Patent Grant
11286172
The presently-disclosed invention relates generally to metal-molybdate materials suitable for use in technetium-99m generators (Mo-99/Tc-99m generators) and methods for making the same.
Technetium-99m (Tc-99m) is the most commonly used radioisotope in nuclear medicine (e.g., medical diagnostic imaging). Tc-99m (m is metastable) is typically injected into a patient which, when used with certain equipment, is used to image the patient's internal organs. However, Tc-99m has a half-life of only six (6) hours. As such, readily available sources of Tc-99m are of particular interest and/or need in at least the nuclear medicine field.
Given the short half-life of Tc-99m, Tc-99m is typically obtained at the location and/or time of need (e.g., at a pharmacy, hospital, etc.) via a Mo-99/Tc-99m generator. Mo-99/Tc-99m generators are devices used to extract the metastable isotope of technetium (i.e., Tc-99m) from a source of decaying molybdenum-99 (Mo-99) by passing saline through the Mo-99 material. Mo-99 is unstable and decays with a 66-hour half-life to Tc-99m. Mo-99 is typically produced in a high-flux nuclear reactor from the irradiation of highly-enriched uranium targets (93% Uranium-235) and shipped to Mo-99/Tc-99m generator manufacturing sites. Mo-99/Tc-99m generators are then distributed from these centralized locations to hospitals and pharmacies through-out the country. Since the number of production sites are limited, and compounded by the limited number of available high flux nuclear reactors, the supply of Mo-99 is susceptible to frequent interruptions and shortages resulting in delayed nuclear medicine procedures.
There at least remains a need, therefore, for a process for producing material suitable for use in technetium-99m generators (Mo-99/Tc-99m generators).
One or more embodiments of the invention may address one or more of the aforementioned problems. Certain embodiments according to the invention provide a process for producing a metal-molybdate (also referred to herein as metal-Mo), such as a metal-Mo material suitable for use in technetium-99m generators. The term “metal-molybdate”, as used herein, generally refers to either a metal-molybdate, metal-molybdenum, molybdenum-metalate, or any form of Mo-metal or metal-Mo species. Processes according to certain embodiments of the invention may comprise reacting a metal molybdenum (Mo) material in a liquid medium (e.g., an aqueous medium) with a first acid (e.g., a mineral acid) to provide a Mo composition and combining the Mo composition with a metal source to provide a metal-Mo composition. Processes according to certain embodiments of the invention may further comprise pH adjusting the metal-Mo composition with a base (e.g., ammonium hydroxide) to precipitate a plurality of metal-Mo particulates (also referred to herein interchangeably as particles). In accordance with certain embodiments of the invention, the metal-Mo particulates may be isolated from or separated from the liquid medium. In accordance with certain embodiments of the invention, the isolated metal-Mo particulates may take the form of a slurry including a residual amount of the liquid medium therein. The isolated metal-Mo particulates may be subjected to heat energy to at least partially dry the metal-Mo particulates. The metal-Mo particulates may be milled and washed. In accordance with certain embodiments of the invention, the processes may comprise irradiating a metal molybdenum target to provide the Mo material as discussed herein. That is, the step of irradiating a metal molybdenum target to provide the Mo material may be carried out prior to the combination of the metal Mo material in a liquid medium with the first acid. The metal molybdenum target, for example, may comprise a tubular capsule comprising metal molybdenum and a plurality of internal metal molybdenum components (e.g., balls, rods, wires, discs, etc.) housed inside of the tubular capsule. Alternatively, the metal molybdenum target, for example, may be one or more metal molybdenum components (e.g., balls, rods, wires, discs, etc.) used alone or in combination, such as a rod with a series of discs. In this regard, certain embodiments of the invention comprise a metal-Mo material produced according to processes disclosed herein.
In some embodiments of the invention, an intermediate product may be present for further processing if so desired.
In yet another aspect, the invention provides the metal-Mo material comprises a plurality metal-Mo particulates.
In accordance with certain embodiments of the invention, the process may comprise irradiating the resulting metal-Mo material comprising a plurality of metal-Mo particulates. For example, the irradiation may be carried out prior to loading the metal-Mo particulates into an elution vessel.
In accordance with certain embodiments of the invention, the metal-Mo material comprises an eluting efficiency of 30% or greater, an eluting efficiency of 80% or greater, 90% or greater, or 95% or greater. The metal-Mo material, in accordance with certain embodiments of the invention, may be disposed in an elution column (e.g., technetium-99m generator) and at least 90% (e.g., at least 95% or at least 99%) of a total technetium content releases from the metal-Mo material via passing an aqueous liquid (e.g., water, saline, dilute acid) through the metal-Mo material.
Other embodiments of the invention are described herein.
The invention now will be described more fully hereinafter with reference to the accompanying drawings, in which some, but not all embodiments of the invention are shown. Indeed, this invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. Like numbers refer to like elements throughout, and wherein:
The invention now will be described more fully hereinafter with reference to the accompanying drawings, in which some, but not all embodiments of the invention are shown. Indeed, this invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification, and in the appended claims, the singular forms “a”, “an”, “the”, include plural referents unless the context clearly dictates otherwise.
The invention provides, according to certain embodiments, a process for producing a metal-molybdate (also referred to herein as metal-Mo), such as a metal-Mo material suitable for use in technetium-99m generators. The term “metal-molybdate”, as used herein, generally refers to either a metal-molybdate, metal-molybdenum, molybdenum-metalate, or any form of Mo-metal or metal-Mo species.
In accordance with certain embodiments, the process may include a step of reacting a metal molybdenum (Mo) material (such as a solid molybdenum metal in a variety of forms including powder and bulk solids of various particle sizes and geometries) in a liquid medium with an acid or acids (e.g., a mineral acid) to provide a Mo composition (e.g., a solution of Mo) and combining the Mo composition with a metal source to provide a metal-Mo composition. Metal molybdenum, for example, is usually produced by powder metallurgy techniques in which Mo powder is hydrostatically compacted and sintered. A metal molybdenum material, in accordance with certain embodiments of the invention, may comprise Mo atoms, consist essentially of Mo atoms, or consist of Mo atoms. Non-limiting examples of a metal molybdenum material include, but are not limited to, natural Mo, enriched Mo (including, but not limited to, Mo enriched in Mo-98), Mo alloys (including, but not limited to, any material where the Mo content is above 50% and the other constituent(s) making the alloy is easily separated from the Mo via chemistry).
Processes according to certain embodiments of the invention may further comprise pH adjusting the metal-Mo composition with a base (e.g., ammonium hydroxide) to precipitate a plurality of metal-Mo particulates. In accordance with certain embodiments of the invention, the process for producing solid metal-Mo may comprise a single-pot process, in which the metal Mo material is transformed into solid metal-Mo particulates in a single pot (i.e., the same tank or pot).
