Repeated distillation / sublimation of rare earth elements

Abstract

The method includes sublimating or distilling an ytterbium composition from an initial solid composition comprising ytterbium and lutetium during a first sublimation / distillation period under an inert or reduced pressure environment and at a first average temperature to leave a lutetium composition comprising a higher weight percent of lutetium than was present in the initial solid composition; collecting the ytterbium composition; and holding the ytterbium composition for a waiting period to form a decayed ytterbium composition, the waiting period being longer than the first sublimation / distillation period; and following the waiting period, sublimating or distilling a purified ytterbium composition from the decayed ytterbium composition during a second sublimation / distillation period under an inert or reduced pressure environment and at a second average temperature to leave a waste composition.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 358,849, filed July 6, 2022, which is incorporated herein by reference in its entirety.

[0002] This disclosure relates generally to the separation of rare earth elements and their purification, and more particularly to the isolation and purification of lutetium from irradiation targets containing other rare earth metals, such as ytterbium. [Background technology]

[0003] Lutetium-177 (Lu-177) is a radioisotope used in the treatment of neuroendocrine tumors, prostate cancer, breast cancer, kidney cancer, pancreatic cancer, and other cancers. In the next few years, approximately 70,000 patients per year will require Lu-177 during their medical treatment.

[0004] Therefore, there is a need for improved techniques for separating and purifying radioisotopes such as Lu-177. Summary of the Invention

[0005] According to a first aspect of the present disclosure, a method includes sublimating or distilling an ytterbium composition from an initial solid composition comprising ytterbium and lutetium during a first sublimation / distillation period under an inert or reduced pressure environment and at a first average temperature in the range of 400°C to 2000°C to leave a lutetium composition comprising a higher weight percent of lutetium than was present in the initial solid composition; collecting the ytterbium composition; and holding the ytterbium composition for a waiting period to form a decayed ytterbium composition, the waiting period being longer than the first sublimation / distillation period; and following the waiting period, sublimating or distilling a purified ytterbium composition from the decayed ytterbium composition during a second sublimation / distillation period under an inert or reduced pressure environment and at a second average temperature in the range of 400°C to 2000°C to leave a waste composition.

[0006] A second aspect includes the method of the first aspect, further including the step of collecting the purified ytterbium composition.

[0007] A third aspect includes the method of the second aspect, further including forming the purified ytterbium composition into an ytterbium target.

[0008] A fourth aspect includes the method of the third aspect, further including irradiating the ytterbium target with neutrons to form a regenerated solid composition comprising ytterbium and lutetium.

[0009] A fifth aspect includes the method of the fourth aspect, further including the step of sublimating or distilling the ytterbium composition from the regenerated solid composition during a third sublimation / distillation period in an inert or reduced pressure environment and at a third average temperature in the range of 400°C to 2000°C to leave a subsequent lutetium composition comprising a higher weight percent of lutetium than was present in the regenerated solid composition.

[0010] A sixth embodiment includes the method of the fifth embodiment, wherein the first average temperature, the second average temperature, and the third average temperature are equal or differ by less than 100°C.

[0011] A seventh aspect includes the method of any of the first to sixth aspects, wherein the purified ytterbium composition includes 0.1 wt% or less Lu-175.

[0012] An eighth aspect includes the method of any of the first through seventh aspects, wherein the purified ytterbium composition includes 0.01 wt% or less Lu-175.

[0013] A ninth aspect includes the method of any of the first through eighth aspects, wherein the purified ytterbium composition comprises 0.005 wt% or less Lu-175.

[0014] A tenth aspect includes the method of any of the first to ninth aspects, wherein the waste composition includes Lu-175 and at least one of one or more of ytterbium oxides, one or more ytterbium silicates, lanthanum, iron, aluminum, nickel, copper, cerium, tin, erbium, cobalt, silicon, chromium, tantalum, titanium, molybdenum, manganese, and mixtures and alloys thereof.

[0015] An eleventh aspect includes the method of the tenth aspect, wherein the waste composition includes 10 mg or more of ytterbium oxide, and further includes the steps of dissolving the ytterbium oxide to form dissolved ytterbium oxide, and metallizing the dissolved ytterbium.

[0016] A twelfth aspect includes the method of any of the first through eleventh aspects, wherein the ytterbium composition includes Yb-176 and Yb-175, and the Yb-175 partially decays to Lu-175 during the waiting period to form a decayed ytterbium composition, and wherein sublimating or distilling the purified ytterbium composition from the decayed ytterbium composition separates the Yb-176 and Lu-175.

[0017] A thirteenth embodiment includes the method of the twelfth embodiment, wherein the purified ytterbium composition includes Yb-176 and the waste composition includes Lu-175.

[0018] A fourteenth aspect includes the method of any of the first to thirteenth aspects, wherein the waiting period is at least one week.

[0019] A fifteenth aspect includes the method of any of the first to fourteenth aspects, wherein the waiting period is at least five weeks.

[0020] A sixteenth aspect includes the method of any of the first to fifteenth aspects, wherein the waiting period is at least eight weeks.

[0021] A seventeenth aspect includes the method of any of the first through sixteenth aspects, wherein during the waiting period, 99% or more of the Yb-175 present in the ytterbium composition decays to Lu-175.

[0022] An eighteenth aspect includes the method of any of the first through seventeenth aspects, wherein during the waiting period, 99.9% or more of the Yb-175 present in the ytterbium composition decays to Lu-175.

[0023] A nineteenth aspect includes the method of any of the first to eighteenth aspects, wherein the inert or reduced pressure environment is 1×10 -8 This is a reduced pressure environment consisting of a reduced pressure in the range of ~2000 torr.

[0024] A twentieth embodiment includes the method of the nineteenth embodiment, wherein the reduced pressure is 1×10 -3 torr or less.

[0025] A twenty-first aspect includes the method of any one of the first to twentieth aspects, wherein the first average temperature is in the range of 450°C to 1500°C.

[0026] A twenty-second embodiment includes the method of any of the first to twenty-first embodiments, wherein the first average temperature is less than 700°C.

