Repeated distillation / sublimation of rare earth elements

Abstract

A method comprising sublimating or distilling an ytterbium composition from an initial solid composition comprising ytterbium and lutetium in an inert or reduced pressure environment at a first average temperature for a first sublimation / distillation period leaving a lutetium composition comprising a higher weight percent of lutetium than lutetium present in the initial solid composition, collecting the ytterbium composition; retaining the ytterbium composition for a waiting period to form a decayed ytterbium composition, where the waiting period is longer than the first sublimation / distillation period; and after the waiting period, sublimating or distilling the refined ytterbium composition from the decayed ytterbium composition in an inert or reduced pressure environment at a second average temperature for a second sublimation / distillation period, leaving a waste composition.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 358,849, filed on July 6, 2022, which is incorporated herein by reference in its entirety. Technical Field

[0003] The present disclosure relates generally to the separation of rare earth elements and their purification. More specifically, the present disclosure relates to the separation and purification of lutetium from irradiated targets including other rare earth metals, such as ytterbium. Background Art

[0004] Lutetium-177 (Lu-177) is a radioisotope used to treat neuroendocrine tumors, prostate cancer, breast cancer, kidney cancer, pancreatic cancer and other cancers. In the coming years, approximately 70,000 patients per year will require Lu-177 as part of their medical treatment.

[0005] Therefore, there is a need for improved techniques for separating and purifying radioisotopes such as Lu-177. Summary of the invention

[0006] According to a first aspect of the present disclosure, a method comprises: subliming or distilling an ytterbium composition from an initial solid composition comprising ytterbium and lutetium at a first average temperature in the range of 400°C to 2000°C in an inert or reduced pressure environment for a first sublimation / distillation period, leaving a lutetium composition comprising a higher weight percentage of lutetium than that present in the initial solid composition, collecting the ytterbium composition; retaining the ytterbium composition for a waiting period to form a decayed ytterbium composition, wherein the waiting period is longer than the first sublimation / distillation period; and after the waiting period, subliming or distilling a refined ytterbium composition from the decayed ytterbium composition in an inert or reduced pressure environment at a second average temperature in the range of 400°C to 2000°C for a second sublimation / distillation period, leaving a waste composition.

[0007] The second aspect includes the method of the first aspect, and further includes collecting the refined ytterbium composition.

[0008] A third aspect includes the method of the second aspect, and further includes forming the refined ytterbium composition into an ytterbium target.

[0009] A fourth aspect includes the method of the third aspect, and further includes irradiating the ytterbium target with neutrons to form a recovered solid composition comprising ytterbium and lutetium.

[0010] The fifth aspect includes the method of the fourth aspect, and also includes subliming or distilling the ytterbium composition from the recovered solid composition in an inert or reduced pressure environment at a third average temperature in the range of 400°C to 2000°C for a third sublimation / distillation period, leaving a subsequent lutetium composition comprising a higher weight percentage of lutetium than that present in the recovered solid composition.

[0011] The sixth aspect includes the method of the fifth aspect, wherein the first average temperature, the second average temperature, and the third average temperature are equal or differ by less than 100°C.

[0012] A seventh aspect includes the method of any of the preceding aspects, wherein the refined ytterbium composition comprises 0.1 wt% or less Lu-175.

[0013] An eighth aspect includes the method of any of the preceding aspects, wherein the refined ytterbium composition comprises 0.01 wt% or less Lu-175.

[0014] A ninth aspect includes the method of any of the preceding aspects, wherein the refined ytterbium composition comprises 0.005 wt% or less Lu-175.

[0015] The tenth aspect includes the method of any of the preceding aspects, wherein the waste composition comprises Lu-175 and at least one of one or more 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.

[0016] An eleventh aspect includes the method of the tenth aspect, wherein the waste composition comprises 10 mg or more of ytterbium oxide, and the method further comprises dissolving the ytterbium oxide to form dissolved ytterbium oxide and metallizing the dissolved ytterbium.