In accordance with certain embodiments, the acid or acids utilized may comprise one or more mineral acids or hydrogen peroxide. In this regard, mineral acids suitable for combination with the metal Mo may comprise hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrofluoric acid, boric acid, hydrobromic acid, perchloric acid, hydroiodic acid, halogen acids (such as HAt where At is Astatine), or any combination thereof. In accordance with certain embodiments, the mineral acid may comprise hydrochloric acid, nitric acid, or a combination thereof. In this regard, the metal Mo may be immersed in the liquid medium and agitated while one or more of the foregoing acids is added to lower the pH of the liquid medium. In accordance with certain embodiments, the step of reacting the metal molybdenum (Mo) material in the liquid medium with the first acid may subject the metal Mo material and/or a metal oxide formed thereby to a process including, but not limited to, oxidation, dissolution, other reaction processes, or a combination thereof.
In accordance with certain embodiments of the invention, the liquid medium may comprise an aqueous medium. In this regard, the liquid medium may comprise water. In accordance with certain embodiments of the invention, the liquid medium consists of water, to which the metal Mo and one or more of the foregoing acids are added.
In accordance with certain embodiments of the invention, the step of reacting the metal molybdenum (Mo) material in the liquid medium with the first acid may be performed at a molar ratio of Mo to acid (Mo:Acid) in a range of about of 0.1:1 to about 10:1.
The step of reacting the metal Mo may further comprise controlling a temperature of the liquid medium (e.g., aqueous medium), in which the metal Mo is immersed at any point during the reaction. In this regard, the temperature control of the liquid medium (e.g., aqueous medium) may comprise the addition of heat to the liquid medium, removal of heat from the liquid medium, no added heat, or a combination thereof. Addition and/or removal of heat may be achieved by a variety of known heat-transfer systems (e.g., internal tank coils, heat exchangers, jacketed tanks, etc.). In accordance with certain embodiments of the invention, for instance, the temperature of the liquid medium may be controlled throughout the reaction by adding and/or removing heat from the liquid medium as desired. In accordance with certain embodiments of the invention, for example, heat may be supplied to the liquid medium, in which the metal Mo is immersed, sufficient to raise the temperature of the liquid medium to or above about 25° C., to or above about 35° C., to or above about 45° C., to or above about 55° C., etc. The temperature of the liquid medium may begin to rise. In this regard, controlling the temperature of the liquid medium by removing heat given off may be desirable, for example, for at least safety concerns. If the liquid medium includes any co-chemicals, the boiling points of such chemicals may, at least partially, dictate the desired maximum temperature to which the liquid medium is allowed to reach. In accordance with certain embodiments of the invention, the temperature of the liquid medium may be controlled by maintaining the temperature of the liquid medium at or below about 80° C., for example, by removal of heat from the liquid medium. In accordance with certain embodiments of the invention, the temperature of the liquid medium may be controlled by maintaining the temperature of the liquid medium at or below about 100° C., at or below about 80° C., at or below about 70° C., at or below about 60° C., at or below about 50° C., at or below about 40° C.
Reacting may further comprise agitating the metal Mo material and the liquid medium during at least a portion of the step. In this regard, the agitation of the metal Mo material and liquid medium may provide an improved interaction of the metal Mo material with the liquid medium as the pH of the liquid medium is reduced via addition of acid (i.e., one or more mineral acids). For example, agitation may provide improved access of the metal Mo material to the acid in the liquid medium and may speed up any resulting reaction process including, but not limited to, oxidation, dissolution, or a combination thereof. In accordance with certain embodiments of the invention, for instance, the agitation may comprise mechanically mixing the metal Mo material and the liquid medium. In accordance with certain embodiments of the invention, the agitation may be improved by utilizing an internal tank baffles to facilitate vertical mixing of the metal Mo and liquid medium.
In accordance with certain embodiments of the invention, the step of combining the metal Mo material may comprise simultaneously, for at least a portion of the step, adding one or more acids to the liquid medium, in which the metal Mo material is immersed, controlling the temperature of the liquid medium, and agitating the metal Mo material and liquid medium. The resulting Mo composition (e.g., a solution of Mo) may then be subjected to further processing.
In accordance with certain embodiments of the invention, a process is provided for producing a metal-molybdate (Ti—Mo) comprising oxidizing a metal molybdenum (Mo) material, in whole or in part, in a liquid medium with a first acid to provide a Mo composition, combining the Mo composition with a metal source to provide a metal-Mo composition, and pH adjusting the metal-Mo composition with a base to precipitate a plurality of metal-Mo particulates.
In accordance with certain embodiments of the invention, a process is provided for producing a metal-molybdate (Ti—Mo) comprising dissolving a metal molybdenum (Mo) material, in whole or in part, in a liquid medium with a first acid to provide a Mo composition, combining the Mo composition with a metal source to provide a metal-Mo composition, and pH adjusting the metal-Mo composition with a base to precipitate a plurality of metal-Mo particulates.
The process parameters and/or process conditions for oxidizing and/or dissolving in the aforementioned embodiments can be the same as discussed herein as for the reacting step.
In accordance with certain embodiments of the invention, after formation of the Mo composition, the process may comprise combining the Mo composition with a metal source to provide a metal-Mo composition.
In accordance with embodiments of the invention, the metal source may comprise an element from the p-block, d-block, or f-block of the periodic table. The p-block of the periodic table includes elements from the six groups beginning with group 3A and ending with group 8A with the exception of helium. The p-block metals generally have high melting points and readily react with nonmetals to form ionic compounds. Metalloids have properties of metals and non-metals and are also in the p-block. The d-block of the periodic table includes elements from groups 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 of the periodic table. These elements are known as the transition metals. A transition metal (also called a transition element) can also be defined by the IUPAC definition that states that a transition metal is “an element whose atom has an incomplete d sub-shell, or which can give rise to cations with an incomplete d sub-shell.” The f-block of the periodic table includes the lanthanide and actinide series. The f-block elements have one or more of their outermost electrons in the f-orbital but none in the d-orbital or p-orbital. The f-orbitals can contain up to seven pairs of electrons.
Non-limiting examples of metal sources are one or more metals, metalates, or metallic salts include, but are not limited to, elemental or unoxidized metal, metal oxide, metal hydroxide, metal halide, nitrate, phosphate, tetrefluoroboride, phosphorous hexafluoride, tosylate, acetate, formate, or any other counter anion capable of producing a soluble salt. This metal, metalate, or metallic salt can exist in various oxidation states Mn+, n=1, 2, 3, 4, 5, 6, and may be capable of forming an oxo-bridge or hydroxo-bridge with another metal, metalate, metallic salt, or molybdate. An oxo-bridge typically refers to an oxygen ion that covalently bonds to a metal in an M-O-M fashion.