[0027] A twenty-third aspect includes the method of any of the first to twenty-second aspects, wherein the first average temperature and the second average temperature are equal or differ by less than 100°C.

[0028] A twenty-fourth aspect includes the method of any of the first to twenty-third aspects, further including the step of chromatographically separating the lutetium composition to further enrich the lutetium in the lutetium composition.

[0029] A 25th aspect includes the method of the 24th aspect, further including the steps of dissolving a lutetium composition in an acid to form a dissolved lutetium solution, adding a chelating agent to the dissolved lutetium solution and neutralizing with a base to form a chelated lutetium solution containing both chelated lutetium and ytterbium, chromatographically separating the chelated lutetium solution, collecting a purified chelated lutetium fraction, and dechelating the lutetium to obtain purified lutetium.

[0030] A 27th aspect includes the method of any of the 1st to 26th aspects, wherein the initial solid composition is contained in a crucible of a sublimation / distillation apparatus, and wherein sublimating or distilling the ytterbium from the initial solid composition comprises heating the crucible such that the ytterbium composition sublimes, distills, or sublimes and distills from the initial solid composition and collects on a collecting substrate of the sublimation / distillation apparatus.

[0031] A twenty-eighth embodiment includes the method of any of the first through twenty-seventh embodiments, wherein the purified ytterbium composition comprises a higher weight percent of ytterbium than was present in the decayed ytterbium composition.

[0032] A twenty-ninth aspect includes the method of any of the first through twenty-eighth aspects, further comprising subjecting the lutetium composition to a non-aqueous separation technique to further enrich the lutetium in the lutetium composition.

[0033] These and additional features provided by the embodiments described herein will be more fully understood when considered in conjunction with the following detailed description and drawings.

[0034] The embodiments illustrated in the drawings are illustrative and exemplary in nature and are not intended to limit the subject matter defined by the claims. The following detailed description of illustrative embodiments can be understood when read in conjunction with the following drawings, in which like structure is designated with like numerals. [Brief explanation of the drawings]

[0035] [Figure 1] FIG. 10 is a Txy diagram for lutetium and ytterbium at a constant pressure of 1 μtorr. [Figure 2] FIG. 1 is a schematic diagram of a chamber for the sublimation of ytterbium and lutetium according to one or more embodiments shown and described herein. [Figure 3]1 is a flowchart outlining a method for repeated sublimation of ytterbium according to one or more embodiments shown and described herein. DETAILED DESCRIPTION OF THE INVENTION

[0036] Referring generally to the drawings, embodiments of the present disclosure are directed to a method for repeatedly separating an ytterbium composition from a solid composition containing ytterbium and lutetium. Specifically, the method includes sublimating the ytterbium composition from an initial solid composition containing ytterbium and lutetium; collecting both the sublimated ytterbium composition and the remaining lutetium composition, which may include a high-purity isotope of lutetium, such as lutetium-177 (Lu-177); and reprocessing the ytterbium composition so that the collected ytterbium composition can be used to collect additional high-purity lutetium, such as additional Lu-177. Lu-177 is used to treat neuroendocrine tumors, prostate cancer, breast cancer, kidney cancer, pancreatic cancer, and other cancers. Approximately 70,000 patients per year will require carrier-free Lu-177 during their medical procedures within the next few years. Lu-177 is useful for numerous medical applications because it emits low-energy beta particles suitable for treating tumors during decay. It also emits several gamma rays, two of which are used in diagnostic tests. Isotopes with both therapeutic and diagnostic characteristics are called "theranostics." Not only is Lu-177 a theranostic, but its half-life of 6.65 days allows for more complex chemistries and easier global distribution. Lu-177 also exhibits chemical properties that allow it to be bound to numerous biomolecules for use in a wide variety of medical procedures.

[0037] There are two main routes to producing Lu-177. One is via a neutron capture reaction with Lu-176: Lu-176(n,γ)Lu-177. This production method is referred to as carrier-added (ca) Lu-177. The carrier is an isotope of the same element (in this case, Lu-176) or a similar element in the same chemical form as the target isotope. In trace chemistry, the target chemical element or isotope does not behave chemically as expected due to its extremely low concentration. Lu-176 effectively dilutes the interaction of Lu-177 with receptor sites in the body, reducing treatment efficiency. Furthermore, isotopes of the same element are not chemically separable and require mass separation techniques. Therefore, the carrier method results in the production of Lu-177, which has limited medical applications.

[0038] The second production method for Lu-177 is the neutron capture reaction of ytterbium-176 (Yb-176) to produce Yb-177 (Yb-176(n,γ)Yb-177), which then rapidly beta decays to Lu-177 (t = 1.911 hours). 1 / 2 ) The impurity of Yb-174 is usually present in Yb-176, resulting in an additional impurity of Lu-175 in the final product. This process is considered a "no carrier added" process. This process can be carried out as ytterbium metal or ytterbium oxide.

[0039] This disclosure describes a process for the separation of Yb and Lu obtained from the no-carrier process. The process includes a distillation / sublimation step to purify Lu and remove excess Yb after irradiation. The excess Yb may be further processed and regenerated for subsequent use (e.g., by neutron irradiation), and the process may include further purification of lutetium using other separation processes, such as chromatographic or non-aqueous separation processes. Due to the limited amount of material that can be processed at any one time during chromatographic or other separation processes, concentrating Lu prior to chromatographic or other separation processes allows for the expansion of product Lu recovery to significantly higher levels than previously obtainable. Combining distillation / sublimation and chromatographic or other separation processes allows for the use of larger targets and the isolation of products via distillation that can then be passed on to chromatographic processes. Furthermore, metal target handling allows for more efficient use of larger targets with more economical recovery. Because the metal targets remain metallic during processing, Yb can be easily incorporated into new targets with minimal manipulation, less labor, and less processing equipment. Furthermore, the use of this sublimation process with existing separation techniques allows for the use of lower neutron flux facilities, significantly improving the irradiability and business competitiveness of Yb targets.