[0017] A twelfth aspect includes the method of any of the preceding aspects, wherein the ytterbium composition comprises Yb-176 and Yb-175, and during a waiting period, Yb-175 partially decays into Lu-175 to form a decayed ytterbium composition, and the Yb-176 and Lu-175 are separated by sublimation or distillation of the refined ytterbium composition from the decayed ytterbium composition.

[0018] A thirteenth aspect includes any of the methods of aspect twelfth, wherein the refined ytterbium composition comprises Yb-176 and the waste composition comprises Lu-175.

[0019] A fourteenth aspect includes the method of any of the preceding aspects, wherein the waiting period is at least 1 week.

[0020] A fifteenth aspect includes the method of any of the preceding aspects, wherein the waiting period is at least 5 weeks.

[0021] A sixteenth aspect includes the method of any of the preceding aspects, wherein the waiting period is at least 8 weeks.

[0022] A seventeenth aspect includes the method of any of the preceding aspects, wherein during the waiting period, 99% or more of the Yb-175 present in the ytterbium composition decays into Lu-175.

[0023] An eighteenth aspect includes the method of any of the preceding aspects, wherein during the waiting period, 99.9% or more of the Yb-175 present in the ytterbium composition decays into Lu-175.

[0024] A nineteenth aspect comprises the method of any of the preceding aspects, wherein the inert or reduced pressure environment comprises 1×10 -8 A reduced pressure environment in the range of 2000 Torr.

[0025] The twentieth aspect includes the method of the nineteenth aspect, wherein the reduced pressure is 1×10 -3 or lower.

[0026] A twenty-first aspect includes the method of any of the preceding aspects, wherein the first average temperature is in the range of 450°C to 1500°C.

[0027] A twenty-second aspect includes the method of any of the preceding aspects, wherein the first average temperature is less than 700°C.

[0028] A twenty-third aspect includes the method of any of the preceding aspects, wherein the first average temperature and the second average temperature are equal or differ by less than 100°C.

[0029] The twenty-fourth aspect includes the method of any of the preceding aspects, further comprising chromatographically separating the lutetium composition to further enrich the lutetium in the lutetium composition.

[0030] The twenty-fifth aspect includes the method of the twenty-fourth aspect, and further includes dissolving the lutetium composition in an acid to form a dissolved lutetium solution, adding a chelating agent to the dissolved lutetium solution and neutralizing it with a base to form a chelated lutetium solution comprising chelated lutetium and ytterbium, and chromatographically separating the chelated lutetium solution, collecting a purified chelated lutetium fraction, and dechelating the lutetium to obtain purified lutetium.

[0031] Aspect twenty-seven includes the method of any of the preceding aspects, wherein the initial solid composition is contained in a crucible of a sublimation / distillation apparatus, and subliming or distilling ytterbium from the initial solid composition includes heating the crucible so that the ytterbium composition is sublimated, distilled, or sublimated and distilled from the initial solid composition and collected on a collection base of the sublimation / distillation apparatus.

[0032] A twenty-eighth aspect includes the method of any of the preceding aspects, wherein the refined ytterbium composition comprises a higher weight percentage of ytterbium than that present in the decayed ytterbium composition.

[0033] The twenty-ninth aspect includes the method of any of the preceding aspects, further comprising subjecting the lutetium composition to a non-aqueous separation technique to further enrich the lutetium in the lutetium composition.

