Method of preparing a solution comprising w-188

Abstract

Disclosed are methods for preparing W-188 solutions, and to methods for obtaining Re-188 from W-188 solutions.

Description

METHOD OF PREPARING A SOLUTION COMPRISING W-188FIELD OF THE INVENTION

[0001] The present invention relates to methods for preparing W-188 solutions, and to methods for obtaining Re-188 from W-188 solutions.BACKGROUND OF THE INVENTION

[0002] The present invention relates to providing W-188 solutions, as a source for generating Re-188. There is a need for Re-188 in therapeutic applications such as the treatment of cancer lesions on or near surfaces of the human body, and in cosmetic applications such as the treatment of scar tissue.

[0003] The most common type of skin cancer is basal cell carcinoma (BCC) usually developing on sun-exposed areas such as the head and neck. Squamous cell carcinoma (SCC) also appears on sun-exposed areas of the body. SCC can also develop in scars or chronic skin sores and the skin of the genital area.

[0004] Radiation therapy using electron beams or low energy X-rays ("soft" X-rays) is one option for treating severe cases of cancer. However, radiation therapy is contraindicated for some non-melanoma skin cancers such as verrucous carcinoma (VC) and patients with genetic predisposition to skin cancer and connective tissue diseases. Further, due to potential negative effects of radiation exposure, radiation therapy is not recommended for patients younger than 60 years. The reason for these constraints is the fact that these therapies affect not only the tumor, but as well affect healthy surrounding and deeper tissue.

[0005] The common approach for radiotherapy implies treatment normally over 4 to 7 weeks in daily radiation doses. The only option for patients that cannot undergo such treatments, or where such treatments turned out unsuccessful, is the use of chemotherapy with significant comorbidity and only a low rate of response.

[0006] In an alternative approach, using radioactive material with low penetration emissions applied directly to the abnormal skin, a very local radiation therapy can be performed allowing for flexibility regarding the lesion extension and site. It has been demonstrated that a synthetic inertresin matrix containing radioactive material can be effectively applied on the surface of a BCC or SCC. One suitable radioactive material for such treatment is the rhenium isotope Re-188.

[0007] After topic application on a (cancerous) skin region, a synthetic inert resin matrix containing such radioactive material dries out within few seconds into a flexible film, and irradiation can be performed strictly limited to the affected area. Depending on intended irradiation dose and penetration depth, rather short treatment times, such as 45 to 90 minutes, typically achieve the desired results. A protective foil placed between skin and the paint is used to avoid direct skin contact with the radioactive material, and can be removed together with the hardened resin after the treatment.

[0008] Naturally occurring rhenium has only one stable isotope, Re-185, which occurs in minority abundance of 37.4%. The major natural isotope is Re-187 (62.6%), which is unstable but has a long half-life (i.e. 4.16*1O10years). Re-186 and Re-188 are artificial isotopes that are used, for example, as radioactive tracer and for other applications in nuclear medicine.

[0009] The beta-emitter Re-188 has proved to be an ideal choice as a radioactive source for radionuclide therapy. Re-188 has a half-life of about 17 hours (decaying to Os-188), and the average penetration of its irradiation into the skin is about 2 to 3 mm (92% of its deposited dose is below 3 mm depth). This is sufficient to treat most BCC and SCC without damaging lower layers of the skin and underlying tissue. Besides beta-emission, Re-188 also emits to about 15% gammairradiation of 155 keV which enables the use of standard nuclear medicine technologies to detect potential contamination.

[0010] Not contemplated by the present invention, but mentioned for better understanding, the beta-emitter Re-186 as well is a suitable radioactive source for radionuclide therapy. Re-186 has a half-life of about 89.25 hours and the average penetration of its irradiation into the skin is about 1.0-1.2 mm (94% of its deposited dose is below 1.0 mm depth). This is sufficient to treat thin BCC and SCC or BCC and SCC located in areas with thin skin (e.g. eye lids, ears) or mucous membranes (lips, genitals) without damaging lower layers of the underlying tissue.

[0011] The suitability of Re-188 as a radioactive source has been demonstrated in an Italian study with over 750 patients, wherein a large variety of BCC and SCC forms, i.e. tumors of verylarge size to relapsing or recurrent forms and multifocal lesions, have been treated successfully in 99% of over 2,000 lesions.

[0012] Re-188 is generated using W-188 / Re-188 generators. Clinics which are able to offer a treatment with Re-188 have their own W-188 / Re-188 generators, and accordingly Re-188 is generated at the location where it is subsequently used in therapy. The current method therefore provides short paths, which is particularly advantageous in view of the short half-life of about 17 hours of Re-188. The possibility to generate Re-188 on-site therefore has been considered as an essential practical requirement for the use of Re-188 in radionuclide therapy.

[0013] Tungsten naturally occurs in several stable isotopes (W-182, W-183, W-184, W-186), accounting together for 99.87% of naturally occurring tungsten. W-180 (0.13%) is a naturally occurring, extremely long-lived unstable isotope, exhibiting a half-life of 1.8*1018years. W-178, W- 179, W-181, W-185, W-187 and W-188 are known artificial isotopes of tungsten. W-188 is a betaemitter decaying to Re-188 with a half-life of 69.4 days, and is used in the production of Re-188.

[0014] The availability of Re-188 in sufficient radioactive concentration is a considerable challenge. Starting from the naturally occurring stable isotope W-186 (abundancy of 28.6%), a double neutron capture route is required for generating W-188, i.e. the parent radionuclide for Re-188. This impedes the availability of Re-188, since W-188 at adequate specific activity can be prepared only in as little as four high flux reactors operating in the world (ORNL; RIAR; BR2; ILL).

[0015] Currently, the main global commercial supply of tungsten-188 (W-188, half-life 69.4 days) is provided by two sources, namely the Oak Ridge National Laboratory (ORNL) in Oak Ridge, USA, and the Research Institute of Atomic Reactors (RIAR) in Dimitrovgrad, Russia. For the double neutron capture reaction: W-186(n,y)W-187(n,y)W-188, a high thermal neutron flux of > lxlO14or even > lxlO15neutrons / cm2 / s needed. Both of the above suppliers host a nuclear research reactor with high thermal neutron flux, namely the "High Flux Isotope Reactor" (HFIR) in ORNL and the "SM-3" reactor in RIAR.

[0016] Generally, irradiation of tungsten enriched in W-186 to produce W-188 is performed by irradiating either tungsten trioxide (WO3) or tungsten metal (W) targets.

[0017] In order to generate W-188 as a source for generating Re-188, ORNL irradiates targets of tungsten metal enriched in W-186, which irradiated targets are subsequently oxidized in targetprocessing to tungsten trioxide WO3. In practice, this oxidation is done by flame burning in oxygen gas. The WO3 powder obtained by the flame burning process then is dissolved in an alkaline environment, i.e. in hot sodium hydroxide (NaOH) under oxidative conditions. The oxidative conditions are needed to ascertain that the oxidation state of tungsten (VI) is maintained. The product obtained in this alkaline dissolution of WO3 in hot sodium hydroxide is sodium tungstate (Na2WO4) (Callahan et al., 1989). One obvious disadvantage of the ORNL process is the oxidation step. Flame burning of a radioactive material is undesired for safety reasons. A further disadvantage of the ORNL process is the dissolution step, which is ineffective and time consuming.

[0018] RIAR takes an alternative approach, by directly irradiating WO3 targets. This approach makes the flame burning step of the ORNL process superfluous. The irradiated WO3 targets subsequently are processed in the same manner as in the ORNL process, i.e. by dissolving in hot NaOH under oxidative conditions, to yield sodium tungstate (Na2WO4). RIAR also further purifies the Na2WO4 solution to improve its radionuclidic purity (IAEA, 2003; Kuznetsov, 2003; Toporov et al., 1997). The RIAR process is able to avoid the disadvantages associated with the flame burning step of the ORNL process, but otherwise is believed to be similar ineffective and time consuming as the ORNL process.

