Molybdenum is loaded on the column as a MoO₄ ²⁻ or hydrated MoO₃solution, typically at a pH of from about 3 to about 4. This loading solution can be prepared, for example, by titrating about 1 mL of a 0.003 mg/L molybdenum-99 stock solution (ca. 3 mg) with 1 M HNO³. Technetium-99m is eluted from the loaded column using a salt solution, such as, without limitation 0.1 M NH₄NO₃, normal saline or both. The eluted technetium-99m solution may be used without further purification. However, in certain embodiments, the technetium-99m solution can be further purified by, for example, loading onto a technetium-99m. concentrator column containing anion exchange resin, for example, AF W 1X8, 100-200 mesh or other anion exchange resin known to those of ordinary skill in the art. The NO₃ ⁻ form (equilibrated with 0.1 M NH₄NO₃). The concentrator column typically is washed with a small amount of salt solution, such as 0.1 M NH₄NO₃, followed by a small amount of deionized water.
Technetium-99m is eluted from the column using a reductive solution, such as a solution containing a complexing agent. In one embodiment, the reductive solution is prepared using an ethylene diamine (EDA) complexing agent. In one example, the reductive solution is prepare using about 0.004 parts SnCl₂, 1 part 10% EDA/H₂O, 1 part 0.1 M NaOH and about 10 parts deionized water. Other suitable complexing agents for eluting technetium-99 include molecules containing at least one amine, amide, ketone, carboxy, and/or sulfhydryl moiety. Particularly useful complexing agents are chelating agents that include at least two of these moieties.
As is known to those of ordinary skill in the art, the complexing agent, such as EDA, can be exchanged for another ligand. For example, upon acidification of a technetium-99m complex to a pH of about 4, the EDA ligand exchanges with other ligands, such as citrate or gluconate. Citrate and gluconate are typical ligands used in processes for labeling tissue specific targeting agents with technetium-99m.

V. EXAMPLES

The foregoing disclosure is further explained by the following non-limiting examples. Unless indicated otherwise, parts are parts by weight, temperature is given in Celsius or is at room temperature and pressure is at or near atmospheric.

Example 1

This example describes the irradiation of a target comprising zirconium to produce a composition comprising molybdenum-99. A target of zirconium metal in the shape of a disk about one inch in diameter and about three millimeters thick was irradiated with an alpha particle beam having an energy of about 28 MeV using the University of Washington's Scandatronix MC-50 cyclotron for ca. 15 minutes. Analysis of the gamma spectrum of the irradiated target shows the presence of molybdenum-99, molybdenum-93m, niobium-96, niobium-95, niobium-92m, and strontium-89.

Example 2

This example demonstrates a method for isolating molybdenum-99 from an irradiated zirconium target. This exemplary method includes the following steps: The irradiated target is dissolved in aqua regia; the aqua regia solution is evaporated leaving a residue; the residue is treated with an alkaline solution; and the soluble molybdenum species are separated from the insoluble zirconium-containing material.
To demonstrate the effectiveness of this method, a 0.5333 g zirconium foil (99.7% purity, 0.2 mm thickness) and 0.0947 g MoO₃were combined and treated with aqua regia (3:1 volume/volume solution of HCl/HNO₃total volume of 6 mL). The mixture was heated gently for approximately 30 minutes to facilitate dissolution. A portion of the resulting solution-containing 0.048 grams of zirconium and 0.0032 grams of molybdenum-was placed in a glass beaker and evaporated to dryness using a hot plate. The residue was suspended in 5 mL of 0.25 M NaOH and heated to boiling for 20 minutes. After cooling, the suspension was centrifuged and the supernatant was analyzed using ICP-AES (inductively-coupled plasma-atomic emission spectroscopy). This analysis indicated that the supernatant had a molybdenum concentration of 0.45 g/L, which represented nearly quantitative recovery of molybdenum. The zirconium concentration of the supernatant was less than 0.012 g/L. Thus, this example demonstrates that molybdenum-99 can be effectively separated from zirconium-containing materials by exploiting the different solubilities of molybdate salts and zirconium species in alkaline solutions.