[0040] Separation of Yb and Lu may exploit, at least in part, the difference in their vapor pressures at a particular temperature and pressure. As an example, at standard temperature and pressure, the boiling point of Yb is 1196°C, while the boiling point of Lu is 3402°C. The difference in vapor pressure at a specified temperature and pressure can be used to separate Yb and Lu via sublimation and / or distillation. Referring now to FIG. 1, graph 50 is a Txy diagram for lutetium and ytterbium at a constant pressure of 1 μtorr. In FIG. 1, line 54 represents the condensed phase composition at a given temperature (i.e., the bubble point), while line 52 represents the vapor phase (i.e., the dew point). Graph 50 was generated using ideal gas and solution assumptions, which are reasonable given the low pressure, high temperature, and chemical similarity of the two components.

[0041] In sublimation, the solid phase of the element is converted directly to a gas phase via heating, and the gas phase can be collected for later use. In distillation, the solid is heated (via the liquid phase) to its boiling point to vaporize it. The vaporized fraction can then be recovered downstream after the vapor is condensed. In this case, the ytterbium is vaporized (and may be collected downstream for later use) to leave a lutetium-enriched material. This may be done on a larger scale, thus increasing the amount of available lutetium. Furthermore, the collected ytterbium can be recycled to a nuclear reactor, particle accelerator, or other neutron generating source to produce additional lutetium in subsequent runs of processing. Indeed, the methods described herein provide an improved technique for recycling collected ytterbium to improve the quantity and quality of subsequently produced lutetium.

[0042] Referring now to FIG. 2 , a schematic diagram of a sublimation / distillation apparatus 100 for separating rare earth elements, such as lutetium and ytterbium, is shown. The sublimation / distillation apparatus 100 includes a chamber 105 with feedthroughs for gas, cooling, vacuum, power, and equipment. The sublimation / distillation apparatus 100 can generate environments within the chamber 105 with various conditions, such as high temperature, low pressure, high levels of inert gas, and low partial pressure of a select gas. The sublimation / distillation apparatus 100 includes a crucible 190 and a heating element 170, which can be housed together in the chamber 105. The chamber 105 can also include a sealable access port 110 that provides a user with selective access to the crucible 190, for example, to access and transfer a sample contained therein. The crucible 190 can be made of a refractory material (e.g., molybdenum or tantalum). In some embodiments, the heating element 170 is an induction heating element, such as a radio frequency (RF) induction coil. In some embodiments, heating element 170 is an electrical resistance heating element, such as any known or yet to be developed heating element configured to heat crucible 190 or a crucible holder (e.g., a holding device thermally and physically coupled to crucible 190) by electrical resistance heating. Crucible 190 may be suspended or supported within an RF induction heating coil. Temperature sensor 180 monitors the temperature of crucible 190, and pressure-sensing instrument 140 monitors the pressure of chamber 105. Sublimation / distillation apparatus 100 also includes a vacuum pump connection 150 and at least one port 200 for the introduction of an inert gas. Vacuum pump connection 150 connects sublimation / distillation apparatus 100 to a vacuum pump, such as a turbomolecular pump, which may be used to achieve high vacuum levels during operation.

[0043] The sublimation / distillation apparatus 100 includes a collecting substrate 160 that forms a cooling surface. The collecting substrate 160 may be actively cooled by a cooling water line 130. The temperature of the collecting substrate 160 may be monitored by a temperature sensor 120. The collecting substrate 160 may include a cold finger 165 (e.g., a cooling rod) that extends from the collecting substrate 160 toward and is positioned directly above the crucible 190. The cold finger 165 and collecting substrate 160 are movable, allowing the open end of the crucible 190 to be open to the vacuum system (e.g., open to the chamber 105) or sealed to the collecting substrate 160. In some embodiments, the cold finger 165 includes an end effector. In fact, the cold finger 165 may extend from the collecting substrate 160 towards the crucible 190 such that when the collecting substrate 160 is sealed onto the crucible 190, the cold finger 165 extends into the crucible 190. Like the collecting substrate 160, the cold finger 165 may also be actively cooled.

[0044] Referring now to Figure 3, Flowchart 10 illustrates a method for the repeated separation of an ytterbium composition from a solid composition comprising ytterbium and lutetium. As indicated by box 12, the method includes sublimating or distilling ytterbium from an initial solid composition 102 (Figure 2) in an inert or reduced pressure environment and at a first average temperature ranging from 400°C to 2000°C during a first sublimation / distillation period, leaving a lutetium composition containing a higher weight percent of lutetium than was present in the initial solid composition 102. The first sublimation / distillation period can vary and depends on the amount of material in the initial solid composition, the average temperature, and the pressure. For example, the first sublimation / distillation period can range from 1 second to 1 week, and the sublimation or distillation can be performed over a period of 100 minutes / g to 1 minute / g of the initial solid composition, such as 1 minute / g, 2 minutes / g, 5 minutes / g, 8 minutes / g, 10 minutes / g, 20 minutes / g, 25 minutes / g, 30 minutes / g, 40 minutes / g, 50 minutes / g, 60 minutes / g, 70 minutes / g, 75 minutes / g, 80 minutes / g, 90 minutes / g, or the like. / g, 100 min / g, or any range having any two of these values as endpoints, or any value in a range having any two of these values as endpoints, may be performed at a rate of from 80 min / g to 2 min / g, 75 min / g to 5 min / g, 75 min / g to 10 min / g, 60 min / g to 20 min / g, 60 min / g to 30 min / g, or 60 min / g to 40 min / g.

[0045] Additionally, during the first sublimation / distillation period, the temperature may be increased from room temperature to the first average temperature at a temperature ramp rate over a period of 10 minutes to 2 hours to minimize, and in some embodiments prevent, blistering or uneven heating of the initial solid composition 102. In some embodiments, prior to heating the initial solid composition 102, the pressure in the environment (e.g., within the chamber 105 of the sublimation / distillation apparatus 100) may be reduced to degas the initial solid composition 102, for example, by reducing the pressure to about 1×10 for a period of about 5 minutes to 1 hour. -6 torr.