[0034] These and additional features provided by the embodiments described herein will be more fully understood from the following detailed description taken in conjunction with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] The embodiments set forth in the accompanying 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 the illustrative embodiments can be understood in conjunction with the following drawings, in which like structures are represented by like reference numerals, wherein:

[0036] Figure 1 shows the Txy diagrams of lutetium and ytterbium at a constant pressure of 1 μTorr;

[0037] Figure 2 schematically illustrates a chamber for sublimation of ytterbium and lutetium according to one or more embodiments shown and described herein; and

[0038] Figure 3 A flow chart outlining a method for repeated ytterbium sublimation according to one or more embodiments shown and described herein is shown. DETAILED DESCRIPTION

[0039] Referring generally to the accompanying drawings, embodiments of the present disclosure relate to methods for repeatedly separating ytterbium compositions from solid compositions comprising ytterbium and lutetium. Specifically, the method includes sublimating the ytterbium composition from an initial solid composition comprising ytterbium and lutetium, collecting the sublimated ytterbium composition and the remaining lutetium composition, which may be depleted of high purity isotopes 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. In the next few years, approximately 70,000 patients per year will require Lu-177 without the addition of a carrier during medical treatment. Lu-177 can be used in many medical applications because it emits low energy beta particles suitable for treating tumors during its decay process. It also emits several gamma rays, two of which are used in diagnostic tests. Isotopes that have both therapeutic and diagnostic properties are called "theranostic" isotopes. Lu-177 is not only theranostic, but also has a half-life of 6.65 days, which allows it to be used in more complex chemistries and is easier to distribute globally. Lu-177 also exhibits chemical properties that allow it to bind to many biomolecules, making it useful in a variety of medical treatments.

[0040] There are two main production routes to produce Lu-177. One is through a neutron capture reaction on Lu-176; Lu-176(n,γ)Lu-177. This production method is called carrier-added (ca)Lu-177. A carrier is an isotope of the same element (Lu-176 in this case) or a similar element that has 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 extremely low concentrations. Lu-176 effectively dilutes the interaction of Lu-177 with receptor sites in the body, thereby reducing the therapeutic effect. In addition, isotopes of the same element cannot be separated by chemical methods and mass separation techniques are required. Therefore, the medical applications of Lu-177 produced by the carrier method are limited.

[0041] The second method of producing Lu-177 is to produce Yb-177 by a neutron capture reaction (Yb-176(n,γ)Yb-177) on ytterbium-176 (Yb-176). Then, Yb-177 rapidly (t 1 / 2 1.911 hours) beta decays to Lu-177. Yb-174 impurity is often present in Yb-176, resulting in the presence of Lu-175 impurity in the final product. This process is considered a "no added support" process. The process can be carried out with ytterbium metal or ytterbium oxide.

[0042] The present disclosure describes a method for separating Yb and Lu obtained from a process without adding a carrier. The method includes a distillation / sublimation step to purify Lu and remove excess Yb after irradiation. Excess Yb can be further processed and recovered (e.g., irradiated with neutrons) for subsequent use, and the method can also include further purifying lutetium using a chromatographic separation process or other separation process (e.g., a non-aqueous separation process). Since the amount of material that can be processed at any one time is limited during the chromatographic separation process or other separation process, the process of enriching Lu before the chromatographic separation or other separation process allows the recovery ratio of the product Lu to be increased to a much higher level than previously obtained. The combination of distillation / sublimation and chromatographic separation or other separation processes allows the use of larger targets and the separation of products by distillation, which are then passed to the chromatographic separation process. In addition, the processing of metal targets allows for more efficient use of larger targets, thereby achieving more economical recovery. Since the metal target remains in a metallic state during processing, Yb can be easily incorporated into new targets with minimal operation, less labor, and less processing equipment. Furthermore, combining this sublimation process with existing separation technologies allows the use of lower flux neutron facilities, which greatly improves the feasibility and commercial competitiveness of irradiating Yb targets.

[0043] The separation of Yb and Lu can be at least partially exploited by the difference in their vapor pressures at a particular temperature and pressure. For 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 particular temperature and pressure can be exploited to separate Yb and Lu by sublimation and / or distillation. Figure 1 , line 50 is the Txy diagram of lutetium and ytterbium at a constant pressure of 1 μTorr. Figure 1 , line 54 represents the condensed phase composition at a given temperature (i.e., bubble point), while line 52 represents the vapor phase (i.e., dew point). Graph 50 is drawn using ideal gas and ideal solution assumptions, which are valid given the low pressure, high temperature, and chemical similarity of the two components.