Example 3

This example describes a method for purifying molybdenum-99 from zirconium containing materials via ion-exchange chromatography. The irradiated target is dissolved in a suitable medium, such as aqua regia. The resulting solution is adjusted to be approximately 4 M in chloride. The solution is passed through an anion-exchange column and the column is washed with 4 M HCl to remove nitrate. The desired molybdenum-99 product is eluted from the column using a dilute acid solution.
The efficacy of this purification method was demonstrated by preparing a solution comprising both zirconium and molybdenum species as follows: a 0.5333 gram zirconium foil (99.7% purity, 0.2 mm thickness) and 0.0947 MoO₃were combined and treated with aqua regia (3:1 volume/volume solution of HCl/HNO₃total volume of 6 mL). The mixture was heated gently for approximately 30 minutes to facilitate dissolution. The resulting solution was diluted with deionized water from its initial chloride concentration of 9 M to a chloride concentration of 4 M and a concentration of 3.5 mM Na, 10.4 mM Mo and 134 mM Zr. 11 mL of the diluted solution was applied to a column of strongly basic anion exchange resin (BioRad AG1-X4, 50-100 mesh 13 grams, ca. 40 mL) and passed through the column at a rate of about 0.5 mL/minute. Then about 50 mL of 4 M HCl (“scrub” solution) was passed through the column, followed by 60 mL of 0.04 M HCl (“strip” solution).
The results of two trials performed according to this protocol are recorded in Table 1.

TABLE 1

eluted feed eluted scrub eluted strip

% recovery solution solution solution

Trial 1:

Mo 0.18 0.07 0.12

Zr 102 1.7 0.024

Trial 2:

Mo 0.1 0.08 0.01

Zr 94 13 0.07
The results recorded in Table 1 demonstrate that Zr species can be separated from Mo species using ion exchange chromatography.
Several additional stripping conditions also were evaluated to improve the recovery of Mo from the ion exchange resin. To evaluate Mo recovery conditions, an analyte solution (0.014 M molybdate) was prepared by dissolving ammonium molybdate (88 mg) in HCl (4 M; 50 mL). Each anion exchange column was prepared using either strongly basic BioRad AG1X4 (ca. 1 gram per column, 50-100 mesh, Cl⁻ form, 5.5 meq reported capacity per gram of dry resin) or weakly basic BioRad AG3X4 (ca. 1.25 grams per column, 100-200 mesh, 5.5 meq reported capacity per gram of dry resin).
For each recovery assay, the resin was conditioned by passing several column volumes of feed solution (4 M HCl) through the resin. The analyte solution (1.5 mL) was added, followed by a feed solution (HCl 4 M). Following the addition of 10-15 mL of 4 M HCl, about 10-15 mL of deionized water (scrub) was added to the column, followed by 10-15 mL of the “strip” solution. The feed, scrub and strip effluents were separately collected and, following acidification by the addition of an equal volume of HCl (6 M), were analyzed for sodium and molybdenum by ICP-AES. The results of this analysis for assays using the strongly basic AG1X4 resin are recorded in Table 2.

TABLE 2

% Mo in % Mo in % Mo in Total

feed scrub strip % Mo

Strip Solution effluent effluent effluent recovery

0.25 M NaOH 0.6 3.3 2.7 6.6

2.5 M NaOH 0.08 1.4 72 73

1 M NaOH 0.3 3.4 35 38

3:1 (v:v) 0.25 0.3 0.2 67 67

M NaOH/30%

H₂O₂solution
The results recorded in Table 2 demonstrate that strongly basic anion-exchange resin retains molybdate from a 4 M HCl solution with high affinity. Moreover, concentrated hydroxide solution or mixed NaOH/H₂O₂solutions can be used successfully to recover molybdate during anion exchange chromatography.
Weakly basic anion exchange resin also can be used to separate zirconium from molybdenum. For example, BioRad AG3X4 weakly basic anion exchange resin (10 grams, 100-200 mesh, 5.5 meq reported capacity per gram of dry resin) was loaded onto a 1.5 cm internal diameter column having, after loading, an approximately 25 mL dead volume. The column was equilibrated using 0.04 M HCl (ca. 25 mL) followed by 4 M HCl (ca. 20 mL). A diluted aqua regia solution containing molybdenum and zirconium (10.5 mL, prepared as described above) was added, followed by 50 mL of 4 M HCl, 20 mL deionized water, and 50 mL of 3 M NaOH. The results of this trial are recorded in Table 3.

TABLE 3

% in feed % in scrub % in strip Total %

effluent effluent effluent recovered

Mo 0.39 14 50 64

Zr 93 7.4 0.32 101
The Mo/Zr separation factor achieved in the above example is about 160. Thus, the results recorded in Table 3 demonstrate that weakly basic amion exchange resin can be used to separate molybdenum species from zirconium species via anion exchange chromatography.