In accordance with embodiments of the invention, the metal source is a metal, metalate, or metallic salt that achieves the following: (1) forms a discrete or complex unit, either a tetrahedral, octahedral, or more complex structure; (2) links with the discrete unit in which the MoxOy is present, wherein x is the number of Mo atoms and y is the number of O atoms; (3) persists under ionizing radiation without mutation and the bond formed with the MoxOy species remains; and/or (4) should the material be synthesized before irradiation of Mo, does not yield any daughter products from neutron bombardment that would be undesirable in the final eluate.
In the case of titanium, the titanium source may comprise a titanium chloride (e.g., TiCl3). In accordance with certain embodiments of the invention, the titanium chloride may comprise titanium(III) chloride (TiCl3), titanium(II) chloride (TiCl2), titanium tetrachloride (TiCl4), or any combination thereof.
In addition to the aforementioned titanium salts, a titanium salt existing in the 2+, 3+, or 4+ oxidation state may also be comprised of counter ions such as nitrates, NO3−, or other halides, F−, Br−, At−, or I−. Further titanium sources may include, but are not limited to, unoxidized titanium metal or metal carbonyl, or be combined in a variety of oxidation states with metal oxides, metal hydroxides, phosphates, tetrefluoroboride, phosphorous hexafluoride, tosylates, acetate, formate, or any other counter anion capable of producing a soluble salt.
In addition to titanium, other metals capable of forming an elutable structure with Mo can also be added in a variety of ratios. These metals may take the form of an unoxidized metal, or the aforementioned salt forms taken by titanium. In addition, these titanium metal substitutes may exist in a variety of oxidation states, Mn+, n=1, 2, 3, 4, 5, 6. Titanium substitutes will come from select p-block, d-block (transition metals), and/or f-block metals. Some of these metals may include, but are not limited to, Aluminum (Al) (p-block), Silicon (Si) (p-block), Tin (Sn) (p-block), Germanium (Ge) (p-block), Zirconium (Zr) (d-block), Hafnium (Hf) (d-block), Vanadium (V) (d-block), Chromium (Cr) (d-block), Manganese (Mn) (d-block), Cobalt (Co) (d-block), Nickel (Ni) (d-block), Iron (Fe) (d-block), Copper (Cu) (d-block), Niobium (Nb) (d-block), Rhodium (Rh) (d-block), Gadolinium (Gd) (f-block), Thorium (Th) (f-block), Cerium (f-block), Uranium (U) (f-block), Praseodymium (Pr) (f-block), or Terbium (Tb) (f-block).
The previously described metals may bond to the Mo unit in a variety of forms. In choosing a metal for an elutable structure, the metal preferably forms a direct covalent bond with the Mo unit. Bonding can occur through any method which will typically be oxo- and hydroxo-, bridges. The bonding form includes, but is not limited to, cyano, nitro, sulfide, nitride amido, acetate, carbonate, phosphate, and carbonyl bonding schemes or any combination of thereof as well as others typically found in inorganic compounds. The metal can bond with the Mo unit without precipitation or without forming its own discrete unit such as an oxide or salt resulting in a homogeneous or heterogeneous mixture of the molybdate unit and the metalate unit. It is preferable that the metal does not act as a binder to a Mo decay product or a Tc decay product.
The step of combining the Mo composition with the metal source to provide the metal-Mo composition, in accordance with certain embodiments of the invention, may comprise adding the metal source to the Mo composition. In accordance with certain embodiments of the invention, the Mo composition is agitated or mixed during addition of the metal source.
The addition of the metal source to the Mo composition may comprise, for example, dropwise addition of the metal source to the Mo composition. In this regard, the addition of the metal source to the Mo composition may comprise administering one drop (e.g., 0.05 mL) of the metal source at a time to an agitating Mo composition. In accordance with certain embodiments of the invention, the number of drops of the metal source added to the Mo composition per minute may vary. The step of combining the Mo composition with the metal source to provide the metal-Mo composition may also comprise adding an acid (e.g. a second mineral acid) to the Mo composition. In accordance with certain embodiments of the invention, the temperature may be dropped, preferably in a range of about 25° C. to about 35° C., when the metal source is added with the acid. The acid may comprise a mineral acid as disclosed above. For example, the mineral acid added to the Mo composition during the combination of the metal source and the Mo composition may comprise hydrochloric acid. In accordance with certain embodiments of the invention, the metal source and the acid (e.g., hydrochloric acid) may be simultaneously added to the Mo composition. For instance, the metal source may comprise a liquid composition including, for example, one or more metal-containing compounds disclosed herein (e.g., TiCl3) and the acid (e.g., hydrochloric acid). In this regard, the addition of the metal source may comprise the simultaneous addition of metal-containing compound(s) and acid. In accordance with certain embodiments of the invention, the resulting metal-Mo composition may comprise a final pH of about 3 or less (e.g., about 2 or less, or about 1 or less) at the end of the step of combining the Mo composition with the metal source. In accordance with certain embodiments of the invention, in the case of titanium, the step of combining the Mo composition with a metal source (e.g., TiCl3) to provide a metal-Mo composition may be performed until a molar ratio of titanium to Mo (metal:Mo) of about 0.1:1 to about 10:1 is reached.
Processes according to certain embodiments of the invention may further comprise pH adjusting the metal-Mo composition with a base to precipitate a plurality of metal-Mo particulates. A base suitable for neutralization of the acid digested salts or soluble salts include, but are not limited to, metal hydroxide(s) such as alkali and alkaline earth metal hydroxides, ammonium hydroxides, sodium hydroxide, quaternary alkyl amine hydroxides, or a combination thereof. In accordance with certain embodiments of the invention, the pH of the metal-Mo composition is adjusted with a base to a pH in the range from about 4 to about 9. As such, in certain embodiments of the invention, the pH of the metal-Mo composition may be adjusted to at least about any of the following: 4, 4.5, 5, 5.5, 6, 6.5, and 7 and/or at most about 9, 8.5, 8, 7.5, 7, 6.5, and 6. During the pH adjustment of the metal-Mo composition, the metal-Mo composition may be subjected to agitation, for example, to mechanical agitation.
In accordance with certain embodiments of the invention, the pH adjustment of the metal-Mo composition may comprise adding the base in a dropwise manner. In this regard, the addition of the base to the metal-Mo composition may comprise administering one drop (e.g., 0.05 mL) of the base at a time to an agitating metal-Mo composition. In accordance with certain embodiments of the invention, the number of drops of the base added to the metal-Mo composition per minute may vary. Other forms of administering the metal source can be used including, but not limited to, a mist, spray, or a combination thereof.