[0019] There is need in the art for efficient methods that are able to provide W-188, in a physical form suitable for generating Re-188, in order to be able of providing the required commercial supply of this radionuclide for therapeutic and cosmetic applications. The method should be safe, cost efficient in production and manageable in terms of radiation protection. Further the method should, if possible, reduce or avoid the drawbacks of the prior art methods for providing the commercial supply of W-188.SUMMARY OF THE INVENTION

[0020] The inventors of the present invention developed a novel pathway for producing W- 188 solutions, by directly irradiating tungsten metal targets and directly dissolving the irradiated tungsten metal targets in liquid medium, in the presence of a peroxide source such as H2O2. The resulting solution comprising W-188 in the form of tungstic acid (H2WO4) contains the tungsten metal target in quantitatively dissolved form. The solution optionally may be further processed for providing W-188 / Re-188 generators, and obtaining Re-188 from the W-188 / Re-188 generators.

[0021] The method according to the present invention represents a departure from the teachings and methods of the prior art. The present invention directly irradiates tungsten metal targets. The irradiated tungsten metal targets conveniently may be dissolved in liquid medium, such as aqueous medium, in the presence of a peroxide source such as H2O2. A strong alkaline medium such as required in the methods of the prior art is not necessary, and the required dissolution times are significantly shortened.

[0022] Subject matter of the present invention is a method for preparing a solution comprising W-188, as defined in claim 1. The dependent claims relate to particular embodiments thereof.

[0023] According to the present invention, a method for preparing a solution comprising W- 188 comprises:(a) providing a tungsten composition comprising W-186 atoms,(b) forming the tungsten composition to a tungsten metal target,(c) sintering the tungsten metal target,(d) irradiating the tungsten metal target with neutrons, wherein at least a part of the W- 186 atoms undergoes a double neutron capture,(e) dissolving the irradiated tungsten metal target in a liquid medium comprising at least one peroxide source.

[0024] According to embodiments, the method may further comprise preparing a solution comprising Re-188 from the solution comprising W-188.DEFINITIONS

[0025] As used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise.

[0026] The terms "comprising", "comprises" and "comprised of" as used herein are synonymous with "including", "includes" or "containing", "contains", and are inclusive or open- ended and do not exclude additional, non-recited members, elements or method steps. It will be appreciated that the terms "comprising", "comprises" and "comprised of" as used herein comprise the terms "consisting of", "consists" and "consists of".

[0027] The term "may" in the context of this application means "is permitted to" or "is able to" and is a synonym for the term "can." The term "may" as used herein does not mean possibility or chance.

[0028] The term "and / or" in the context of this application means one or the other or both. For example, an aqueous solution of A and / or B means an aqueous solution of A alone, an aqueous solution of B alone and an aqueous solution of a combination of A and B.

[0029] As used herein, the term "optionally" means that the corresponding step or feature may or may not be present. It includes both possibilities.

[0030] Unless specifically indicated otherwise, all values, ranges, percentages etc. in the present disclosure are "by-weight". Further, the total amount of components for a given entity adds up to 100 percent-by-weight.

[0031] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

[0032] The term "composition" as used herein denotes a mixture or blend comprising at least two components. Compositions may comprise at least two particle components, for example at least two tungsten metal particles, or two particles in the form of tungstate. Other compositions comprise at least one functional component (such as, for example, a peroxide) and at least one solvent component (such as water). A composition may be present in any suitable physical form,for example in the form of powders, or in the form of liquids of varying viscosities (including solutions and dispersions).

[0033] Terms such as "W-188" or "Re-188" are used herein to denote isotopes, or radionuclides. These terms are used herein interchangeably with terms such as for example "188W" or "188Re". The terms are intended to increase the readability by attempting to avoid superscripts. Analogously, terms such as "Na2WO4" are used herein interchangeably with terms such as for example "Na2WO4", and are intended to increase the readability by attempting to avoid subscripts.

[0034] As used herein, the term "tungsten metal" denotes the metal, i.e., the element tungsten (W). The term "tungsten" as used herein encompasses oxidized forms such as tungsten oxide (WO3), tungstic acid (H2WO4), monomeric tungsten acid anions (tungstates) such as for example hydrogen tungstate (HWO4 and tungstate (WO42, and oligomeric or polymeric tungsten acid anions such as ditungstate (W2O72), paratungstate (W7O246), tungstate Y (W10O324), or metatungstate (W12O406).

[0035] The term "target" as used herein denotes a shaped body which has sufficient structural rigidity in order to withstand destruction or disintegration due to mechanical forces during handling and, more importantly, to withstand destruction or disintegration under the harsh reactor conditions during irradiation cycles (typically lasting several weeks). During irradiation, tungsten targets inside the reactor are exposed to high temperature and pressure. These conditions, together with formation of rhenium and osmium isotopes in high thermal neutron flux, such as volatile osmium-191 (half-life 15.4 days), create a harsh environment which demands high structural stability from the targets.

[0036] "Tungsten metal targets" as used herein may be formed from tungsten metal, in particular by tungsten (metal) powders of any suitable particle size, or from tungsten in dissolved or dispersed form, such as tungstate. For forming a "tungsten metal target", tungsten powder such as tungsten oxide powder may be compacted by conventional techniques to any desired shape, and the shaped body obtained is heat-treated under a reducing atmosphere for converting the tungsten oxide to tungsten metal. Alternatively, for forming a "tungsten metal target", tungsten metal powder may be compacted by conventional techniques to any desired shape, and the shaped body obtained optionally may be heat-treated for further stabilization. Irrespective ofthe method or starting material used, "tungsten metal powder(s)" and "tungsten metal targets" preferably are handled under an atmosphere essentially free of oxygen, or free of oxygen, in order to avoid surface oxidation. Further, irrespective of the method or starting material used, the "tungsten metal targets" obtained are subsequently sintered (again under an atmosphere essentially free of oxygen, or free of oxygen) in order to provide them with the required structural rigidity for withstanding reactor conditions.

[0037] According to an alternative approach, "tungsten metal targets" may be prepared from dissolved or dispersed tungsten, in particular by 3D-printing. 3D-printed targets typically are prepared by 3D-printing of a tungsten target precursor using an ink comprising dissolved tungsten or dispersed tungsten (oxide). Such inks typically comprise a polymerizable organic system to provide the necessary shape for a 3D-printed article. Alternatively, such inks may comprise organic rheology modifiers providing a viscosity high enough for a 3D-printed article essentially maintaining the designed shape by drying. After printing, the tungsten target precursors typically are dried, and any organic matter is removed by decomposition. The tungsten targets obtained are heat-treated under a reducing atmosphere for converting tungsten in any form present to tungsten metal, As above, and "tungsten metal targets" preferably are handled under an atmosphere essentially free of oxygen, or free of oxygen, in order to avoid surface oxidation, and are subsequently sintered (again under an atmosphere essentially free of oxygen, or free of oxygen) in order to provide them with the required structural rigidity for withstanding reactor conditions.

[0038] The term "target" is intended in particular for distinction over bulk tungsten (metal) powders, or bulk aggregates of tungsten (metal) powders. Powders are disadvantageous from a handling viewpoint and, more importantly, from a reactor safety viewpoint. Neutron capture as a result of the irradiation causes a volume change of the material. For bulk powders, such volume change may easily damage the containers used for sealing the targets during the irradiation inside the high thermal neutron flux reactor. Damaged containers per se are inacceptable for operational safety of the reactor, and inacceptable for the laboratory processing the irradiated targets.

[0039] The exact physical form or dimensions of the targets are uncritical for the present invention. It is recommendable, however, to avoid massive, big-sized targets, as massive targets contribute to prolonging the time required for dissolution. Another disadvantage of large targets isgreater self-absorption of neutrons, which lowers irradiation efficiency. The inventors found out, that a ring-shape or donut-shape is convenient for rapid dissolution of the (irradiated) targets. It is believed that a donut-shape provides for sufficient structural rigidity, and simultaneously is able to provide a favourable ratio of surface area to volume in order to favour dissolution of the targets in the presence of peroxide according to the present invention. Suitable dimensions for donutshaped tungsten metal targets include outside diameters in the millimetre range, for example 2.0 to 12.0 mm, and donut tori in the submillimetre to millimetre range, for example 0.50 to 4.0 mm. Donut-shaped tungsten metal targets having an outside diameter of about 5.50 mm, a diameter of the donut torus of about 1.50 mm, and a weight of approximately 0.750 grams per target, have been processed, for example, with the method according to the present invention, and gave highly satisfying results.