Example 4

This example describes the purification of technetium-99 from molybdenum-99. Molybdenum-99 produced according to Example 2 or Example 3 is used to prepare a 0.003 mg/L molybdenum-99 stock solution (0.1 M in NH₄NO₃). 10 mL of the stock solution is loaded onto a generator having an alumina stationary phase and is eluted with 0.1 M in NH₄NO₃(10 mL). The eluted solution is loaded onto a technetium-99m concentrator column (2×10 mm, Dowex AG W 1X8, 100-200 mesh, NO₃form preequilibrated with the 0.1 M NH₄NO₃). After loading the column is washed with 2 mL of 0.1 M NH₄NO₃, followed by 2 mL of deionized H₂O. Technetium-99m is stripped from the column with 5×0.5 mL of EDA reagent (a freshly prepared mixture of 4.0 mg of SnCl₂, 1 mL of 10% EDA/H₂O, 1.0 mL of 0.1 M NaOH and 10 mL of H₂O, purged with N₂). Greater than 75% of technetium-99m is eluted in the first two 0.5 mL portions of EDA reagent. The specific volume of technetium-99m is 0.35 mCi/mL after elution from the alumina column, and 2.7 mCi/mL after concentration a factor of 8 increase in concentration thereof.
The present invention has been described with respect to certain preferred embodiments. However, the present invention should not be limited to the particular features described. Instead, the scope of the invention should be determined by the following claims.

Claims

1. A system for producing molybdenum-99, comprising:

an alpha particle source for producing an alpha particle beam having a beam diameter and a beam axis; and

a target comprising zirconium-96 arranged such that at least a portion of the alpha particle beam intersects the target, the target capable of producing an irradiated material comprising molybdenum-99 when the target is exposed to the alpha particle source.

2. The system according to claim 1, wherein the target is enriched in zirconium-96.

3. The system according to claim 2, wherein the target has a zirconium-96 concentration of at least about 10%.

4. The system according to claim 2, wherein the target has a zirconium-96 concentration of at least about 50%.

5. The system according to claim 2, wherein the target has a zirconium-96 concentration of at least about 90%.

6. The system according to claim 2, wherein the target has a zirconium-96 concentration of about 95%.

7. The system according to claim 1, wherein the target has a thickness when positioned substantially parallel relative to the beam axis of from about 0.05 mm to about 1 mm.

8. The system according to claim 1, wherein the target has a width when positioned substantially perpendicular relative to the beam axis of less than about the beam diameter.

9. The system according to claim 1, wherein the target comprises a disk, a ribbon, a wire or combinations thereof.

10. The system according to claim 9, wherein the disk is rotatable relative to the beam axis.

11. The system according to claim 10, wherein the disk has a diameter of from about 1 to about 30 cm.

12. The system according to claim 1, further comprising a bath for harvesting irradiated material from the target.

13. The system according to claim 1, further comprising a focused ion beam source for removing irradiated material from the target.

14. The system according to claim 1, further comprising means for removing irradiated material from the target.

15. The system according to claim 1, wherein the alpha particle source is a table-top generator.

16. The system according to claim 14, wherein the target has a thickness such that it can be irradiated to a depth of at least about 100 μms to produce molybdenum-99, irradiated material on the target harvested, and unexposed target material irradiated a second time to produce molybdenum-99.

17. The system according to claim 1, wherein the alpha particle source is a cyclotron.

18. The system according to claim 1, wherein the alpha particle source is an accelerator.

19. The system according to claim 1, wherein the alpha particle beam has a flux of at least about 10¹⁶α/(cm²)s.

20. The system according to claim 1, wherein the alpha particle beam has an energy of from about 10 to about 30 MeV.

21. The system according to claim 1, wherein the alpha particle beam has an energy distribution centered at about 15 MeV.

22. The system according to claim 1, wherein the alpha particle beam is substantially monoenergetic having an energy of about 15 MeV.

23. A process for producing molybdenum-99, comprising:

providing a zirconium target; and

irradiating at least a portion of the target with alpha particles, thereby producing an irradiated target portion comprising molybdenum-99.

24. The process according to claim 23, further comprising separating the molybdenum-99 from other target species.

25. The process according to claim 24, wherein separating comprises chemical separation.

26. The process according to claim 25, wherein separating comprises mass difference separation.

27. The process according to claim 26, wherein the mass difference separation comprises plasma separation.

28. The process according to claim 23, further comprising removing at least a part of the irradiated target portion from the target.

29. The process according to claim 23, wherein removing comprises contacting the irradiated target portion with a solvent thereby producing an irradiated target solution.

30. The process according to claim 29, wherein the solvent is aqua regia.

31. The process according to claim 30, further comprising evaporating the aqua regia, thereby yielding a residue comprising zirconium and molybdenum-99.

32. The process according to claim 31, further comprising contacting the residue with an alkaline solution to selectively dissolve molybdenum species.

33. The process according to claim 23, wherein the irradiating at least a portion of the target includes exposing the target to an alpha particle beam having a flux of at least about 10¹⁶α/(cm²)s.

34. The process according to claim 30, further comprising adjusting the concentration of the irradiated target solution to a chloride molarity of from about 4 to about 8 and subjecting the solution to ion exchange chromatography.