The metal-Mo composition after the pH adjustment step includes the plurality of precipitated metal-Mo particulates from the pH adjustment, and may be subjected to a cooling or chilling step either during pH adjustment and/or subsequent to the pH adjustment. In accordance with certain embodiments of the invention, the step of cooling the metal-Mo composition may comprise reducing the temperature of the metal-Mo composition to between about 0° C. to about 20° C. (e.g., about 3° C. to about 10° C.). As such, in certain embodiments of the invention, the step of cooling the metal-Mo composition may comprise reducing the temperature of the metal-Mo composition to at least about any of the following: 3° C., 5° C., 8° C., 10° C., and 12° C. and/or at most about 20° C., 15° C., 12° C., and 10° C.
Regardless of whether or not the metal-Mo composition after precipitation of the plurality of metal-Mo particulates is subjected to the cooling step discussed above, the metal-Mo composition may be subjected to a separating operation (e.g., a solid-liquid separation). In this regard, processes according to certain embodiments of the invention may comprise separating the plurality of metal-Mo particulates from the liquid medium (e.g., unwanted bulk liquid medium). In this regard, the metal-Mo particulates may be isolated from or separated from the unwanted liquid medium. In accordance with certain embodiments of the invention, the isolated metal-Mo particulates may take the form as slurry including a residual amount of the liquid medium therein. In accordance with certain embodiments of the invention, the step of separating the plurality of metal-Mo particulates from the liquid medium may comprising filtering (e.g., vacuum-filtering) or centrifuging the metal-Mo composition to retain at least most of the plurality of metal-Mo particulates. Filtering media may include, but are not limited to, paper, sintered metal, metal mesh, or a combination thereof. A primary and/or a secondary filtering media may be used. The separating step may comprise utilization of a metal filtering surface, wherein at least most of the plurality of metal-Mo particulates are retained on the metal filtering surface. As noted above, the isolated or retained metal-Mo particulates may take the form as a slurry including a residual amount of the liquid medium therein.
In accordance with certain embodiments of the invention, the isolated or retained metal-Mo particulates (e.g., in the form of a slurry) may be subjected to heat energy to at least partially dry the metal-Mo particulates. During exposure to heat energy, the residual liquid medium entrained in the metal-Mo particulates begins to evaporate. The metal-molybdate molecules, however, remain in a somewhat amorphous solid state without any strong crystal state.
The step of subjecting the plurality of metal-Mo particulates to heat energy, in accordance with certain embodiments of the invention, may comprise exposing the plurality of metal-Mo particulates to infrared radiation. In accordance with certain embodiments of the invention, the infrared radiation comprises a wavelength from about 700 nm to about 1400 nm. As such, in certain embodiments of the invention, the infrared radiation may comprise a wavelength from at least about any of the following: 700, 750, 800, 850, 900, 920, 940, 960, 980, and 1000 nm and/or at most about 1400, 1300, 1200, 1150, 1100, 1080, 1060, 1040, 1020, and 1000 nm.
In accordance with certain embodiments of the invention, the heat energy source may comprise convective heating, freeze drying, an infrared heater, such as one or more light-emitting-diodes (LEDs), quartz crystal, quartz infrared heating elements, and incandescent light bulbs producing infrared light. In accordance with certain embodiments of the invention, the operating temperature may be controlled to be from about 20° C. to about 80° C. In this regard, the operating temperature may comprise at least about any of the following: 20° C., 30° C., 40° C., 45° C., 50° C., 55° C., and 60° C. and/or at most about 80° C., 75° C., 70° C., 65° C., and 60° C.
Subsequent to subjecting the metal-Mo particulates to heat energy, the metal-Mo particulates may optionally be subjected to a milling or grinding operation. In accordance with certain embodiments of the invention, the metal-Mo particulates may be milled by many commercially available mills, such as ball mills, hammer mills, high pressure grinding mills, tower mills, and wet mills (e.g., conical wet mill).
In accordance with certain embodiments of the invention, the average size of the plurality of metal-Mo particulates after the milling step may comprise from about 10 microns to about 1275 microns (e.g., about 100 microns to about 200 microns, about 630 microns to about 1015 microns, etc.). In accordance with certain embodiments of the invention, for example, the average size of the plurality of metal-Mo particulates after the milling step may comprise from at least about any of the following: 10, 50, 75, 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 925, and 950 microns and/or at most about 1275, 1250, 1225, 1200, 1175, 1150, 1125, 1100, 1050, 1000, and 950 microns.
In accordance with certain embodiments of the invention, select particle sizes can be selected by mechanical filters, chemical filters, or a combination thereof.
The milled metal-Mo particulates, according to certain embodiments of the invention, may be subjected to a washing step.
In accordance with certain embodiments of the invention, the washed metal-Mo particulates may be collected and dried to remove most of the washing liquid. The drying operation is not particularly limited. After drying the post-washed metal-Mo particulates, the metal-Mo particulates may tend to agglomerate together. As such, the metal-Mo particulates may be subjected to a second milling process, in which the second milling process comprises a dry-milling process and the plurality of metal-Mo particulates after the second milling step may comprise from about 10 microns to about 1275 microns (e.g., about 100 microns to about 200 microns, about 630 microns to about 1015 microns, etc.). In accordance with certain embodiments of the invention, for example, the average size of the plurality of metal-Mo particulates after the second milling step may comprise from at least about any of the following: 10, 50, 75, 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 925, and 950 microns and/or at most about 1275, 1250, 1225, 1200, 1175, 1150, 1125, 1100, 1050, 1000, and 950 microns.
In accordance with certain embodiments of the invention, the processes may comprise irradiating a metal molybdenum target to provide the Mo material as discussed herein. The metal molybdenum target, for example, may comprise a tubular capsule comprising metal molybdenum and a plurality of internal metal molybdenum components (e.g., balls, rods, wires, discs, etc.) housed inside of the tubular capsule. For example, the tubular capsule may comprise a first end, a second end, and a wall connecting the first end and the second end to define a hollow cavity therein. In this regard, the plurality of internal metal molybdenum components (e.g., balls, rods, wires, discs, etc.) may be packed within the hollow cavity of the tubular capsule. In accordance with certain embodiments of the invention, at least the first end may be configured to allow access to the hollow cavity for loading and optionally unloading the plurality of internal metal molybdenum components (e.g., balls, rods, wires, discs, etc.). In this regard, at least the first end (or a portion thereon) may be configured to be removed from the tubular capsule to provide access to the hollow cavity. In accordance with certain embodiments of the invention, the metal Mo material in the reacting step comprises the plurality of internal metal molybdenum components, the tubular capsule, or both.