[0040] The term "irradiating" is used herein to refer to the process by which tungsten metal targets are exposed, according to the invention, to a neutron flux. Depending on the irradiation facility, the thermal neutron flux density may vary. For the required double neutron capture reaction, high flux reactors providing for a high thermal neutron flux of > lxlO14or even > lxlO15neutrons / cm2 / s are needed. The exposition time (interval) required typically is several weeks, and the exact duration is decided by the reactor operator. Irradiation by high thermal neutron flux inside the reactor implies a harsh environment for the targets, involving high temperature and pressure, and formation of rhenium and osmium isotopes, and inter alia the formation of volatile isotopes.

[0041] The term "sintering" as used herein is defined as the thermal transformation of bulk materials into compact solids at temperatures below their melting point. In the sintering process, porosity in targets made from compacted powder particles is decreased to form a solid mass. In the sintering process, material diffuses to pores, which diffusion process is facilitated by high temperatures.

[0042] The term "about" is understood to mean ±10.0 percent of the recited number, numbers or range of numbers. According to embodiments, the term "about" is understood to mean ±2.0 percent of the recited number, numbers or range of numbers.

[0043] Ranges defined throughout the specification include the end values, i.e. a range of 1 to 10 implies that both 1 and 10 are included in the range. For the avoidance of doubt, the applicant shall be entitled to any equivalents according to applicable law.

[0044] The term "consisting essentially of" denotes the absence of additional, not specifically recited components in an entity such as a composition in an amount of more than 1.0% by weight, based on the total weight of the entity. In particular, the term "consisting essentially of" denotes the absence of additional, not specifically recited components in an amount of more than 0.5% by weight, for example more than 0.1% by weight, such as more than 0.01% by weight in an entity. It goes without saying that any additional, not specifically recited component is compatible with the specifically recited components and does not interfere with the function thereof.

[0045] The term "consisting of" denotes the absence of additional, not specifically recited components in an entity such as a composition in an amount below the detection limit, assuming that detectability is on a ppm (parts per million) basis (by weight). In particular, the term "consisting of" denotes the absence of additional, not specifically recited components in an amount of more than 50 ppm-by-weight, for example more than 10 ppm-by-weight, such as more than 10 ppm-by-weight in an entity. It goes without saying that any additional, not specifically recited component is compatible with the specifically recited components and does not interfere with the function thereof.

[0046] The term "essentially free" of a particular component denotes an amount of less than 1.0% by weight of the respective component in an entity such as a composition, based on the total weight of the entity. In particular, the term "essentially free" denotes an amount of less than 0.5% by weight, for example less than 0.1% by weight, such as less than 0.01% by weight of the respective component in the entity.

[0047] The term "free" of a particular component denotes an amount below the detection limit, assuming that detectability is on a ppm (parts per million) basis (by weight). In particular, the term "free" of a particular component denotes an amount below 50 ppm-by-weight, for example less than 10 ppm-by-weight, such as less than 5 ppm-by-weight of the respective component in the entity.

[0048] Reference throughout this specification to "one embodiment" or "preferred embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases "in one embodiment" or "in a preferred embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment but may refer to different embodiments of the present invention. Furthermore, the features, structures or characteristics may be combined in any suitable manner, as would be apparent to a person skilled in the art from this disclosure, in one or more embodiments. Furthermore, while some embodiments described herein include some, but not other features included in other embodiments, combinations of features of different embodiments are meant to be within the scope of the subject matter, and form different embodiments, as would be understood by those in the art. For example, in the appended claims, any of the claimed embodiments can be used in any combination.

[0049] Every document cited herein, including any cross referenced or related patent or application, is hereby incorporated herein by reference in its entirety unless expressly excluded or otherwise limited. The citation of any document is not an admission that it is prior art with respect to any invention disclosed or claimed herein or that it alone, or in any combination with any other reference or references, teaches, suggests, or discloses any such invention. Further, to the extent that any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term in this document shall govern.

[0050] Measurement techniques described herein are well known to a person skilled in the art and therefore do not limit the present invention.

[0051] In the following disclosure, different aspects of the subject matter are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.DETAILED DESCRIPTION OF THE INVENTION1 Method for preparing W-188 solutions

[0052] Subject matter of the present invention is a novel pathway for producing W-188 solutions, by irradiating tungsten metal targets and directly dissolving the irradiated tungsten metal targets in liquid medium, in the presence of a peroxide source such as H2O2. The resulting solution comprising W-188 in the form of tungstic acid (H2WO4) contains quantitatively dissolved tungsten metal target. The solution optionally may be further processed chemically, by removing impurities or by-products, and by concentrating on generator columns, if desired. The W-188 solutions obtainable by the present invention are suitable for providing W-188 / Re-188 generators, and for obtaining Re-188 from the W-188 / Re-188 generators. The Re-188 produced is an important radionuclide for therapeutic applications such as the treatment of cancer lesions on body surfaces, and in cosmetic applications such as the treatment of scar tissue.

[0053] Subject matter of the present invention accordingly is a method for preparing a solution comprising W-188. The method according to the present invention comprises:(a) providing a tungsten composition comprising W-186 atoms,(b) forming the tungsten composition to a tungsten metal target,(c) sintering the tungsten metal target,(d) irradiating the tungsten metal target with neutrons, wherein at least a part of the W- 186 atoms undergoes a double neutron capture,(e) dissolving the irradiated tungsten metal target in a liquid medium comprising at least one peroxide source.

[0054] According to embodiments, the tungsten composition used in step (a) of the present invention may be a tungsten metal composition comprising minor amounts of processing aids, but typically formed by 98.0 or more percent-by-weight of tungsten metal, based on the total weight of the composition. According to preferred embodiments, the tungsten metal composition essentially consists of tungsten metal (powder). According to a specific embodiment, the tungsten metal composition consists of tungsten metal (powder).

[0055] The particle size and particle size distribution of the tungsten metal powder in the tungsten metal composition is not particularly limited, provided the tungsten metal powder has aparticle size and particle size distribution suitable for being processed into a shaped target body. An average particle size within the range of 0.10 to 500.0 pm of the tungsten metal powder is considered suitable for the purposes of the present invention. Typically, the average particle size of the tungsten metal powder may be within the range of 0.50 to 200.0 pm. For example, the tungsten metal powder may have an average particle size within the range of 1.0 to 100.0 pm.

[0056] Forming the tungsten metal composition to a tungsten metal target in step (b) is not particularly limited, and may be done by conventional techniques. For example, according to embodiments, the tungsten metal composition may be provided in a mold cavity, and compacted by applying pressure. The compacted body of tungsten metal starting material is sufficiently stable to withstand handling operations, at least the handling operations required at this stage of the method. Pressed sintered targets instead of bulk powders provide for operational safety in handling, during the reactor stage, and later on in the processing laboratory. In case tungsten metal should escape the container(s) in which the material is sealed during irradiation and processing, handling of (shaped) targets provides by far more safety than handling of a powdery target material.

[0057] Further stabilization of the compacted tungsten metal target may be achieved by heat treatment. If a heat treatment is carried out, the exact temperature for a stabilizing heat treatment is not critical. A suitable temperature range is, for example, 650-880°C. According to embodiments, such stabilizing heat treatment may be carried out for example at a temperature within a range of 700-850°C, for example at a temperature of about 850°C. The duration of the stabilizing heat treatment again is uncritical. Intervals of 0.5 to 5.0 hours were found out to give sufficient stabilization for handling operations before sintering. According to embodiments, the stabilizing heat treatment may be carried out, for example, for an interval of 1.0 to 4.0 hours.

[0058] When the tungsten metal target is prepared using a tungsten metal composition as starting material, all steps involving "tungsten metal powder(s)" and "tungsten metal targets", including in particular steps (a) and (b), preferably are handled under an atmosphere essentially free of oxygen, or free of oxygen, in order to avoid surface oxidation. For example, the steps may be carried out under a hydrogen atmosphere essentially free of oxygen, or free of oxygen.