35. The process according to claim 23, further comprising contacting the target with a fluoridating agent.

36. The process according to claim 35, wherein contacting the irradiated target with the fluoridating agent produces fluoride species comprising MoF₅, MoF₆or both.

37. The process according to claim 36, wherein the fluoridating agent comprises at least one of NF₃and HF.

38. The process according to claim 36, wherein contacting the irradiated target with the fluoridating agent comprises activating the fluoridating agent with microwave radiation.

39. The process according to claim 28, wherein removing at least a part of the irradiated target portion from the target comprises sputtering.

40. The process according to claim 39, wherein sputtering employs a focused ion beam.

41. The process according to claim 28, wherein removing at least a part of the irradiated target portion from the target comprises mechanical milling.

42. The process according to claim 28, wherein removing and irradiating are performed in a continuous process.

43. Molybdenum-99 produced by the process of claim 23.

44. A technetium generator comprising molybdenum-99 produced by the process of claim 23.

45. A process for producing technetium-99m, comprising:

providing a zirconium target comprising at least about 50% zirconium-96; and

irradiating the zirconium target with alpha particles, thereby producing an irradiated target comprising molybdenum-99.

46. The process according to claim 45, further comprising purifying the molybdenum-99 to produce purified molybdenum-99.

47. The process according to claim 46, further comprising loading the purified molybdenum-99 onto an adsorbent column.

48. The process according to claim 47, further comprising allowing at least a portion of the purified molybdenum-99 to decay to technetium-99m.

49. The process according to claim 48, further comprising eluting the technetium-99m from the adsorbent column.

50. Technetium-99m produced by the process of claim 49.

51. A process, comprising:

providing a target comprising zirconium;

irradiating the target;

removing a portion of the target including molybdenum-99 formed during irradiation; and

irradiating a remaining unexposed portion of the target.

52. The process according to claim 51, further comprising purifying molybdenum-99 from the removed portion of the target.

53. The process according to claim 52, wherein purifying molybdenum-99 comprises ion-exchange chromatography.

54. The process according to claim 52, wherein purifying molybdenum-99 comprises selectively dissolving molybdenum-99 in a solvent.

55. The process according to claim 52, wherein purifying molybdenum-99 comprises forming a molybdenum fluoride.

56. A medical radioisotope composition consisting essentially of zirconium and molybdenum-99.

57. A composition comprising at least one molybdenum fluoride, wherein the molybdenum fluoride comprises molybdenum-99.

58. The composition according to claim 57 wherein the molybdenum fluoride comprises at least about 80% molybdenum-99.

59. The composition according to claim 57, wherein the molybdenum fluoride comprises at least about 90% molybdenum-99.

60. The medical radioisotope composition according to claim 56, further comprising a carrier.

61. A medical radioisotope composition, comprising molybdenum-99, wherein the medical radioisotope composition has an SPA value of at least about 19.2×10⁴Ci/gm at discharge.

62. The medical radioisotope composition according to claim 61, wherein the medical radioisotope composition has an SPA value of at least about 38×10⁴Ci/gm at discharge.

63. A medical radioisotope composition, comprising molybdenum-99, wherein the composition is substantially free of actinides.

64. The medical radioisotope composition according to claim 61, wherein the medical radioisotope composition is substantially free of radioactive isotopes of strontium, ruthenium, tellurium and iodine.

65. The medical radioisotope composition according to claim 61, further comprising a carrier.

66. The medical radioisotope composition according to claim 65, wherein the carrier comprises saline.

67. The medical radioisotope composition according to claim 61, further comprising a technetium generator.

68. A medical radioisotope composition, comprising:

molybdenum-99;

at least one of molybdenum-93m and niobium-96; and

a carrier.

69. The medical radioisotope composition according to claim 68, wherein the carrier is saline.

70. The medical radioisotope composition according to claim 68, contained in a technetium generator.

71. A zirconium target for the production of molybdenum-99, comprising a zirconium disk, the disk being mounted on a spindle, such that the disk is rotatable about an axis substantially parallel to the disk's smallest dimension, wherein the zirconium disk is capable of producing molybdenum-99 when irradiated with an alpha particle source.

72. The zirconium target according to claim 71, wherein the target is enriched in zirconium-96.

73. The zirconium target according to claim 71, wherein the spindle is electrically connected to the disk and to ground.

74. A target for the production of molybdenum-99, comprising a substrate and a coating comprising zirconium-96, wherein the target is capable of producing molybdenum-99 when irradiated with an alpha particle source.

75. The target according to claim 74, further comprising an interlayer between the coating and the substrate.

76. The target according to claim 74, wherein the coating is enriched in zirconium-96.

77. The target according to claim 74, wherein the coating has a thickness of from about 200 μm to about 1 cm.

78. The target according to claim 74, wherein the coating is sputter-coated on the substrate.