[0044] In the sublimation process, the solid phase of the element is converted directly into a gas phase by heating, which can then be collected for later use. In the distillation process, the solid is heated to its boiling point (via the liquid phase) and evaporated. After the vapor condenses, the evaporated fraction can be recovered downstream. In this case, the ytterbium is evaporated (and can be collected downstream for later use), leaving behind a lutetium-rich material. This can be done on a large scale, thus increasing the amount of lutetium available. Notably, the collected ytterbium can be used to be recycled to a reactor, particle accelerator or other neutron generating source to produce more ytterbium in subsequent process runs. In fact, the methods described herein provide an improved technique for recycling collected ytterbium to increase the quantity and quality of the lutetium subsequently produced.

[0045] Reference now Figure 2, schematically illustrates a sublimation / distillation apparatus 100 for separating rare earth elements (e.g., lutetium and ytterbium). The sublimation / distillation apparatus 100 includes a chamber 105 having gas, cooling, vacuum, power, and instrument feedthroughs. The sublimation / distillation apparatus 100 can create an environment with a variety of conditions (e.g., high temperature, low pressure, high concentration of inert gas, and low partial pressure of selected gas) in the chamber 105. 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 in the crucible 190. 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, the heating element 170 is a resistive heating element, for example, any known or yet to be developed heating element that is configured to heat the crucible 190 or a crucible support (e.g., a holding device that is thermally and physically coupled to the crucible 190) by resistive heating. The crucible 190 may be suspended or supported within an RF induction heating coil. A temperature sensor 180 monitors the temperature of the crucible 190, and a pressure sensing instrument 140 monitors the pressure of the chamber 105. The sublimation / distillation apparatus 100 also includes a vacuum pump connection 150 and at least one port 200 for the introduction of an inert gas. The vacuum pump connection 150 connects the sublimation / distillation apparatus 100 to a vacuum pump (e.g., a turbomolecular pump), which can be used to achieve a high vacuum level during operation.

[0046] The sublimation / distillation apparatus 100 includes a collection substrate 160 that forms a cold surface. The collection substrate 160 can be actively cooled by a cooling water line 130. The temperature of the collection substrate 160 can be monitored by a temperature sensor 120. The collection substrate 160 can also include a cold finger 165 (e.g., a cooling rod) that extends from the collection substrate 160 to the crucible 190 and is directly disposed above the crucible 190. The cold finger 165 and the collection substrate 160 are movable, which allows the open end of the crucible 190 to be opened to the vacuum system (e.g., to the chamber 105) or sealed to the collection substrate 160. In some embodiments, the cold finger 165 includes an end effector. In fact, the cold finger 165 can extend from the collection substrate 160 to the crucible 190, so that when the collection substrate 160 is sealed to the crucible 190, the cold finger 165 extends into the crucible 190. Like the collection substrate 160, the cold finger 165 can also be actively cooled.

[0047] Reference now Figure 3, flow chart 10 depicts a method for repeatedly separating ytterbium compositions from solid compositions comprising ytterbium and lutetium. As shown in block 12, the method includes subliming or distilling ytterbium ( Figure 2 ), for a first sublimation / distillation period, leaving a lutetium composition comprising a higher weight percent of lutetium than that present in the initial solid composition 102. The first sublimation / distillation period can vary, depending on the amount of material in the initial solid composition, the average temperature, and the pressure. For example, the first sublimation / distillation period can be in the range of 1 second to 1 week, and the sublimation or distillation can occur at a rate of 100 min / g to 1 min / g of the initial solid composition, such as 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, such as 1 min / g initial solid composition, 2 min / g, 5 min / g, 8 min / g, 10 min / g, 20 min / g, 25 min / g, 30 min / g, 40 min / g, 50 min / g, 60 min / g, 70 min / g, 75 min / g, 80 min / g, 90 min / g, 100 min / g, or any range with any two of these values ​​as endpoints, or any value within a range with any two of these values ​​as endpoints.