[0046] 2 and 3, the initial solid composition 102 may be contained in a crucible 190, and sublimating or distilling the ytterbium from the initial solid composition 102 in box 12 may comprise heating the crucible 190, for example, with a heating element 170, such that the ytterbium composition sublimes, distills, or sublimes and distills from the initial solid composition 102 and, in some embodiments, is collected on a collection substrate 160, including on a cold finger 165. The temperature of the initial solid composition 102 may be monitored indirectly through the crucible 190, for example, with a temperature sensor 180. For example, the initial collection of the ytterbium composition (e.g., "separated ytterbium composition") on the collection substrate 160 is indicated by box 14 in FIG. 3. Upon collection, the ytterbium composition may include both Yb-176 and Yb-175. The lutetium composition remaining in, for example, crucible 190 may also be collected, as shown in box 16. As described above, the lutetium composition comprises a higher weight percent of lutetium than was present in initial solid composition 102. As described in more detail below, the lutetium composition collected in box 16 may be chromatographically separated to further enrich the lutetium in the lutetium composition. Alternatively, the lutetium composition collected in box 16 may be subjected to a non-aqueous separation technique, such as a non-aqueous electrolytic reduction process using mercury, to further enrich the lutetium in the lutetium composition.

[0047] Next, in box 18, the ytterbium composition is held for a waiting period. The waiting period is longer than the first sublimation / distillation period. For example, the waiting period can be at least 4 days, e.g., at least 5 days, at least 6 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 15 weeks, or longer, e.g., at least 52 weeks or at least 104 weeks. During the waiting period, Yb-175 present in the ytterbium composition partially decays to Lu-175, forming a decaying ytterbium composition. The half-life of Yb-175 is approximately 4 days. In fact, over an 8-week waiting period, 99.991% of the Yb-175 present in the ytterbium composition decays to Lu-175. In some embodiments, the ytterbium composition can then be held for a waiting period during which 50% or more, e.g., 75% or more, 90% or more, 95% or more, 95% or more, 99.3% or more, 99.5% or more, 99.7% or more, 99.9% or more, 99.95% or more, 99.97% or more, 99.99% or more, 99.995% or more, 99.999% or more, or 99.9999% or more of the Yb-175 present in the ytterbium composition decays to Lu-175.

[0048] Lu-175 is stable and non-radioactive. Lu-175 is also a contaminant in Lu-177-based radiopharmaceuticals. Because Lu-175 is stable and non-radioactive, it reduces the specific activity of Lu-177-based radiopharmaceuticals. Lu-175 can also result in the formation of Lu-176m during irradiation following the processes described herein (e.g., in the step shown as box 26 in Figure 3). Minimization of Lu-175 and Lu-176m may be necessary for some radiopharmaceutical products to meet purity requirements. Table 1 below contains additional details about Lu-175 and Lu-176. As shown in Table 1, the production of Lu-177m2 results from Lu-176, has a half-life of approximately 160 days, and is harmful to patients because it can persist in the body and potentially cause damage to non-target cells. [Table 1]

[0049] Retaining the ytterbium composition allows a majority of the Yb-175 to decay to Lu-175, forming a decayed ytterbium composition. This allows the Lu-175 to be removed from the decayed ytterbium composition by an additional sublimation step. Indeed, following the waiting period, the method may further comprise sublimating or distilling the purified ytterbium composition from the decayed ytterbium composition in box 20, e.g., using sublimation / distillation apparatus 100 (or a different sublimation / distillation apparatus) in an inert or reduced pressure environment at a temperature in the range of 400°C to 2000°C, to leave a waste composition containing newly formed Lu-175 (e.g., Lu-175 formed by decay during the waiting period). For example, the purified ytterbium composition may collect on collection substrate 160 and / or cold finger 165 of sublimation / distillation apparatus 100, while the waste composition may remain in crucible 190. The purified ytterbium composition comprises Lu-175 at 0.1 weight percent (wt%) or less, e.g., 0.05 wt% or less, 0.02 wt% or less, 0.01 wt% or less, 0.005 wt% or less, 0.004 wt% or less, 0.003 wt% or less, 0.002 wt% or less, 0.001 wt% or less, 0.0005 wt% or less, 0.0001 wt% or less, or a range having any two of these values as endpoints. Furthermore, in embodiments where the waste composition includes 10 mg or more of ytterbium oxide, the method may further comprise dissolving the ytterbium oxide and metallizing the dissolved ytterbium to ytterbium metal, which can be purified for reuse.

[0050] By separating the purified ytterbium composition and the waste composition, the purified ytterbium composition contains a higher weight percent of ytterbium than was present in the decayed ytterbium composition. In addition to Lu-175, the waste composition may further contain one or more ytterbium oxides, one or more ytterbium silicates, and elements with low vapor pressures, such as lanthanum, iron, aluminum, nickel, copper, cerium, tin, erbium, cobalt, silicon, chromium, tantalum, titanium, molybdenum, manganese, and mixtures and alloys thereof. Each of these is undesirable in Lu-177-based radiopharmaceuticals. Furthermore, these impurities may also be undesirable when the purified ytterbium composition is irradiated (see 26 below). Without intending to be limited by theory, if the impurities are irradiated and activated in a neutron source facility, such as a nuclear reactor, the impurities may cause excess radiation doses to facility operators. In other words, removing the waste composition from the decayed ytterbium composition (i.e., forming purified ytterbium) acts as a purification step that removes the impurities that form the waste composition from the decayed ytterbium composition.