The metal molybdenum target may comprise a plurality of metal molybdenum discs (e.g., circular discs) that each comprise a length, a width, and a thickness in the z-direction. In this regard, the thickness may comprise a value that is less than both the length and width. In accordance with certain embodiments of the invention, the thickness comprises from about 2 microns to about 260 microns (e.g., from about 10 microns to about 150 microns). In accordance with certain embodiments of the invention, for example, the thickness comprise from at least about any of the following: 2, 10, 20, 30, 40, 50, 60, 70, 80, 90, and 100 microns and/or at most about 275, 260, 250, 225, 200, 175, 150, 140, 130, 120, 110, and 100 microns. In accordance with certain embodiments of the invention, the plurality of metal molybdenum discs are packed in a side-by-side relationship in the z-direction inside the tubular capsule. In accordance with certain embodiments of the invention, a plurality of metal molybdenum discs may be used without a capsule. In accordance with certain embodiments of the invention, the metal molybdenum discs may be formed from metal molybdenum sheets by, for example, a stamping process. In accordance with certain embodiments of the invention, the metal Mo material in the reacting step comprises the plurality of metal molybdenum discs, the tubular capsule component, or both.
As noted above, the metal molybdenum target that may be irradiated to provide the Mo material may comprise a tubular capsule and/or a plurality of metal molybdenum components (e.g., balls, rods, wires, discs, etc.).
The metal molybdenum target, according to certain embodiments of the invention, may be irradiated, for example, by neutron capture in a fission reactor. In accordance with certain embodiments of the invention, the Mo material as disclosed herein may be provided by a variety of Mo production technologies including, for example, fission reactors (e.g., reprocessed uranium, low-enriched uranium, and highly enriched uranium), particle accelerators, and neutron capture. In accordance with certain embodiments of the invention, the metal molybdenum target may be irradiated by any type of reactor in which the Mo target can be inserted. Non-limiting examples of reactors include, but are not limited to, High Flux Isotope Reactor (HFIR), a CANDU reactor (e.g., CANDU reactor, CANDU6 reactor, CANDU9 reactor, Advanced CANDU reactor (ACR), etc.). Other non-limiting examples of reactors are power reactors and research reactors including, but not limited to, University of Missouri Research Reactor (MURR), National Institute of Standards and Technology (NIST) Reactor, MIT Nuclear Research Reactor (MITR), and Advanced Test Reactor (ATR).
In this regard, the origin of the Mo material as disclosed herein is not particularly limited in accordance with certain embodiments of the invention.
In accordance with certain embodiments of the invention, for example, the average size of the plurality of metal-Mo particulates may comprise from at least about any of the following: 10, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 925, and 950 microns and/or at most about 1275, 1250, 1225, 1200, 1175, 1150, 1125, 1100, 1050, 1000, and 950 microns.
In accordance with certain embodiments of the invention, the metal-Mo material comprises an eluting efficiency of 30% or greater, an eluting efficiency of 80% or greater, 90% or greater, or 95% or greater. The metal-Mo material, in accordance with certain embodiments of the invention, may be disposed in an elution column to provide a technetium-99m generator and at least 90% (e.g., at least 95% or at least 99%) of a total technetium content releases from the metal-Mo material via passing an aqueous liquid (e.g., water, saline, dilute acid) through the metal-Mo material. In this regard, certain embodiments of the invention enable the use of larger elution columns (e.g., technetium-99m generators). For instance, the standard 20 milliliter saline eluting may extract technetium from elution columns much larger than the standard 3 milliliter elution column size. Accordingly, certain embodiments of the invention enable achievement of target Tc-99m activities from smaller than expected Mo activities. Consequently, reactors with lower fluxes may be used to provide commercially viable product to the industry and a greater number of reactors may participate in suitable Mo generation.
In this regard, certain embodiments of the invention enable use of elution columns (e.g., technetium-99m generators) exceeding the standard 3 milliliter size (e.g., 5 mL, 10 mL, 12 mL, 15 mL, 20 mL, 25 mL, 30 mL, 60 mL, or 100 mL) such that the use of reactors with smaller fluxes to produce the desired target technetium activity are now viable. For example, lower flux reactors that traditionally could not be utilized for generating a high enough specific activity of technetium for commercial purposes may now be viably utilized in accordance with certain embodiments of the invention. In this regard, a variety of reactors may be used to supply Mo to processes in accordance with certain embodiments of the invention.
As noted above, metal-Mo materials in accordance with certain embodiments of the invention enable the use of elution columns exceeding the standard 3 milliliter size (e.g., 5 mL, 10 mL, 12 mL, 15 mL, 20 mL, 25 mL, 30 mL, 60 mL, or 100 mL) such that the use of reactors with smaller fluxes to produce the desired target technetium activity are now viable.
Accordingly, the present invention also provides an elution pig configured to accept a variety of sizes of elution columns which will allow a variety of reactors (e.g. reactors of high flux and/or low flux) to be integrated into the supply chain for the production of Tc-99m. In accordance with certain embodiments of the invention, the elution pig may be configured to accept a variety of different sized elution columns including 3 mL, 5 mL, 10 mL, 12 mL, 15 mL, 20 mL, 25 mL, 30 mL, 60 mL, 100 mL or any combination thereof.
In accordance with certain embodiments of the invention, the metal-Mo particles may be irradiated prior to being loaded into a cask transfer case or an elution column. This step can eliminate the optional step of irradiating a metal molybdenum target at the front end of the process. Among the advantages of such a post-irradiation process step are that the chemical process can be performed without radiological control thereby reducing or eliminating radioactive waste generation, and that there is a decrease in processing time resulting in higher initial activity of the metal-Mo particles.
In accordance with certain embodiments of the invention, another process for producing a metal-molybdate material is provided. As illustrated in
In accordance with certain embodiments of the invention, a process for producing a metal-molybdate material with an optional post-irradiation step is provided.
The processes of
It is possible to use at a minimum, a concentration of 2 to 15 molar nitric acid in step 315 of
In yet another aspect, the present invention provides a cask transfer case and process. In order to move the highly radioactive Mo material from the reactor to the location for chemical processing (e.g., addition to metal source, etc.) or to move the irradiated metal-Mo particles, certain embodiments of the invention provide a cask transfer case that may shield personnel from undesirable doses of radioactivity. The cask transfer case may also allow for safe loading of the Mo material and transfer of the Mo material as well as unloading of the Mo material.
These and other modifications and variations to the invention may be practiced by those of ordinary skill in the art without departing from the spirit and scope of the invention, which is more particularly set forth in the appended claims. In addition, it should be understood that aspects of the various embodiments may be interchanged in whole or in part. Furthermore, those of ordinary skill in the art will appreciate that the foregoing description is by way of example only, and it is not intended to limit the invention as further described in such appended claims. Therefore, the spirit and scope of the appended claims should not be limited to the exemplary description of the versions contained herein.