[0059] According to other embodiments, the tungsten composition used in step (a) of the present invention may comprise tungsten in an oxidic form, i.e. in the form of tungstate(s)(tungstic acid) or tungsten oxide(s). An oxidic tungsten composition may comprise minor amounts of processing aids, but typically is formed by 80.0 or more percent-by-weight of oxidic tungsten, based on the total weight of the composition. According to preferred embodiments, the tungsten composition essentially consists of, or consists of tungsten oxide (powder). Again, particle size and particle size distribution of oxidic tungsten powder in the tungsten composition is not particularly limited, and average particle sizes within the range of 0.10 to 500.0 pm of oxidic tungsten powder is considered suitable for the purposes of the present invention. Typically, the average particle size of oxidic tungsten powder may be within the range of 0.50 to 200.0 pm, for example, within the range of 1.0 to 100.0 pm.

[0060] Forming the tungsten composition to a tungsten metal target in step (b) again is not particularly limited, and may be done, for example, by compacting a tungsten composition provided in a mold cavity by applying pressure. The compacted body of oxidic tungsten starting material is sufficiently stable to withstand handling operations, at least the handling operations required at this stage of the method. Further stabilization of the compacted tungsten target is achieved by heat treatment, which heat treatment is carried out under a reducing atmosphere. The reducing atmosphere converts oxidic tungsten in any form present to tungsten metal, in order to provide the "tungsten metal targets" to be used in the subsequent step(s) of the method according to the present invention. The reducing atmosphere conveniently is a hydrogen atmosphere essentially free of oxygen, or free of oxygen. The temperature for the heat treatment is not particularly critical. A suitable temperature range is, for example, 650-880°C. According to embodiments, the heat treatment under the reducing atmosphere may be carried out for example at a temperature within a range of 700-850°C, for example at a temperature of about 850°C. The duration of the heat treatment again is uncritical, and intervals of 0.5 to 5.0 hours were found sufficient for reducing oxidic tungsten to tungsten metal, and for achieving the stabilization required for handling operations before sintering. According to embodiments, the heat treatment may be carried out, for example, for an interval of 1.0 to 4.0 hours. Any further handling of the "tungsten metal targets" preferably is carried out in an inert atmosphere essentially free of oxygen, or free of oxygen, such as a hydrogen atmosphere.

[0061] According to other embodiments, the tungsten composition used in step (a) may be a fluid composition comprising tungsten in dissolved and / or dispersed form. Such fluid tungsten composition further comprises a solvent, typically an aqueous solvent. For example, the solventessentially may comprise water, and optionally one or more organic chelating agents, which may assist in holding the tungsten in dissolved or dispersed form. The fluid composition may further comprise organic rheology modifiers for adjusting rheological characteristic of the composition.

[0062] According to embodiments, the fluid tungsten composition is an ink suitable for 3D- printing. 3D-printing inks typically comprise a polymerizable system, in particular a photopolymerizable system for curing the printed ink in the desired shape. Polymerizable systems include one or more polymerizable monomers, and optionally a crosslinker. Photopolymerizable systems typically further include a photoinitiator. A suitable 3D ink for use in the present invention may comprise 20.0 to 60.0 percent-by-weight ammonium metatungstate or paratungstate, 30.0 to 40.0 percent-by-weight water, 10.0 to 30.0 percent-by-weight monomer, 0.20 to 2.50 percent-by- weight crosslinking agent, and 0.20 to 2.50 percent-by-weight photoinitiator, each based on the total weight of the 3D ink, and wherein all components sum up to 100.0 percent-by-weight. An exemplary 3D ink for use in the present invention may comprise about 50.0 percent-by-weight ammonium metatungstate, about 35.0 percent-by-weight water, about 15.0 percent-by-weight acrylic acid monomer, about 1.0 percent-by-weight crosslinking agent, and about 1.0 percent-by- weight photoinitiator, each based on the total weight of the 3D ink, and wherein all components sum up to 100.0 percent-by-weight. TPO (2,4,6-trimethylbenzoyl-diphenylphosphine oxide) is suitable, for example, as a photoinitiator. PEGDA (polyethylene glycol dimethacrylate) is suitable, for example, as a crosslinker.

[0063] According to embodiments, step (b) of the method according to the present invention comprises 3D-printing the fluid tungsten composition, thereby producing a tungsten target precursor, which precursor subsequently is first converted to a tungsten target, and finally is converted to the "tungsten metal target" for irradiation in step (d) of the method according to the present invention. 3D-printing is carried out as is usual in the art by printing thin layers of the composition (having a thickness for example in the range of 20.0 to 500.0 micrometers, such as about 100.0 micrometers), and subsequently curing the layers, such as by exposing the printed layer(s) to radiation having a suitable wavelength for the photoinitiator.

[0064] The 3D-printed tungsten target precursors subsequently are dried, under conditions compatible with the cured organic system, and avoiding harsh conditions in order to reduce breakage. Suitable drying conditions encompass, for example, drying at room temperature forseveral days, followed by drying at temperatures of about 50.0 to 80.0°C. Drying may be carried out in ambient air. During the drying step, the 3D-printed tungsten target precursors typically shrink significantly, in the order of 10.0 to 20.0 percent.

[0065] Converting 3D-printed tungsten target precursors to tungsten targets comprises decomposing organic matter originating from the fluid composition and the 3D-printing method, such as organic chelating agents, organic rheology modifiers, unreacted components of the (photo)polymerizable system, cured (polymerized) organic matter, and ammonia originating from the counter ion. Decomposing organic matter conveniently may be done by exposing the organic matter to elevated temperatures, for example in a reducing atmosphere such as a hydrogen atmosphere. Conditions for decomposing organic matter typically encompass holding the tungsten target precursors at elevated temperatures, for example exposing the tungsten target precursors to a temperature ramp increasing from room temperature up to about 450 to 500°C.

[0066] Converting tungsten targets to tungsten metal targets comprises reducing the oxygen present in oxidic tungsten (tungsten oxide(s) and tungstate(s)), thereby producing pure tungsten (i.e. tungsten metal), or the corresponding targets, respectively. Reducing oxidic tungsten comprises heat treating the tungsten targets under a reducing atmosphere essentially free of oxygen, or free of oxygen. According to embodiments, heat treating is carried out under a hydrogen atmosphere at a temperature within a range of 650-880°C, for example at a temperature within a range of 700-850°C. The duration of the heat treatment is uncritical, and intervals of 0.5 to 5.0 hours were found sufficient for reducing oxidic tungsten to tungsten metal, and for achieving the stabilization required for handling operations before sintering. According to embodiments, the heat treatment may be carried out, for example, for an interval of 1.0 to 4.0 hours. Any further handling of the "tungsten metal targets" preferably is carried out in an inert atmosphere essentially free of oxygen, or free of oxygen, such as a hydrogen atmosphere.

[0067] If desired, the steps of converting 3D-printed tungsten target precursors to tungsten targets by decomposing organic matter, and converting tungsten targets to tungsten metal targets by reducing the oxygen present in oxidic tungsten may be carried out in a single, combined step. A single converting step may be carried out, for example, by exposing the tungsten target precursors, under a reducing (hydrogen) atmosphere essentially free of oxygen, or free of oxygen,to a temperature ramp increasing from room temperature up to a temperature of about 650- 880°C, for example a temperature within a range of 700-850°C.

[0068] The tungsten metal targets obtained in step (b) of the method according to the present invention essentially consist of, or consist of tungsten metal. Considering that the isotope W-186 required for the envisaged double neutron capture route constitutes merely about 28.6% of naturally occurring tungsten, using tungsten metal enriched in W-186 atoms is preferable for improved efficiency. According to embodiments, W-186 atoms constitute 95.0 or more percent- by-weight of the tungsten metal. According to even more specific embodiments, the W-186 atoms constitute 96.0 to 99.99 percent-by-weight of the tungsten metal.

[0069] Following the formation of the tungsten metal targets obtained in step (b) of the method according to the present invention, the tungsten metal targets obtained are further processed in step (c) by sintering in order to provide the target with the structural rigidity required for being able to withstand the harsh reactor conditions. The sintering temperature (and interval) is, to a certain extent a trade-off between structural rigidity and dissolution properties of the irradiated targets in step (e) of the method according to the present invention. Higher sintering temperatures and longer intervals provide for high structural rigidities giving more safety during the long irradiation cycles lasting several weeks, but they slow down the dissolution characteristics. Vice versa, lower sintering temperatures and shorter intervals decrease the structural rigidities, but enable rapid dissolution. Efficient dissolution is an important requirement in target processing, in order to keep processing times as short as possible.