[0051] 2 and 3 , the method next includes collecting the purified ytterbium composition in box 22 and forming (e.g., compressing, pelletizing, etc.) the purified ytterbium composition into an ytterbium target in box 24. In some embodiments, the ytterbium target comprises ytterbium pellets, which may be formed by pelletizing the purified ytterbium composition. The ytterbium pellets may include various shapes, such as spherical, cylindrical, or oval. In some embodiments, the ytterbium target comprises ytterbium foil. The ytterbium target is substantially homogeneous to promote uniform heat transfer and uniform irradiation. Next, in box 26, the ytterbium target may be irradiated with neutrons to form a regenerated solid composition comprising ytterbium and lutetium. The ytterbium target may be irradiated with neutrons generated using a nuclear reactor, a particle accelerator such as an ion beam source, or any other known or yet to be developed neutron source. In some embodiments, in box 26, the ytterbium target is packaged in a tube, which may have sealable ends. For example, the tube may be a quartz tube or a titanium tube, and the tube may have a diameter ranging from 0.5 cm to 2 cm, such as a 1 cm diameter. The tube is then placed in an inert overpack (e.g., aluminum) suitable for irradiation. In some embodiments, the inert overpack is sealed and resistant to water or air ingress. In other embodiments, the inert overpack is not sealed. The inert overpack is irradiated for several hours to several days (depending on the flux and batch requirements) with neutrons generated using a nuclear reactor, a particle accelerator such as an ion beam source, or any other known or yet to be developed neutron source to generate Lu-177 in the Yb-176 target and form a regenerated solid composition.

[0052] After neutron irradiation, the regenerated solid composition may be returned to sublimation / distillation apparatus 100 (or a different sublimation / distillation apparatus) for further processing. For example, a sealed overpack containing the regenerated solid composition may be loaded into a processing hot cell or isolator. For the additional sublimation / distillation step, within the hot cell or isolator, which may include an inert environment, the irradiated Yb metal target is removed and placed inside crucible 190 of sublimation / distillation apparatus 100 (or a different sublimation / distillation apparatus) and placed within chamber 105. Indeed, the method then includes, in box 28, sublimating or distilling a ytterbium composition (e.g., a subsequent ytterbium composition) from the regenerated solid composition during a third sublimation / distillation period under an inert or reduced pressure environment and at a third average temperature in the range of 400°C to 2000°C, leaving a subsequent lutetium composition containing a higher weight percent of lutetium than was present in the regenerated solid composition. The third sublimation / distillation period may be the same length as the first sublimation / distillation period and may operate at the same temperature ramp rate, temperature, and pressure. Next, in box 30, a subsequent lutetium composition is collected, and in box 32, a subsequent ytterbium composition is also collected. The process may then be repeated for subsequent ytterbium compositions, beginning with box 18. That is, the subsequent ytterbium composition is held for a waiting period, sublimated or distilled to remove waste composition (box 20), collected (box 22), formed (box 24), irradiated (box 26), and sublimated / distilled to separate and collect additional lutetium (boxes 28 and 30). This process may be repeated multiple times to collect additional lutetium.

[0053] 2 and 3, in boxes 16 and 30, the produced lutetium compositions are collected as the crucible 190 cools. Once the crucible 190 has cooled to a temperature of 150° C. or less, such as 100° C. or less, 80° C. or less, or 50° C. or less, the lutetium compositions are dissolved in acid for removal from the crucible 190 and transfer to a chromatographic separation device. The crucible 190 may be passively cooled (e.g., by removing heat from the heating element 170 and waiting a period of time) or actively cooled. Indeed, similar to the lutetium compositions collected in box 16, the lutetium compositions collected in box 30 may be chromatographically separated to further enrich the lutetium in the composition or sample, as described in more detail below.

[0054] Further referring to FIGS. 2 and 3, the first average temperature in the first sublimation / distillation period, the second average temperature in the second sublimation / distillation period, and the third average temperature in the third sublimation / distillation period are each in the range of 400°C to 2000°C, for example, 450°C to 1500°C, 450°C to 1200°C, 450°C to 1000°C, 400°C to 1000°C, 400°C to 900°C, 400°C to 800°C, 450°C to 700°C, 400°C to less than 700°C, 400°C to 695°C, 450°C to 690°C, 450°C to 685°C, 450°C to 69 ... The temperature may be 80°C, 450°C to 675°C, 450°C to 670°C, 450°C to 665°C, 450°C to 660°C, 450°C to 655°C, 450°C to 650°C, 450°C to 645°C, 450°C to 640°C, 450°C to 635°C, 450°C to 630°C, 450°C to 625°C, 470°C to about 630°C, 800°C to 2000°C, over 800°C to 2000°C, 1000°C to 2000°C, 1200°C to 2000°C, 1500°C to 2000°C, or any range having any two of these values as endpoints. In practice, temperatures for sublimation and / or distillation (e.g., ambient temperatures) may be 400°C, 425°C, 450°C, 470°C, 475°C, 500°C, 525°C, 550°C, 575°C, 600°C, 625°C, 640°C, 650°C, 655°C, 660°C, 665°C, 670°C, 675°C, 680°C, 685°C, 690°C, 695°C, 698°C, 700°C, 725°C, 750 ... The average temperature may be 0° C., 775° C., 800° C., 850° C., 900° C., 950° C., 1000° C., 1100° C., 1200° C., 1300° C., 1400° C., 1500° C., 1600° C., 1700° C., 1800° C., 1900° C., 2000° C., any range having any two of these values as endpoints, or any value in a range having any two of these values as endpoints. In some embodiments, the first average temperature, the second average temperature, and the third average temperature are equal or differ by less than 100° C.

[0055] Also, according to various embodiments, the pressure of the environment at any of the temperatures and temperature ranges described above and during the first, second, and third sublimation / distillation periods is between 2000 torr and 1×10 -8 torr, 1520 torr ~ 1 × 10 -8 torr, 1000 torr to 1×10-8 torr, 760 torr to 1×10 -8 torr, 700 torr to 1×10 -8 torr, 500 torr to 1×10 -8 torr, 250 torr to 1×10 -7 torr, 100 torr to 1×10 -6 torr, 1 torr to 1 × 10 -6 torr, 1×10 -1 torr~1×10 -6 torr, 1×10 -3 below torr, 1×10 -5 below torr, 1×10 -6 torr or less, 2000 torr to 1×10 -1 torr, 1520 torr to 1 torr, 1000 torr to 1 torr, 760 torr to 1 torr, 760 torr to 250 torr, any range having any two of these values as endpoints, or any range of values in a range having any two of these values as endpoints.