[0048] In addition, during the first sublimation / distillation period, the temperature can be increased from room temperature to a first average temperature at a certain temperature increase rate over a period of 10 minutes to 2 hours to minimize and in some embodiments prevent bubbling or uneven heating of the initial solid composition 102. In some embodiments, before heating the initial solid composition 102, the pressure in the environment (e.g., in the chamber 105 of the sublimation / distillation apparatus 100) can be reduced to degas the initial solid composition 102. For example, the pressure can be reduced to about 1×10 -6 It lasts from about 5 minutes to 1 hour.

[0049] Reference now Figure 2 and 3, the initial solid composition 102 may be contained in a crucible 190, and subliming or distilling ytterbium from the initial solid composition 102 at block 12 may include heating the crucible 190, for example, using a heating element 170, such that the ytterbium composition sublimes, distills, or both sublimes and distills from the initial solid composition 102 and is collected on a collection substrate 160, including, in some embodiments, on a cold finger 165. The temperature of the initial solid composition 102 may be monitored indirectly by the crucible 190, for example, using a temperature sensor 180. Initial collection (e.g., on a collection substrate 160) of the ytterbium composition (e.g., a "separated ytterbium composition") may be performed by Figure 3 176 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 percentage of lutetium than that present in the initial solid composition 102. The lutetium composition collected at box 16 may be subjected to chromatographic separation to further enrich the lutetium in the lutetium composition, as described in more detail below. Alternatively, the lutetium composition collected at box 16 may be subjected to a non-aqueous separation technique to further enrich the lutetium in the lutetium composition, such as a non-aqueous electrolytic reduction process using mercury.

[0050] Next, at box 18, the ytterbium composition is retained 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, such as 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, such as at least 52 weeks or at least 104 weeks. During the waiting period, the Yb-175 present in the ytterbium composition partially decays into Lu-175, forming a decayed ytterbium composition. The half-life of Yb-175 is about 4 days. In fact, during the 8-week waiting period, 99.991% of the Yb-175 present in the ytterbium composition decays into Lu-175. In some embodiments, the ytterbium composition can be retained for a waiting period, after which 50% or more of the Yb-175 present in the ytterbium composition decays into Lu-175, 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.

[0051] 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 be used during the next irradiation of the methods described herein (e.g., during Figure 3 The step shown in the middle box 26) leads to the formation of Lu-176m. It may be necessary to minimize Lu-175 and Lu-176m to meet the purity requirements of certain radiopharmaceutical products. Table 1 below includes more detailed information on Lu-175 and Lu-176. As shown in Table 1, Lu-177m2 is produced from Lu-176 and has a half-life of about 160 days, which poses a hazard to patients because it may remain in the body and may cause off-target cell damage.

[0052] Table 1

[0053]

[0054] Retaining the ytterbium composition allows a majority of the Yb-175 to decay into Lu-175 and form a decayed ytterbium composition. This allows the Lu-175 to be removed from the decayed ytterbium composition by an additional sublimation step. In practice, after the waiting period, at box 20, the method also includes sublimating or distilling the refined ytterbium composition from the decayed ytterbium composition at a temperature of 400°C to 2000°C in an inert or reduced pressure environment, for example using the sublimation / distillation apparatus 100 (or a different sublimation / distillation apparatus), leaving a waste composition including newly formed Lu-175 (e.g., Lu-175 formed by decay during the waiting period). For example, the refined ytterbium composition can be collected on the collection base 160 and / or the finger-shaped cold finger 165 of the sublimation / distillation apparatus 100, and the waste composition can be retained in the crucible 190. The refined ytterbium composition comprises 0.1 weight percent (wt.%) or less Lu-175, 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 of values ​​with any two of these values ​​as endpoints. Additionally, in embodiments where the waste composition comprises 10 mg or more of ytterbium oxide, the method may further comprise dissolving the ytterbium oxide and metallizing the dissolved ytterbium into ytterbium metal, which may be refined for reuse.