[0070] According to the present invention the sintering of the tungsten metal targets typically is carried out under an inert atmosphere essentially free of oxygen, or free of oxygen. In particular, the sintering step may be carried out under a hydrogen atmosphere essentially free of oxygen, or free of oxygen.

[0071] A suitable temperature range in the sintering step of the tungsten metal targets is rather broad, ranging generally from 900°C to 3400°C. The structural rigidity of the targets obtained when sintering at temperatures near the lower end of the range may be less than desired, in particular when sintering for a short time interval. On the other hand, targets sintered at temperatures near this lower end of the range will have excellent dissolvability, resulting in short processing times. Sintering the targets at temperatures near the upper end of the range willprovide for excellent structural rigidity, but the dissolvability will decrease to an extent considered undesirable. If the targets are sintered at temperature near the higher end of the range, the temperature is selected to be sufficiently below the melting point (of W-186), so that melting or even softening of the targets is avoided (the melting point of naturally occurring tungsten is 3422°C).

[0072] According to embodiments, the temperature in step (c) is selected within the range of 1100°C to 2800°C. For example, the tungsten metal targets may be sintered in step (c) at a temperature within the range of 1150°C to 2400°C, such as 1200°C to 2100°C. From a viewpoint of excellent dissolution characteristics, a sintering temperature range of 1300°C to 1800°C is preferred. A particular preferred sintering temperature range, under a viewpoint of excellent dissolution characteristics, is the range of 1350°C to 1600°C.

[0073] Suitable time intervals for sintering step (c) are not particularly limited, but should be selected sufficiently long in order to obtained the structural rigidity required for irradiation. Generally, time intervals within 3.0 to 12.0 hours are considered suitable for giving the required structural rigidity. Time intervals within the range of 4.0 to 10.0 hours were successfully tested, for example, and time intervals between 4.5 and 6.0 hours for the sintering step are particularly preferred.

[0074] The inventors found out that the appearance of the targets observed near the end or at the end of the sintering step provides an indication of the dissolution behavior of the targets in step (e) according to the present invention. Sintering at higher temperatures results in a glossy appearance of the targets, which in turn implies slower dissolution characteristics. Vice versa, sintering at lower temperatures results in a lusterless appearance of the targets, which in turn implies more rapid dissolution characteristics. It is presently believed that the different appearances are related to surface porosity, with a "glossier" appearance corresponding to lower (or closed) surface porosity and a "lusterless" appearance corresponding to higher (or open) surface porosity. For example, sintering at 1400°C or 1550°C, respectively, yielded tungsten metal targets with higher surface porosity and excellent dissolution characteristics, while sintering at 2800°C yielded tungsten metal targets having excellent structural rigidity, but which needed significantly more time for dissolving.

[0075] Generally, the focus of the present invention is on good dissolution characteristics. Sintered tungsten metal targets having a "lusterless" appearance therefore are usually preferable over the sintered targets having a "glossier" appearance.

[0076] The method according to the present invention preferably avoids oxidation of the tungsten metal starting material to tungsten oxide. Presence of tungsten oxide may have a negative impact on the mechanical stability of the targets, and on the dissolution characteristics. It is therefore preferred, in order to reduce oxidation as far as possible, that all steps until dissolving the targets in step (d) of the method according to the present invention are carried out under an inert atmosphere essentially free of oxygen or free of oxygen.

[0077] According to preferred embodiments, the method according to the present invention therefore comprises carrying out steps (a) through (c) under an inert atmosphere essentially free of oxygen, or free of oxygen. It has been found out that hydrogen gas is a particularly suitable inert gas for use in steps (a) through (c). According to particular embodiments, steps (a) through (c) may be carried out under a hydrogen atmosphere essentially free of oxygen, or free of oxygen.

[0078] For irradiation, the targets necessarily have to be transported to the reactor. In order to facilitate handling of the targets, and to essentially exclude the presence of oxygen from the surrounding atmosphere, the targets preferably are sealed in containers, again under an inert atmosphere essentially free of oxygen, or free of oxygen. It has been found out that helium gas is a particularly suitable inert gas at this stage of the method. Suitable containers include, for example, glass ampoules, quartz (glass) ampoules, titanium metal ampoules and titanium alloy ampoules. The method therefore may further comprise, according to embodiments, prior to irradiating in step (d), sealing the sintered tungsten metal target in a glass or quartz or titanium ampoule under a helium atmosphere essentially free of oxygen, or free of oxygen.

[0079] Irradiation of the sintered tungsten metal targets subsequently is done - as already described above - inside one of the reactors able to provide the required high thermal neutron flux for the double neutron capture reaction. Such reactors typically provide a thermal neutron flux of lxlO14or more neutrons / cm2 / s, for example a thermal neutron flux of lxlO15or more neutrons / cm2 / s.

[0080] After irradiation, the tungsten metal targets are dissolved in step (e) of the method according to the present invention. To that aim, the irradiated radioactive tungsten metal targets are removed from their containers, and added to a liquid medium, in which they are dissolved. The liquid medium used in dissolving step (e) typically will be an aqueous composition. For dissolving step (e), avoiding contact with oxygen such as ambient air oxygen is no longer an issue. Accordingly, there are no particular requirements regarding the atmosphere when removing the targets from the containers, and ambient air is a suitable atmosphere.

[0081] The liquid medium used in dissolving step (e) comprises at least one peroxide source. The usual peroxides are suitable, and the at least one peroxide source of the liquid medium may be selected, for example, from the group consisting of hydrogen peroxide, calcium peroxide, urea peroxide, perborates and percarbonates. The concentrations of the at least one peroxide source used in dissolving step (e) preferably are rather high, in order to effectively dissolve the radioactive tungsten metal targets in short processing times. According to embodiments, the at least one peroxide source is present in an amount in the range of 10.0 to 80.0 percent-by-weight, based on the total weight of the liquid medium. In particular, the concentration of the at least one peroxide source may be in the range of 20.0 to 50.0 percent-by-weight, based on the total weight of the liquid medium. High concentrations of the at least one peroxide source, for example in the range of 35.0 to 50.0 percent-by-weight, based on the total weight of the liquid medium, will provide for conveniently brief dissolution intervals.

[0082] A particularly preferred peroxide source used in the liquid medium of dissolving step (e) is hydrogen peroxide. In case hydrogen peroxide is a peroxide source in the liquid medium, and in particular if hydrogen peroxide is the sole peroxide source in the liquid medium, the hydrogen peroxide preferably may be present in an amount in the range of 10.0 to 60.0 percent-by-weight, based on the total weight of the liquid medium. According to embodiments, the hydrogen peroxide may be present in an amount in the range of 15.0 to 50.0 percent-by-weight, based on the total weight of the liquid medium. According to even more preferred embodiments under a viewpoint of fast dissolution of the irradiated radioactive tungsten metal targets, the hydrogen peroxide may be present in an amount in the range of 20.0 to 40.0 percent-by-weight, based on the total weight of the liquid medium. For example, the hydrogen peroxide may be present in an amount in the range such of 25.0 to 34.90 percent-by-weight, based on the total weight of the liquid medium.

[0083] According to embodiments, the liquid medium used in dissolving step (e) may comprise a peroxide stabilizer. Suitable peroxide stabilizers for the purposes of the present invention comprise phosphoric acid, pyrophosphoric acid, phosphonic acid, salts thereof, and derivates of the foregoing. These peroxide stabilizers may be used alone, or any combination of these stabilizers may be used in dissolving step (e).

[0084] A specific example of a suitable peroxide stabilizer, in particular if the at least one peroxide source is hydrogen peroxide, is aminotrimethylene phosphonic acid (ATMP). According to embodiments of the method using a peroxide stabilizer, the said peroxide stabilizer comprises aminotrimethylene phosphonic acid (ATMP). Stabilizers such as ATMP act by increasing the decomposition temperature of peroxide, in particular hydrogen peroxide, and accordingly are able of reducing the risk of thermal runaway reactions when dissolving the targets in step (e).