[0056] In boxes 18 and 30, the sublimation / distillation process results in a lutetium composition (e.g., an "initial collection of lutetium composition" and a "subsequent collection of lutetium composition") that is enriched in lutetium compared to the initial or regenerated solid composition entering the process. Yield and purity can be measured in several ways. For example, in some embodiments, the treatment results in a ytterbium mass reduction in the initial or regenerated solid composition of 10:1 to 10,000:1, such as 25:1, 50:1, 75:1, 50:1, 150:1, 200:1, 400:1, 500:1, 750:1, 1000:1, 2000:1, 3000:1, 4000:1, 5000:1, 6000:1, 7000:1, 8000:1, 9000:1, or any range incorporating any two of these values as endpoints. In other words, after sublimation / distillation is complete, there is 10 to 10,000 times less ytterbium in the sample than before treatment (i.e., than was present in the initial or regenerated solid composition). In some embodiments, the recovered ytterbium composition (i.e., the contents of the crucible that is acid-dissolved) will contain 1 wt% to 90 wt% ytterbium based on the total remaining mass, which is subsequently separated in a chromatographic process as described below. In other embodiments, the ytterbium collected from sublimation / distillation is collected in an amount of 90 wt% to 99.999 wt% of the ytterbium present in the initial or regenerated solid composition. A purification step may also be performed to remove other trace metals and contaminants. For example, materials such as metals, metal oxides, or metal ions of K, Na, Ca, Fe, Al, Si, Ni, Cu, Pb, La, Ce, Lu (non-radioactive), Eu, Sn, Er, and Tm may be removed. In other words, the methods described herein include the step of subjecting a sample containing Yb-176 and Lu-177 to sublimation, distillation, or a combination thereof to remove at least a portion of the Yb-176 from the sample and form a Lu-177 enriched sample.

[0057] It has been determined that purifications of 100:1 reduction of Yb (i.e., a 100-fold reduction in the amount of Yb present) or greater can be achieved, for example, 200:1 or greater, 500:1 or greater, 1000:1 or greater, 2000:1 or greater, 4000:1 or greater, 8000:1 or greater, 10000:1 or greater, up to about 40000:1. On the other hand, higher reductions of Yb may be necessary to meet the purity requirements for some pharmaceutical products. Therefore, additional purification may be performed before use in pharmaceutical applications. Such purification may be performed using chelating agents and / or chromatographic separation.

[0058] As described herein, any of the above lutetium compositions or lutetium-enriched samples may be chromatographically separated to further enrich the lutetium in the composition or sample. Such chromatographic separation may include column chromatography, plate chromatography, thin-layer chromatography, or high-performance liquid chromatography. Illustrative processes for purifying lutetium may be those described in U.S. Pat. Nos. 7,244,403 and 9,816,156, both of which are incorporated herein by reference in their entireties. However, it should be understood that other chromatographic separation techniques may be used to further enrich the lutetium separated using the techniques described herein. In one aspect, the process may include dissolving the lutetium and ytterbium compositions remaining in the crucible after sublimation in an acid and applying the resulting solution to a chromatographic column or plate. This may include plate chromatography material, a chromatographic column, an HPLC chromatography column, an ion exchange column, or the like.

[0059] As an illustrative example, a solution of lutetium in dilute HCl (i.e., 0.01-5N HCl) can be prepared. This can be applied to a solution-packed or dry ion-exchange column, and the lutetium can be eluted with an additional wash of dilute HCl. This is outlined in U.S. Pat. No. 7,244,403, where the solution susceptible to treatment is generally a dilute solution of a strong acid, usually HCl. The resin bed can be in the form of a strong anion exchange resin in a column, and contact occurs by passing the solution through the column. In some embodiments, the resin is a strong basic anion exchange resin cross-linked to about 8%. First, an HCl solution is passed through the column to form an HCl-treated column, then a NaCl solution is passed through the HCl-treated column to form a NaCl-treated column, and then sterile water is passed through the NaCl-treated column. These preparative steps aid in eluting a sterile, non-pyrogenic product. The resin can then be dried before the addition of the lutetium solution. In some embodiments, the anion exchange resin is in powder form, typically with particles sized between 100 mesh and 200 mesh. Sterile gas pressure can be applied to the head of the column to accelerate the flow of the solution through the column. This can be accomplished by injecting a sterile gas, preferably air, into the top of the column to push the Lu-177 solution through the column. The Lu-177 recovered from such processing can be of higher purity than before column chromatography on the anion exchange column.

[0060] In other embodiments, the process can also include the use of a cation exchange resin for the purification of lutetium from a composition that also contains ytterbium (e.g., further separation of any ytterbium remaining in the lutetium composition). As an illustrative example, and as outlined in U.S. Pat. No. 9,816,156, a method includes the steps of: loading a first column packed with a cation exchange material with a Lu / Yb mixture dissolved in a mineral acid; exchanging the protons of the cation exchange material for ammonium ions using an NHCl solution; and washing the cation exchange material of the first column with water. The outlet of the first column is connected to the inlet of a second column, which is also packed with a cation exchange material. A gradient of water and chelating agent, starting from 100% HO to 0.2 M chelating agent, is then added to the columns at the inlet of the first column to elute lutetium from the first and second columns. Illustrative examples of chelating agents include, but are not limited to, α-hydroxyisobutyric acid (HIBA), citric acid, citrate, butyric acid, butyrate, EDTA, EGTA, and ammonium ion. The method may also include determining the radiation dose at the outlet of the second column to recognize elution of the Lu-177 compound and collecting the first Lu-177 eluate from the outlet of the second column in a container, followed by protonating the chelating agent to inactivate it for complexation with Lu-177. The method may also include the steps of loading a final column packed with a cation exchange material by continuously delivering the acidic lutetium eluate to the inlet of the final column, washing out the chelating agent with dilute mineral acid at a concentration less than about 0.1 M, removing traces of other metal ions from the lutetium solution by washing the cation exchange material of the final column with mineral acids of various concentrations ranging from about 0.01 to 2.5 M, and eluting the Lu-177 ions from the final column with highly concentrated mineral acid at about 1 M to 12 M. Finally, the eluate containing lutetium of higher purity than that loaded onto the column is collected, and the solvent and mineral acid may be removed by evaporation.