This application claims priority from U.S. provisional patent application Ser. No. 62/463,020, filed on Feb. 24, 2017, in the United States Patent and Trademark Office and from U.S. provisional patent application Ser. No. 62/592,737, filed on Nov. 30, 2017, in the United States Patent and Trademark Office. The disclosures of which are incorporated herein by reference in their entireties.
| Number | Name | Date | Kind |
|---|---|---|---|
| 3140393 | Busch | Jul 1964 | A |
| 3436354 | Molinski | Apr 1969 | A |
| 3607007 | Chiola | Sep 1971 | A |
| 3666822 | Grasselli | May 1972 | A |
| 3752769 | Lewis et al. | Aug 1973 | A |
| 4123497 | Ruddock | Oct 1978 | A |
| 4141861 | Courty | Feb 1979 | A |
| 4273745 | Laferty et al. | Jun 1981 | A |
| 4280053 | Evans | Jul 1981 | A |
| 4360495 | Bauer | Nov 1982 | A |
| 4440729 | Jonsson | Apr 1984 | A |
| 4487850 | Li | Dec 1984 | A |
| 4525331 | Cheresnowsky et al. | Jun 1985 | A |
| 4738834 | Moore et al. | Apr 1988 | A |
| 4756746 | Kemp, Jr. et al. | Jul 1988 | A |
| 4760638 | Ott et al. | Aug 1988 | A |
| 4782231 | Svoboda et al. | Nov 1988 | A |
| 5382388 | Ehrhardt et al. | Jan 1995 | A |
| 5397902 | Castner et al. | Mar 1995 | A |
| 5615238 | Wiencek et al. | Mar 1997 | A |
| 5802438 | Bennett | Sep 1998 | A |
| 5821186 | Collins | Oct 1998 | A |
| 5846455 | David et al. | Dec 1998 | A |
| 6103295 | Chan et al. | Aug 2000 | A |
| 6113795 | Subramaniam et al. | Sep 2000 | A |
| 6136740 | Jones | Oct 2000 | A |
| 6160862 | Wiencek et al. | Dec 2000 | A |
| 6166284 | Oelsner | Dec 2000 | A |
| 6394945 | Chan et al. | May 2002 | B1 |
| 6638205 | Chan et al. | Oct 2003 | B1 |
| 6676988 | Chan et al. | Jan 2004 | B2 |
| 6793798 | Chan et al. | Sep 2004 | B2 |
| 8270555 | Hannah et al. | Sep 2012 | B2 |
| 8318113 | Barbosa | Nov 2012 | B2 |
| 8437443 | Russell, II et al. | May 2013 | B2 |
| 8488733 | Allen et al. | Jul 2013 | B2 |
| 8542789 | Russell, II et al. | Sep 2013 | B2 |
| 8569713 | Evers | Oct 2013 | B2 |
| 8638899 | Smith et al. | Jan 2014 | B2 |
| 8699651 | Bloomquist et al. | Apr 2014 | B2 |
| 8753590 | Barbosa | Jun 2014 | B2 |
| 8781055 | Toth et al. | Jul 2014 | B2 |
| 8822950 | Evers | Sep 2014 | B2 |
| 8842798 | Russell et al. | Sep 2014 | B2 |
| 8872124 | Graves et al. | Oct 2014 | B2 |
| 8900340 | Abenthung et al. | Dec 2014 | B2 |
| 8911695 | Hasan | Dec 2014 | B2 |
| 8932091 | Nicholson et al. | Jan 2015 | B2 |
| 8953731 | Fawcett et al. | Feb 2015 | B2 |
| 8989335 | Tsang | Mar 2015 | B2 |
| 9047997 | Tsang | Jun 2015 | B2 |
| 9076561 | Brown | Jul 2015 | B2 |
| 9183959 | Bloomquist et al. | Nov 2015 | B2 |
| 9239385 | Fawcett et al. | Jan 2016 | B2 |
| 9240253 | Varnedoe et al. | Jan 2016 | B2 |
| 9285487 | Graves et al. | Mar 2016 | B2 |
| 9362009 | Russell, II et al. | Jun 2016 | B2 |
| 9396825 | Bloomquist et al. | Jul 2016 | B2 |
| 9443629 | Tsang | Sep 2016 | B2 |
| 9550704 | Chi et al. | Jan 2017 | B2 |
| 9576691 | Tsang | Feb 2017 | B2 |
| 9587292 | Lapi et al. | Mar 2017 | B2 |
| 10820404 | Cross et al. | Oct 2020 | B2 |
| 20050063514 | Price et al. | Mar 2005 | A1 |
| 20050156144 | Fukushima | Jul 2005 | A1 |
| 20060144793 | Dadachov | Jul 2006 | A1 |
| 20070086909 | Abenthung et al. | Apr 2007 | A1 |
| 20070133731 | Fawcett et al. | Jun 2007 | A1 |
| 20070155976 | Hunter et al. | Jul 2007 | A1 |
| 20080006606 | Magnaldo | Jan 2008 | A1 |
| 20090135990 | Poon et al. | May 2009 | A1 |
| 20090274258 | Holden et al. | Nov 2009 | A1 |
| 20100266083 | Bloomquist et al. | Oct 2010 | A1 |
| 20110006186 | Allen et al. | Jan 2011 | A1 |
| 20110009686 | Allen et al. | Jan 2011 | A1 |
| 20110051872 | Rickard et al. | Mar 2011 | A1 |
| 20110051875 | Bloomquist et al. | Mar 2011 | A1 |
| 20110079108 | Lapi et al. | Apr 2011 | A1 |
| 20110096887 | Piefer | Apr 2011 | A1 |
| 20110250107 | Varnedoe et al. | Oct 2011 | A1 |
| 20110280356 | Tsang | Nov 2011 | A1 |
| 20110286565 | Tsang | Nov 2011 | A1 |
| 20120027152 | Reese et al. | Feb 2012 | A1 |
| 20120073958 | Abenthung et al. | Mar 2012 | A1 |
| 20120285294 | Shanks et al. | Nov 2012 | A1 |
| 20130039822 | Hasan | Feb 2013 | A1 |
| 20130136221 | Nishikata et al. | May 2013 | A1 |
| 20130220928 | Oelsner | Aug 2013 | A1 |
| 20130301769 | Schaffer et al. | Nov 2013 | A1 |
| 20130312570 | Barbosa | Nov 2013 | A1 |
| 20130336436 | Allen et al. | Dec 2013 | A1 |
| 20140029710 | Wilson et al. | Jan 2014 | A1 |
| 20140133617 | Bloomquist et al. | May 2014 | A1 |
| 20140140462 | Barbosa | May 2014 | A1 |
| 20140192942 | Tsechanski | Jul 2014 | A1 |
| 20140231709 | Barbosa | Aug 2014 | A1 |
| 20140234186 | Barbosa | Aug 2014 | A1 |
| 20150023876 | Cope et al. | Jan 2015 | A1 |
| 20150139870 | Hasan | May 2015 | A1 |
| 20150243395 | Tsang | Aug 2015 | A1 |
| 20150243396 | Tsang | Aug 2015 | A1 |
| 20160023182 | Tadokoro et al. | Jan 2016 | A1 |
| 20160141061 | Burgett | May 2016 | A1 |