[0085] If used, the peroxide stabilizer(s) is / are used in conventional concentrations. ATMP, for example, typically is used in concentrations of up to about 400 ppm. Higher ATMP concentrations do not appear improving any further the protective effect.

[0086] According to embodiments, the liquid medium of dissolving step (e) has a pH below 6.5, that is a pH below 6.5 prior to or at the time when adding the irradiated radioactive tungsten metal targets. A low pH is able of reducing the risk of thermal runaway reactions when dissolving the targets in step (e). Typically, a liquid medium comprising 10.0 to 50.0 percent-by-weight hydrogen peroxide, will exhibit a pH between 4.0 to 5.3 at the start of dissolving step (e), i.e. prior to adding the irradiated radioactive tungsten metal targets, or shortly after adding the targets.

[0087] There are no particular restrictions for the conditions used during dissolving step (e). As already noted above, avoiding contact with oxygen of the targets is no longer an issue, and the further processing of the irradiated targets may be done at normal pressure and at temperatures of below 10°C to above 80°C under air ambient atmosphere. High temperatures bear a risk of thermal runaway reactions, and temperatures above 80°C therefore should be avoided. A temperature range of 10°C to 80°C, at ambient pressure, and under ambient air atmosphere are considered suitable conditions for carrying out dissolving step (e). For example, a temperature range of 10°C to 35°C, in particular at room temperature, at ambient pressure, and ambient air atmosphere are considered suitable conditions for carrying out dissolving step (e). For more rapid dissolution, elevated temperatures, for example 40°C to 65°C, may be preferable.

[0088] In particular when using the at least one peroxide source in a low concentration, an elevated temperature will help keeping a reasonable time interval for dissolving the irradiated targets. In addition, lower peroxide concentrations also bear a significantly decreased risk of thermal runaway reactions, so that a combination of elevated temperatures and lower peroxide concentrations in dissolving the targets in step (e) may be an option. According to embodiments, the conditions for dissolving step (e) are selected to achieve complete dissolution in 120 minutes or less, in particular 60 minutes or less. Complete dissolution in 30 minutes or less is particularly desirable. On the other hand, dissolution of at least 5.0 percent-by-weight within 120 minutes, preferably at least 10.0 percent-by-weight within 120 minutes is considered acceptable.

[0089] During dissolution of the irradiated radioactive tungsten metal targets aided by the action of hydrogen peroxide, for example, the liquid medium becomes even more acidic. The tungsten dissolved will be present in the liquid medium in the form of hydrogentungstate (HW04 ), tungstate (WO42j, and / or in the form of oligomeric or polymeric tungsten acid anions such as ditungstate (W2O72, paratungstate (W7O246), tungstate Y (W10O324), or metatungstate (W12O406). Bringing the pH up to an alkaline value is believed to essentially eliminate such oligomeric or polymeric forms. According to embodiments, the method therefore may further comprise adjusting the pH of the solution obtained in dissolving step (e) to an alkaline value. For example, the value may be adjusted to pH 13.0-14.0. Adjusting the value may be done by adding any desired base, for example sodium hydroxide.

[0090] An added advantage of bringing the value up to alkaline is that the commercially available W-188 solutions are adjusted to pH 13.0-14.0. By adjusting the pH, the solution obtained at the end of dissolving step (e) accordingly is adapted to the commercially available products, for better compatibility.2 Method of further processing dissolved W-188 to Re-188

[0091] Further subject matter of the present invention is a method of further processing the solution comprising W-188 finally obtained after completion of dissolving step (e), in order to obtain the sought-after radionuclide Re-188. The method starts with the solution comprising W- 188 finally obtained after completion of dissolving step (e), and further comprises:(f) adjusting the solution to pH 3.0,(g) adsorbing W-188 from the solution of step (f) on a ceramic adsorbent,(h) washing the ceramic adsorbent,(i) allowing for decay of W-188 to Re-188,(j) eluting Re-188 from the ceramic adsorbent, to obtain a solution comprising Re-188.

[0092] In step (f) of the method, the solution is adjusted to pH 3.0 in order to provide a standardized pH environment. The pH-adjusted solution then is applied in step (g) to a ceramic adsorbent. According to embodiments, the ceramic adsorbent may be selected from alumina, silica, zirconia, titania, manganese oxide, tantalum oxide, or a combination thereof. A ceramic adsorbent particularly preferred in this step is alumina. W-188 present in the solution is adsorbed in step (g) on the ceramic adsorbent in the form of tungstate. In practice, the solution typically will be applied in step (g) to a chromatographic column filled with the ceramic adsorbent.

[0093] Following adsorption of W-188 in the form of tungstate on the ceramic adsorbent, such as alumina, the ceramic adsorbent is washed in step (h) in order to remove impurities and byproducts from irradiation step (d) and / or dissolving step (e). A suitable washing solution is acetate solution. During washing step (h), W-188 in the form of tungstate remains adsorbed. The ceramic adsorbent (column) loaded with W-188 in the form of tungstate is termed a W-188 / Re-188 generator.

[0094] W-188 in the form of tungstate, and adsorbed on the ceramic adsorbent, is stored for sufficient time in order to allow for decay of W-188 to Re-188, with a half-life of W-188 of 69.4 days. As W-188 is present in the form of tungstate, any Re-188 formed will be present in the form of perrhenate.

[0095] After a time interval considered suitable by the user of the generator, i.e. after having allowed for sufficient decay from W-188 to Re-188, the formed Re-188 (in the form of perrhenate) is selectively eluted from the ceramic adsorbent in step (j) of the method. During selective elution of the perrhenate, the adsorbed tungstate remains adsorbed on the ceramic adsorbent. A suitable solution for selectively eluting perrhenate is aqueous sodium chloride solution. The aqueous sodium chloride solution suitably may have a concentration of 0.9 percent-by-weight of sodium chloride. Higher sodium chloride solutions are believed to be suitable as well.

[0096] The solution obtained in step (j) may be used as obtained, or may be further purified. In case further purification should be desired, the method of producing Re-188, according to embodiments, may further comprise:(k) treating the solution comprising Re-188 obtained in step (j) with a cation exchanger,(l) adsorbing Re-188 from the cation-exchanged solution according to step (k) on a ceramic adsorbent,(m) washing the ceramic adsorbent,(n) eluting Re-188 from the ceramic adsorbent, to obtain a purified solution comprising Re-188.

[0097] The purification method starts with the solution comprising Re-188 eluted in step (j) from the ceramic adsorbent, and continues with purifying the solution obtained via ion exchange. In practice, the solution typically will be applied in step (k) to a chromatographic column filled with the ion exchanger. The ion exchanger conveniently may be cation exchange resin, for example silver cation exchange resin such as Dowex 50Wx8 strong cation exchange resin. The Re-188 (in the form of perrhenate) will flow through the cation exchange column, while chloride anions are removed from the Re-188 solution by reaction with Ag+ ions, and precipitation as AgCl.

[0098] In step (I), the supernatant obtained from the cation exchange column is brought into contact with a ceramic adsorbent, and Re-188 present in the supernatant as perrhenate is adsorbed thereby on the ceramic adsorbent. According to embodiments, the ceramic adsorbent used in this step may be selected for example from alumina, silica, zirconia, titania, manganese oxide, or a combination thereof. A particularly preferred ceramic adsorbent used in this adsorption step (I) is silica. An example of a commercially available silica adsorbent suitable for this step is silica gel with quaternary ammonium modification, strongly alkaline anion exchanger (SAX). In practice, the supernatant typically will be applied in step (I) to a chromatographic column filled with the ceramic adsorbent.

[0099] Following adsorption of Re-188 in the form of perrhenate on the ceramic adsorbent, such as silica, the ceramic adsorbent is washed in step (m) in order to further remove impurities. A suitable washing solution is water. During washing step (m), Re-188 in the form of perrhenate remains adsorbed.