[0061] In a further aspect, the process can include dissolving the lutetium composition (which may contain some remaining ytterbium) in an acid to form a dissolved lutetium / ytterbium solution, adding a chelating agent to the dissolved lutetium / ytterbium solution and neutralizing with a base to form a chelated lutetium / ytterbium solution containing both chelated lutetium and ytterbium, and chromatographically separating the chelated solution, collecting a purified chelated lutetium fraction, and dechelating the lutetium to obtain purified lutetium. The purified chelated lutetium fraction has a higher purity of lutetium than that of the lutetium in the dissolved lutetium / ytterbium solution. Using such a chromatographic process, a high level of lutetium purity can be obtained. For example, the purified lutetium obtained after chromatographic separation and workup can contain greater than 99% pure Lu-177 on an isotopic basis. This includes greater than 99.9%, greater than 99.99%, greater than 99.999% or greater than 99.9999% pure Lu-177 on an isotopically basis.

[0062] Using the previous technique, an ytterbium metal or metal oxide target is irradiated to form Lu-177. The target is then dissolved in acid, a chelating agent is added, the solution is neutralized with base to form the chelated metal, chromatographic separation is performed, and the purified metal is dissociated / dechelated from the chelating agent. However, due to chromatographic limitations, starting from a low-purity source of lutetium (i.e., an irradiated ytterbium oxide target) results in low chromatographic efficiency, and each chromatographic cycle yields only a small fraction of purified lutetium, even on a preparative scale. The use of purified lutetium after distillation / sublimation as described above offers surprising advantages for producing higher-purity rare earth metals, particularly lutetium, on a larger scale and in a shorter period of time than can be achieved by either distillation or chromatography alone.

[0063] The initial dissolution of lutetium in acid can be carried out using hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, peroxosulfuric acid, perchloric acid, methanesulfonic acid, trifluoromethanesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, or a mixture of any two or more thereof. The acid concentration can be 0.01M to 6M, and / or the base concentration can be 0.01M to 6M, including concentrations of 1M to 6M and 2M to 6M. A chelating agent is then added along with a base (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, NH4OH, or an alkylammonium hydroxide) to neutralize the acid and produce chelated lutetium. The chelated Lu-177 will now contain other impurities. It will contain, for example, Yb, and it may contain K, Na, Ca, Fe, Al, Si, Ni, Cu, Pb, La, Ce, Lu (other than Lu-177), Eu, Sn, Er, and Tm. HPLC is then performed. HPLC can be performed on any suitable column and eluted with any suitable mobile phase, each of which can be varied under different method development scenarios. As an example, the column can be a cation exchange column, an anion exchange column, a reversed-phase C18 column, etc., and the mobile phase can be any determined to achieve separation.

[0064] For further purification, the chelated Lu-177 is then loaded onto a high-performance liquid chromatography (HPLC) system (a reversed-phase C18 column with 12-14 vol% methanol), where it is eluted at a higher purity than when loaded onto the column. Acidification of the chelated Lu-177 with HCl liberates it from the chelator as the chloride salt.

[0065] The mobile phase may be aqueous or organic. Illustrative examples include, but are not limited to, water, alcohols, alkanes, ethers, esters, acids, bases, and aromatics. In various embodiments, the mobile phase may include water, methanol / water, methanol / trifluoroacetic acid / water, and / or methanol mobile phases.

[0066] After purification of the chelated lutetium via HPLC, a dechelation process is performed to obtain the purified lutetium as a lutetium solution and / or ionic material. In some embodiments, the dechelation process comprises contacting the purified chelated lutetium fraction with an acid, which may be hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, peroxosulfuric acid, perchloric acid, methanesulfonic acid, trifluoromethanesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, or a mixture of any two or more thereof. The concentration of the acid may be between 0.01M and 6M, and / or the concentration of the base is between 0.01M and 6M, including concentrations between 1M and 6M and between 2M and 6M.

[0067] As explained above, the process described herein may be used to separate lutetium and ytterbium. However, if differences in boiling / sublimation points exist, it may be used to separate either rare earth metals and / or actinide metals, followed by further purification using chromatographic separation in the presence of various chelating agents. Rare earth elements that can be chelated for purification include cerium (Ce), dysprosium (Dy), erbium (Er), europium (Eu), gadolinium (Gd), holmium (Ho), lanthanum (La), lutetium (Lu), neodymium (Nd), praseodymium (Pr), promethium (Pm), samarium (Sm), scandium (Sc), terbium (Tb), thulium (Tm), ytterbium (Yb), and yttrium (Y). In some embodiments, the method comprises chromatographic separation of rare earth elements from a mixture of at least two metal ions, wherein at least one of the metal ions is Ce, Dy, Er, Eu, Gd, Ho, La, Lu, Nd, Pr, Pm, Sm, Sc, Tb, Tm, Yb, or Y.

[0068] As used herein, the terms "approximately," "about," "substantially," and similar terms are intended to have broad meanings consistent with common and accepted usage by those of ordinary skill in the art to which the subject matter of this disclosure pertains. It should be understood by those of ordinary skill in the art reviewing this disclosure that these terms allow for the description of particular features described and claimed without limiting the scope of those features to the precise numerical values or idealized geometric configurations provided. Accordingly, these terms should be interpreted as indicating that insubstantial or insignificant variations or modifications of the subject matter described and claimed are considered to be within the scope of the disclosure as set forth in the appended claims.