| 20160148712 | Sandquist | May 2016 | A1 |
| 20170032860 | Tsang | Feb 2017 | A1 |
| 20170048962 | Zeisler et al. | Feb 2017 | A1 |
| 20170251547 | Ito | Aug 2017 | A1 |
| 20180244535 | Russell, II et al. | Aug 2018 | A1 |
| 20180244536 | Russell, II et al. | Aug 2018 | A1 |
| Number | Date | Country |
|---|---|---|
| 009481 | Apr 2000 | AR |
| 019754 | Mar 2002 | AR |
| 077648 | Sep 2011 | AR |
| 102621 | Mar 2017 | AR |
| 104305 | Jul 2017 | AR |
| 104411 | Jul 2017 | AR |
| 105386 | Sep 2017 | AR |
| 2321183 | Oct 1999 | CA |
| 2506391 | Nov 2005 | CA |
| 2643841 | May 2009 | CA |
| 2653871 | Aug 2009 | CA |
| 2723224 | Nov 2009 | CA |
| 2724024 | Nov 2009 | CA |
| 2698773 | Oct 2010 | CA |
| 2767395 | Jan 2011 | CA |
| 2713237 | Feb 2011 | CA |
| 2933961 | Aug 2011 | CA |
| 2735612 | Oct 2011 | CA |
| 2806584 | Feb 2012 | CA |
| 2816648 | May 2012 | CA |
| 2832750 | Oct 2012 | CA |
| 2841617 | Jan 2013 | CA |
| 2871305 | Oct 2013 | CA |
| 2915775 | Oct 2013 | CA |
| 2876018 | Dec 2013 | CA |
| 2895929 | Jun 2014 | CA |
| 2915070 | Dec 2014 | CA |
| 1035719 | Aug 1997 | CN |
| 1035720 | Aug 1997 | CN |
| 1035736 | Aug 1997 | CN |
| 101905155 | Dec 2010 | CN |
| 103650061 | Mar 2014 | CN |
| 2841607 | Dec 2016 | EP |
| 2748825 | Mar 2017 | EP |
| 1157117 | Jul 1969 | GB |
| 10-0936016 | Jan 2010 | KR |
| 10-1365797 | Mar 2014 | KR |
| 10-1370189 | Mar 2014 | KR |
| 10-1542708 | Aug 2015 | KR |
| 10-1587837 | Jan 2016 | KR |
| 10-1754430 | Jul 2017 | KR |
| 2403086 | Nov 2010 | RU |
| 2462793 | Sep 2012 | RU |
| 2560966 | Aug 2015 | RU |
| 2014147619 | Jun 2016 | RU |
| 2630475 | Sep 2017 | RU |
| 927753 | May 1982 | SU |
| WO 1992016949 | Oct 1992 | WO |
| WO 1994004463 | Mar 1994 | WO |
| WO 1994004463 | Mar 1994 | WO |
| WO 1995016996 | Jun 1995 | WO |
| WO 1997001852 | Jan 1997 | WO |
| WO 2000003399 | Jan 2000 | WO |
| WO 2007041730 | Apr 2007 | WO |
| WO 2009135163 | Nov 2009 | WO |
| WO 2009135163 | Feb 2010 | WO |
| WO 2007041730 | May 2010 | WO |
| WO 2010132043 | Nov 2010 | WO |
| WO 2011005736 | Jan 2011 | WO |
| WO 2011093938 | Aug 2011 | WO |
| WO 2011126522 | Oct 2011 | WO |
| WO 2011126522 | Dec 2011 | WO |
| WO 2011156446 | Dec 2011 | WO |
| WO 2011093938 | Jan 2012 | WO |
| WO 2012018752 | Feb 2012 | WO |
| WO 2012048077 | Apr 2012 | WO |
| WO 2011156446 | May 2012 | WO |
| WO 2012125994 | Sep 2012 | WO |
| WO 2013010047 | Jan 2013 | WO |
| WO 2017012655 | Jan 2013 | WO |
| WO 2013027207 | Feb 2013 | WO |
| WO 2012125994 | Apr 2013 | WO |
| WO 2012125994 | Jun 2013 | WO |
| WO 2013082699 | Jun 2013 | WO |
| WO 2013159201 | Oct 2013 | WO |
| WO 2013027207 | Jan 2014 | WO |
| WO 2014163956 | Oct 2014 | WO |
| WO 2014186898 | Nov 2014 | WO |
| WO 2016023112 | Feb 2016 | WO |
| WO 2016023113 | Feb 2016 | WO |
| WO 2016075212 | May 2016 | WO |
| WO 2016081484 | May 2016 | WO |
| WO 2016081675 | May 2016 | WO |
| WO 2016108939 | Jul 2016 | WO |
| WO 2016173664 | Nov 2016 | WO |
| WO 2016207054 | Dec 2016 | WO |
| WO 2017082748 | May 2017 | WO |
| WO 2018156828 | Aug 2018 | WO |
| WO 2018156835 | Aug 2018 | WO |
| WO 2018156910 | Aug 2018 | WO |
| Entry |
|---|
| Scadden et al (“Radiochemistry of Molybdenum”, National Academy of Sciences, 1960, pp. 1-38). (Year: 1960). |
| J. V. Evans et al., “Zircomium Molybdate Gel as a Generator for Technetium-99mm—I. The Concept and its Evaluation.” Appl. Radiat. Isot. vol. 38, No. 1, pp. 19-23 (1987). |
| P.W. Moore et al., “Zircomium Molybdate Gel as a Generator for Technetium-99mm—II. High Activity Generators.” Appl. Radiat. Isot. vol. 38, No. 1, pp. 25-29 (1987). |
| Osso et al., “Preparation of a Gel of Zirconium Molybdate for Use in the Generators of. 99Mo-99mTc Prepared with 99Mo Produced by the 98Mo(n,g )99Mo Reaction,” Presented at the 1998 International Meeting on Reduced Enrichment for Research and Test Reactors; Oct. 18-23, 1998; Sao Paulo, Brazil. |
| Monroy-Guzman et al., “Magnesium-Molybdate Compounds as a Matrix for 99Mo/99mTc Generators,” Pharmaceuticals 2011, 4(2), 215-232. |
| Amin et al., “Effect of Al:Mo molar ratio on elution performance of 99Mo/99mTc generators based on Al99Mo gels,” J Radioanal Nucl Chem (2016) 309;485-492. |
| Guedes-Silva et al., “Influence of Alumina Phases on the Molybdenum Adsorption Capacity and Chemical Stability for 99Mo/99mTc Generators Columns,” Materials Research (2017); 19(4): 791-794. |
| Gopalakrishna et al., “Preparation of 99Mo from the 100Mo(γ, η) reaction and chemical separation of 99mTc,” J Radioanal Nucl Chem (2016) 308:431-438. |
| Fasih et al., “Preparation and evaluation of nano-crystalline titania as sorbent for 99Mo/99mTc generator,” Separation and Science Technology (2016) 51:13, 2115-2121. |
| Pupillo et al., “Accelerator based production of 99Mo: a comparison between the 100Mo(p,x) and 96Zr(α,n) reactions,” J Radioanal Nucl Chem (2015) 305:73-78. |