[0100] Finally, Re-188 (in the form of perrhenate) is selectively eluted from the ceramic adsorbent in step (n) of the method. A suitable solution for selectively eluting perrhenate is aqueous sodium chloride solution. The aqueous sodium chloride solution suitably may have a concentration of 0.9 percent-by-weight of sodium chloride. Higher sodium chloride solutions are believed to be suitable as well.3 Examples

[0101] Tungsten metal targets were made as described herein by compacting tungsten metal powder. The tungsten metal powder used was enriched in W-186, with an isotopic purity of about 99.80%. The tungsten metal powder was formed to donut-shaped bodies, which then were compacted and heat-treated at a temperature of about 850°C for about 2.0 hours. The targets had an outside diameter of about 5.50 mm and a diameter of the donut torus of about 1.50 mm. The weight was approximately 0.750 grams per target. The above processing steps were carried out in a hydrogen atmosphere essentially free of oxygen.

[0102] Subsequently, the targets were sealed in quartz glass ampoules under helium atmosphere. Samples were sintered as indicated in the table below, and subsequently dissolved under the conditions indicated in the table below.

[0103] Samples A and B both completely dissolved within 20 minutes. Less than 1% Sample C was not completely dissolved after 120 minutes.4 References

[0104] Callahan, A. P., Rice, D.E., Knapp, F.F., Jr., 1989. Re-188 for therapeutic applications from an alumina based W-188 / Re-188 radionuclide generator system, NucCompact 20, 3-6

[0105] International Atomic Energy Agency, 2003. Manual for Reactor Produced Radioisotopes. IAEA-TECDOC-1340, IAEA, Vienna

[0106] Knapp, F.F., Jr., 1989. Rhenium-188: A generator-derived radioisotope for cancer therapy, Cancer Biotherapy Radiopharm. 13, 337-349

[0107] Knapp, F.F., Jr., Callahan, A.P., Beets, A.L., Mirzadeh, S., Hsieh, B.-T., 1994. Processing of reactor-produced tungsten-188 for fabrication of clinical scale alumina-based tungsten- 188 / rhenium-188 generators, Appl. Rad. Isot. 45, 1123-1128

[0108] Kuznetsov, R.A., 2003. Purification of W-188 from impurities - Technology for 188W- 188Re generator: Current status and development prospects. RIAR, Dimitrovgrad (in Russian)

[0109] EP1933331B1, "Column system for creating a solution with high specific activity"

[0110] Toporov, Y.G., Tarasov, Y.G., Kuznetsov, R.A., Gontcharova, G.V., 1997. Production of W-188, Book of Abstracts, Second Russian Conf, on Radiochemistry, Dimitrovgrad. RIAR,Dimitrovgrad (in Russian)

[0111] Truong, H.T., Kim, Y.H., Lee, M.S., 2017. Solvent Extraction of Tungsten(VI) from Moderate Hydrochloric Acid Solutions with LIX 63, Korean J. Met. Mater. 55 (6), 405-411StatementsMethod for preparing a solution comprising W-188, the method comprising:(a) providing a tungsten composition comprising W-186 atoms,(b) forming the tungsten composition to a tungsten metal target,(c) sintering the tungsten metal target,(d) irradiating the tungsten metal target with neutrons, wherein at least a part of the W- 186 atoms undergoes a double neutron capture,(e) dissolving the irradiated tungsten metal target in a liquid medium comprising at least one peroxide source.The method according to statement 1, wherein the tungsten composition of step (a) is a tungsten metal composition essentially consisting of tungsten metal powder, or consisting of tungsten metal powder.The method according to statement 2, wherein the tungsten metal powder has an average particle size within the range of 0.10 to 500.0 pm, in particular an average particle size within the range of 0.50 to 200.0 pm, for example an average particle size within the range of 1.0 to 100.0 pm.The method according to statement 2 or 3, wherein step (b) comprises providing tungsten metal powder in a mold cavity, and compacting the tungsten metal powder, thereby producing a tungsten metal target.The method according to statement 4, comprising stabilizing the tungsten metal target obtained in step (b) by heat treating the tungsten metal target.The method according to statement 5, wherein heat treating is carried out at a temperature within a range of 650-880°C, for example at a temperature within a range of 700-850°C.The method according to statement 5 or 6, wherein the stabilizing heat treatment is carried out for an interval of 0.5 to 5.0 hours, for example 1.0 to 4.0 hours.The method according to any of statements 2 to 7, wherein steps (a) and (b) are carried out under an inert atmosphere essentially free of oxygen, or free of oxygen.The method according to any of statements 2 to 8, wherein steps (a) and (b) are carried out under a hydrogen atmosphere essentially free of oxygen, or free of oxygen.The method according to statement 1, wherein the tungsten composition of step (a) is a fluid composition comprising tungsten in dissolved and / or dispersed form.The method according to statement 10, wherein the fluid tungsten composition further comprises an aqueous solvent, and optionally a rheology modifier.The method according to statement 10 or 11, wherein step (b) comprises 3D-printing the fluid tungsten composition to produce a tungsten target precursor, and converting the tungsten target precursor to a tungsten target.The method according to any of statements 10 to 12, wherein the fluid composition is a 3D- printing ink comprising a polymerizable system, for example a photopolymerizable system.The method according to statement 12 or 13, wherein converting the tungsten target precursor to a tungsten target comprises drying in ambient air.The method according to any of statements 12 to 14, further comprising decomposing organic matter.The method according to any of statements 12 to 15, further comprising subjecting the tungsten target to a reducing treatment, thereby producing a tungsten metal target.The method according to statement 16, comprising heat treating the tungsten target under a reducing atmosphere essentially free of oxygen, or free of oxygen.The method according to statement 16 or 17, wherein heat treating is carried out under a hydrogen atmosphere at a temperature within a range of 650-880°C, for example at a temperature within a range of 700-850°C.The method according to any of statements 16 to 18, wherein heat treating is carried out under a hydrogen atmosphere for an interval of 0.5 to 5.0 hours, for example 1.0 to 4.0 hours.The method any of the preceding statements, wherein the tungsten is enriched in W-186 atoms.The method any of the preceding statements, wherein the W-186 atoms constitute 95.0 or more percent-by-weight, based on the weight of tungsten metal, in particular wherein the W-186 atoms constitute 96.0 to 99.99 percent-by-weight, based on the weight of tungsten metal.The method according to any of the preceding statements, wherein in step (c) the tungsten metal target is sintered at a temperature within the range of 900°C to less than 2800°C, in particular within the range of 1100°C to 2700°C.The method according to any of the preceding statements, wherein in step (c) the tungsten metal target is sintered at a temperature within the range of 1200°C to 2100°C, in particular within the range of 1300°C to 1800°C, for example within the range of 1350°C to 1600°C.The method according to any of the preceding statements, wherein in step (c) the tungsten metal target is sintered for an interval of 3.0 to 12.0 hours, in particular 4.0 to 10.0 hours, for example 4.5 to 6.0 hours.The method according to any of the preceding statements, wherein sintering is carried out under an inert atmosphere essentially free of oxygen, or free of oxygen.The method according to any of the preceding statements, wherein sintering is carried out under a hydrogen atmosphere essentially free of oxygen, or free of oxygen.The method according to any of the preceding statements, further comprising, prior to irradiating in step (d), sealing the sintered tungsten metal target in a container under an inert atmosphere essentially free of oxygen, or free of oxygen.The method according to any of the preceding statements, further comprising, prior to irradiating in step (d), sealing the sintered tungsten metal target in a glass or quartz or titanium ampoule under a helium atmosphere essentially free of oxygen, or free of oxygen.The method according to any of the preceding statements, wherein in step (d) the sintered tungsten metal target is irradiated at a thermal neutron flux of lxlO14or more neutrons / cm2 / s, for example at a thermal neutron flux of lxlO15or more neutrons / cm2 / s.The method according to any of the preceding statements, wherein the liquid medium of step (e) is an aqueous composition.The method according to any of the preceding statements, wherein the liquid medium of step (e) comprises at least one peroxide source selected from the group consisting of hydrogen peroxide, calcium peroxide, urea peroxide, perborates and percarbonates.The method according to any of the preceding statements, wherein the at least one peroxide source is present in an amount in the range of 10.0 to 80.0 percent-by-weight, inparticular in the range of 20.0 to 50.0 percent-by-weight, for example in the range of 35.0 to 50.0 percent-by-weight, based on the total weight of the liquid medium. The method according to any of the preceding statements, wherein the at least one peroxide source in the liquid medium is hydrogen peroxide. The method according to statement 33, wherein the hydrogen peroxide is present in an amount in the range of 10.0 to 60.0 percent-by-weight, in particular in the range of 15.0 to 50.0 percent-by-weight, for example in the range of 20.0 to 40.0 percent-by-weight, such as in the range of 25.0 to 34.90 percent-by-weight, based on the total weight of the liquid medium. The method according to any of the preceding statements, wherein the liquid medium of step (e) comprises a peroxide stabilizer. The method according to statement 35, wherein the peroxide stabilizer comprises phosphoric acid, pyrophosphoric acid, phosphonic acid, a salt thereof, a derivate thereof, or a combination thereof. The method according to statement 36, wherein the peroxide stabilizer comprises aminotrimethylene phosphonic acid. The method according to any of the preceding statements, wherein the liquid medium of step (e) has a pH below 6.5 prior to addition of the irradiated tungsten metal target. The method according to any of the preceding statements, wherein step (e) is carried out at a temperature of 10°C to 80°C, at ambient pressure, under air ambient atmosphere. The method according to any of the preceding statements, wherein step (e) is carried out at a temperature of 10°C to 35°C, at ambient pressure, under air ambient atmosphere. The method according to any of the preceding statements, further comprising adjusting the pH of the solution obtained in step (e) to pH 13.0-14.0 by adding sodium hydroxide. Method for preparing a solution comprising Re-188 from the solution comprising W-188 obtained according to any of the preceding statements, the method comprising:(f) adjusting the solution to pH 3.0,(g) adsorbing W-188 from the solution of step (f) on a ceramic adsorbent,(h) washing the ceramic adsorbent,(i) allowing for decay of W-188 to Re-188,(j) eluting Re-188 from the ceramic adsorbent, to obtain a solution comprising Re-188. The method according to statement 42, wherein the ceramic adsorbent is selected from alumina, silica, zirconia, titania, manganese oxide, tantalum oxide, or a combination thereof, in particular wherein the ceramic adsorbent is alumina. The method according to statement 42 or 43, wherein in step (g) the solution is applied to a chromatographic column filled with the ceramic adsorbent. The method according to any of statements 42 to 44, wherein in step (h) the ceramic adsorbent is washed with acetate solution. The method according to any of statements 42 to 45, wherein in step (j) Re-188 is eluted from the ceramic adsorbent using aqueous sodium chloride solution, in particular using an aqueous sodium chloride solution having a concentration of 0.9 percent-by-weight, or more, of sodium chloride. The method of any of statements 42 to 46, further comprising:(k) treating the solution comprising Re-188 obtained in step (j) with a cation exchanger,(l) adsorbing Re-188 from the supernatant obtained in step (k) on a ceramic adsorbent,(m) washing the ceramic adsorbent,(n) eluting Re-188 from the ceramic adsorbent, to obtain a purified solution comprising Re-188. The method according to statement 47, wherein is step (k) the solution is applied to a chromatographic column filled with the cation exchanger. The method according to statement 47 or 48, wherein the ceramic adsorbent is selected from alumina, silica, zirconia, titania, manganese oxide, tantalum oxide, or a combination thereof, in particular wherein the ceramic adsorbent is silica. The method according to any of statements 47 to 49, wherein in step (I) the solution is applied to a chromatographic column filled with the ceramic adsorbent. The method according to any of statements 47 to 50, wherein in step (m) the ceramic adsorbent is washed with water.The method according to any of statements 47 to 51, wherein in step (n) Re-188 is eluted from the ceramic adsorbent using aqueous sodium chloride solution, in particular using an aqueous sodium chloride solution having a concentration of 0.9 percent-by-weight, or more, of sodium chloride.