[0069] As used herein, the term "coupled" and variations thereof mean joining two members directly or indirectly to one another. Such joining can be static (e.g., permanent or fixed) or movable (e.g., removable or releasable). Such joining can be achieved by directly joining two members to one another, by joining two members to one another using a separate intervening member and any additional intermediate members that are joined to one another, or by joining two members to one another using an intervening member that is integrally formed with one of the two members as a single unit. When "coupled" or variations thereof are modified by additional terms (e.g., directly coupled), the general definition of "coupled" provided above is modified by the plain language meaning of the additional terms (e.g., "directly coupled" means joining two members without any separate intervening members), resulting in a definition narrower than the general definition of "coupled" provided above. Such joining can be mechanical, electrical, optical, or fluid.

[0070] References herein to the location of elements (e.g., "top," "bottom," "upper," "lower") are merely used to describe the orientation of various elements in the drawings. It should be noted that the orientation of various elements may differ according to other exemplary embodiments, and such variations are intended to be encompassed by the present disclosure.

[0071] Although the figures and description may indicate a particular order of method steps, the order of such steps may differ from that shown and described unless otherwise specified above. Also, two or more steps may occur simultaneously or with partial concurrence unless otherwise specified above. Such variations may depend, for example, on the software and hardware systems selected and the designer's choice. All such variations are within the scope of the disclosure. Similarly, software implementations of the described methods may be accomplished by standard programming techniques using rule-based logic and other logic to accomplish the various connecting, processing, comparing, and determining steps.

[0072] While particular embodiments have been illustrated and described herein, it should be understood that various other changes and modifications can be made without departing from the spirit and scope of the claimed subject matter. Moreover, although various aspects of the claimed subject matter are described herein, such aspects need not be utilized in combination. It is therefore intended by the appended claims to cover all such changes and modifications within the scope of the claimed subject matter.

Claims

1. sublimating or distilling an ytterbium composition from an initial solid composition comprising ytterbium and lutetium in an inert or reduced pressure environment and at a first average temperature in the range of 400°C to 2000°C during a first sublimation / distillation period, thereby leaving a lutetium composition comprising a higher weight percent of lutetium than was present in said initial solid composition; collecting the ytterbium composition; holding the ytterbium composition for a waiting period to form a decayed ytterbium composition, the waiting period being longer than the first sublimation / distillation period; following the waiting period, sublimating or distilling a purified ytterbium composition from the decayed ytterbium composition during a second sublimation / distillation period in an inert or reduced pressure environment and at a second average temperature in the range of 400°C to 2000°C, thereby leaving a waste composition; A method for providing

2. The method of claim 1 , further comprising collecting the purified ytterbium composition.

3. The method of claim 2 further comprising forming the purified ytterbium composition into an ytterbium target.

4. 4. The method of claim 3, further comprising irradiating the ytterbium target with neutrons to form a regenerated solid composition comprising ytterbium and lutetium.

5. 5. The method of claim 4, further comprising sublimating or distilling an ytterbium composition from the regenerated solid composition in an inert or reduced pressure environment and at a third average temperature in the range of 400°C to 2000°C during a third sublimation / distillation period, thereby leaving a subsequent lutetium composition comprising a higher weight percent of lutetium than was present in the regenerated solid composition.

6. 2. The method of claim 1, wherein the purified ytterbium composition comprises no more than 0.01 wt. % Lu-175.

7. 10. The method of claim 1, wherein the waste composition comprises Lu-175 and at least one of one or more of ytterbium oxides, one or more ytterbium silicates, lanthanum, iron, aluminum, nickel, copper, cerium, tin, erbium, cobalt, silicon, chromium, tantalum, titanium, molybdenum, manganese, and mixtures and alloys thereof.

8. 8. The method of claim 7, wherein the waste composition comprises 10 mg or more of ytterbium oxide, and further comprising the steps of: dissolving the ytterbium oxide to form dissolved ytterbium oxide; and metallizing the dissolved ytterbium.

9. 2. The method of claim 1, wherein the ytterbium composition comprises Yb-176 and Yb-175, the Yb-175 partially decaying to Lu-175 during the waiting period to form the decayed ytterbium composition, and wherein sublimating or distilling the purified ytterbium composition from the decayed ytterbium composition separates the Yb-176 and Lu-175.

10. 10. The method of claim 9, wherein the purified ytterbium composition comprises Yb-176 and the waste composition comprises Lu-175.

11. The method of claim 1 , wherein the waiting period is at least one week.

12. 10. The method of claim 1, wherein during the waiting period, 90% or more of the Yb-175 present in the ytterbium composition decays to Lu-175.

13. 10. The method of claim 1, wherein during the waiting period, 99% or more of the Yb-175 present in the ytterbium composition decays to Lu-175.

14. The pressure reduction is 1×10 －３ 2. The method of claim 1, wherein the first average temperature is in the range of 450°C to 1500°C, and the first average temperature is equal to or less than 1000 torr.

15. The method of claim 1 , wherein the first average temperature is less than 700° C.

16. The method of claim 1 , wherein the first average temperature and the second average temperature are equal or differ by less than 100° C.

17. 10. The method of claim 1, further comprising the step of chromatographically separating the lutetium composition to further enrich the lutetium in the lutetium composition.

18. 18. The method of claim 17, further comprising the steps of: dissolving the lutetium composition in an acid to form a dissolved lutetium solution; adding a chelating agent to the dissolved lutetium solution and neutralizing with a base to form a chelated lutetium solution containing both chelated lutetium and ytterbium; chromatographically separating the chelated lutetium solution, collecting a purified chelated lutetium fraction, and dechelating the lutetium to obtain purified lutetium.

19. 2. The method of claim 1 , wherein the initial solid composition is contained in a crucible of a sublimation / distillation apparatus, and wherein sublimating or distilling the ytterbium from the initial solid composition comprises heating the crucible such that the ytterbium composition sublimes, distills, or sublimes and distills from the initial solid composition and collects on a collection substrate of the sublimation / distillation apparatus.

20. 2. The method of claim 1, wherein the purified ytterbium composition comprises a higher weight percent of ytterbium than was present in the decayed ytterbium composition.

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