| Pupillo et al., “Experimental cross section evaluation for innovative 99Mo production via the (α,n) reaction on 96Zr target,” J Radioanal Nucl Chem (2014) 302:911-917. |
| El-Absy et al., “Preparation of 99Mo/99mTc generator based on alumina 99Mo-molybdate (VI) gel,” J Radioanal Nucl Chem (2014) 299:1859-1864. |
| Iller et al., “Synthesis and structural investigations of gel metal oxide composites WO3—ZrO2, WO3—TO2, WO3—ZrO2—SiO2, and their evaluation as materials for the preparation of 188W/188Re generator,” Applied Radiation and Isotopes 75 (2013) 115-127. |
| Chakravarty et al., “Nano Structured Metal Oxides as Potential Sorbents for 188W/188Re Generator: A Comparative Study,” Separation Science and Technology (2013) 48:4, 607-616. |
| Chakravarty et al., :An electrochemical procedure to concentrate 99mTc availed from a zirconium- [99Mo] molybdate gel generator, Applied Radiation and Isotopes 70 (2012) 375-379. |
| Mostafa et al., “Labeling of ceftriaxone for infective inflammation imaging using 99mTc eluted from 99Mo 99mTc generator based on zirconium molybdate,” Applied Radiation and Isotopes 68 (2010) 1959-1963. |
| Tereshatov et al., “Isocratic anion exchange separations of Group V elements,” J Radioanal Nucl Chem (2010) 286:9-16. |
| Davarpanah et al., “Influence of drying conditions of zirconium molybdate gel on performance of 99mTc gel generator,” Applied Radiation and Isotopes 67 (2009) 1796-1801. |
| Sahoo et al., “Synthesis, Characterization, and Photocatalytic Properties of ZrMo2O8,” J. Phys. Chem. C 2009, 113, 10661-10666. |
| Sahoo et al., “Synthesis, structure and photocatalytic properties of β-ZrMo2O8,” Bull. Mater. Sci., vol. 32, No. 3, Jun. 2009, pp. 337-342. |
| Magnaldo et al., “Nucleation and crystal growth of zirconium molybdate hydrate in nitric acid,” Chemical Engineering Science 62 (2007) 766-774. |
| Monroy-Guzman et al., “Titanium Molybdate Gels as Matrix of 99Mo/99mTc Generators,” Journal of Nuclear and Radiochemical Sciences, vol. 8, No. 1, pp. 11-19, 2007. |
| Monroy-Guzman et al., “Production optimization of 99Mo/99mTc zirconium molybate gel generators at semi-automatic device: DISIGEG,” Applied Radiation and Isotopes 70 (2012) 103-111. |
| Monroy-Guzman et al., “99Mo/99mTc Generators Performances Prepared from Zirconium Molybate Gels,” J. Braz. Chem. Soc., vol. 19, No. 3, 380-388, 2008. |
| Monroy-Guzman et al., “Determination of Mo, W and Zr in molybdates and tungstates of zirconium and titanium,” Journal of Radioanalytical and Nuclear Chemistry, vol. 271, No. 3 (2007) 523-532. |
| Monroy-Guzman et al., “Effect of Zr:Mo ratio on 99mTc generator performance based on zirconium molybdate gels,” Applied Radiation and Isotopes 59 (2003) 27-34. |
| International Search Report and Written Opinion of corresponding International Application PCT/US2018/019335, dated May 7, 2018. |
| International Search Report and Written Opinion of corresponding International Application PCT/US2018/019322, dated Jul. 11, 2018. |
| International Search Report and Written Opinion of corresponding International Application PCT/US2018/019443, dated Jul. 9, 2018. |
| Monroy-Guzman et al., “Titanium Molybdate Gels as Matrix of 99Mo/99mTc Generators”, Journal of Nuclear and Radiochemical Sciences, vol. 8, No. 1 (Jan. 2007), p. 11-19 (p. 11, col. 1, para 1; p. 11, col. 2, para 4; p. 12; p. 13, col. 1, para 3; p. 13, col. 2, para 12; p. 14; p. 16, col. 1, para 3; p. 16, col. 2, para 1; p. 17, col. 2, para 1; p. 18, col. 1, para 2; p. 18, col. 2, para 1; abstract; title; tables 1-2; figure 2D, 3B and 4A. |
| Extended European Search Report, European Application No. 18758354.7, dated Nov. 25, 2020, 7 pages. |
| Extended European Search Report, European Application No. 18757129.4, dated Nov. 25, 2020, 6 pages. |
| Office Action from U.S. Appl. No. 15/902,534 dated Sep. 11, 2020. |
| Office Action and Search Report from Russian Patent Application No. 2019129820 dated Jun. 2, 2020. |
| Office Action and Search Report from Russian Patent Application No. 2019129825 dated Aug. 10, 2020. |
| Lidin R.A, et al., Khimicheskie svojstva neorganichheskikh veshchestv, Moscow, Kimia 1997, pp. 388, section 772, reaction 3. (not in English) (See Office Actions and Search Reports from Russian Patent Application Nos. 2019129820 and 2019129825). |
| Australian Examination Report from Australian Patent Application No. 2018224128 dated Feb. 24, 2020. |
| International Preliminary Report on Patentability, PCT/2018/019322, dated Aug. 27, 2019, 17 pages. |
| International Preliminary Report on Patentability, PCT/2018/019335, dated Aug. 27, 2019, 21 pages. |
| International Preliminary Report on Patentability, PCT/2018/019443, dated Aug. 27, 2019, 5 pages. |
| Number | Date | Country | |
|---|---|---|---|
| 20180244536 A1 | Aug 2018 | US |
| Number | Date | Country | |
|---|---|---|---|
| 62592737 | Nov 2017 | US | |
| 62463020 | Feb 2017 | US |