Claims

CLAIMS1 Method for preparing a solution comprising W-188, the method comprising:(a) providing a tungsten composition comprising W-186 atoms,(b) forming the tungsten composition to a tungsten metal target,(c) sintering the tungsten metal target,(d) irradiating the tungsten metal target with neutrons, wherein at least a part of the W- 186 atoms undergoes a double neutron capture,(e) dissolving the irradiated tungsten metal target in a liquid medium comprising at least one peroxide source.2 The method according to claim 1, wherein the tungsten composition of step (a) is a tungsten metal composition essentially consisting of tungsten metal powder, or consisting of tungsten metal powder.3 The method according to claim 1 or 2, comprising compacting tungsten metal powder, thereby producing a tungsten metal target, and stabilizing the tungsten metal target obtained by heat treating.4 The method according to claim 3, wherein the stabilizing heat treatment is carried out at a temperature within a range of 650-880°C, for example at a temperature within a range of 700-850°C, for an interval of 0.5 to 5.0 hours, for example 1.0 to 4.0 hours.5 The method according to claim 1, comprising 3D-printing a fluid composition comprising tungsten in dissolved and / or dispersed form to produce a tungsten target precursor, and converting the tungsten target precursor to a tungsten metal target.6 The method according to any of the preceding claims, wherein the tungsten is enriched in W-186 atoms, in particular wherein the W-186 atoms constitute 95.0 or more percent-by- weight, based on the weight of tungsten metal, for example wherein the W-186 atoms constitute 96.0 to 99.99 percent-by-weight, based on the weight of tungsten metal.7 The method according to any of the preceding claims, wherein in step (c) the tungsten metal target is sintered at a temperature within the range of 900°C to less than 2800°C, in particular within the range of 1100°C to 2700°C.The method according to any of the preceding claims, wherein in step (c) the tungsten metal target is sintered at a temperature within the range of 1200°C to 2100°C, in particular within the range of 1300°C to 1800°C, for example within the range of 1350°C to 1600°C. The method according to any of the preceding claims, wherein in step (c) the tungsten metal target is sintered for an interval of 3.0 to 12.0 hours, in particular 4.0 to 10.0 hours, for example 4.5 to 6.0 hours. The method according to any of the preceding claims, wherein sintering is carried out under an inert atmosphere essentially free of oxygen, or free of oxygen, and wherein the method optionally further comprises, prior to irradiating in step (d), sealing the sintered tungsten metal target in a container under an inert atmosphere essentially free of oxygen, or free of oxygen. The method according to any of the preceding claims, wherein the liquid medium of step (e) comprises at least one peroxide source selected from the group consisting of hydrogen peroxide, calcium peroxide, urea peroxide, perborates and percarbonates, in particular wherein the at least one peroxide source is present in an amount in the range of 10.0 to 80.0 percent-by-weight, in particular in the range of 20.0 to 50.0 percent-by-weight, for example in the range of 35.0 to 50.0 percent-by-weight, based on the total weight of the liquid medium. The method according to any of the preceding claims, wherein the at least one peroxide source in the liquid medium is hydrogen peroxide, in particular wherein the hydrogen peroxide is present in an amount in the range of 10.0 to 60.0 percent-by-weight, in particular in the range of 15.0 to 50.0 percent-by-weight, for example in the range of 20.0 to 40.0 percent-by-weight, such as in the range of 25.0 to 34.90 percent-by-weight, based on the total weight of the liquid medium. The method according to any of the preceding claims, wherein the liquid medium of step (e) comprises a peroxide stabilizer, in particular wherein the peroxide stabilizer comprises phosphoric acid, pyrophosphoric acid, phosphonic acid, a salt thereof, a derivate thereof, or a combination thereof. Method for preparing a solution comprising Re-188 from the solution comprising W-188 obtained according to any of the preceding statements, the method comprising:(f) adjusting the solution to pH 3.0,(g) adsorbing W-188 from the solution of step (a) on a ceramic adsorbent,(h) washing the ceramic adsorbent,(i) allowing for decay of W-188 to Re-188,(j) eluting Re-188 from the ceramic adsorbent, to obtain a solution comprising Re-188. The method according to claim 14, further comprising:(k) treating the solution comprising Re-188 obtained in step (j) with a cation exchanger,(l) adsorbing Re-188 from the supernatant obtained in step (k) on a ceramic adsorbent,(m) washing the ceramic adsorbent,(n) eluting Re-188 from the ceramic adsorbent, to obtain a purified solution comprisingRe-188.

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