[0055] By separating the refined ytterbium composition from the waste composition, the refined ytterbium composition comprises a higher weight percentage of ytterbium than that present in the decayed ytterbium composition. In addition to Lu-175, the waste composition may also comprise 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. In addition, these impurities may also be undesirable when the refined ytterbium composition is irradiated (see box 26 below). Without being limited by theory, if the impurities are irradiated and activated in a neutron source facility (e.g., a reactor), these impurities may cause excessive radiation doses to the facility operator. In other words, removing the waste composition from the decayed ytterbium composition (ie, forming refined ytterbium) acts as a purification step to remove impurities from the decayed ytterbium composition that formed the waste composition.

[0056] Still refer to Figure 2 and 3 , at frame 22, the method next includes collecting the refined ytterbium composition and forming (e.g., pressing, pelletizing, etc.) the refined ytterbium composition into an ytterbium target at frame 24. In some embodiments, the ytterbium target includes ytterbium particles, which can be formed by pelletizing the refined ytterbium composition. The ytterbium particles can include a variety of shapes, such as spherical, cylindrical, rectangular, etc. In some embodiments, the ytterbium target includes ytterbium foil. The ytterbium target is substantially homogeneous to promote uniform heat transfer and uniform radiation. Next, at frame 26, the ytterbium target can be irradiated with neutrons to form a recovered solid composition comprising ytterbium and lutetium. The ytterbium target can be irradiated with neutrons produced using a nuclear reactor, a particle accelerator (e.g., an ion beam source), or any other known or undeveloped neutron source. In some embodiments, at frame 26, the ytterbium target is packaged into a tube, which can have a sealable end. In some embodiments, the tube is placed in an inert outer package (such as aluminum) suitable for radiation. In some embodiments, the inert outer package is sealed and is not subject to the immersion of water or air. In other embodiments, the inert outer package is unsealed. The inert outer package is subjected to the radiation of neutrons produced by a nuclear reactor, a particle accelerator (such as an ion beam source) or any other known or undeveloped neutron source, and continues for several hours to several days (depending on flux and batch requirements), to generate Lu-177 in the Yb-176 target, to form a solid composition recovered.

[0057] After neutron irradiation, the recovered solid composition can be returned to the sublimation / distillation apparatus 100 (or a different sublimation / distillation apparatus) for additional processing. For example, the sealed outer package containing the recovered solid composition can be placed in a processing hot chamber or isolator. Within the hot chamber or isolator (which may include an inert environment), the irradiated Yb metal target is removed and placed in a crucible 190, and then placed in the chamber 105 of the sublimation / distillation apparatus 100 (or a different sublimation / distillation apparatus) for additional sublimation / distillation steps. In fact, at box 28, the method next includes sublimating or distilling the ytterbium composition (e.g., a subsequent ytterbium composition) from the recovered solid composition in an inert or reduced pressure environment at a third average temperature in the range of 400°C to 2000°C, continuing a third sublimation / distillation period, leaving a subsequent lutetium composition containing a higher weight percentage of lutetium than the lutetium present in the recovered solid composition. The length of the third sublimation / distillation period can be the same as the length of the first sublimation / distillation period, and can be operated at the same temperature ramp rate, temperature and pressure. Next, at frame 30, a subsequent lutetium composition is collected, and in frame 32, a subsequent ytterbium composition is also collected. Then, starting from frame 18, the process can be repeated for the subsequent ytterbium composition. That is, the subsequent ytterbium composition is retained for a waiting period, sublimed or distilled to remove the waste composition (frame 20), collected (frame 22), formed (frame 24), irradiated (frame 26), and sublimed / distilled to separate and collect additional lutetium (frames 28 and 30). The process can be repeated multiple times to collect additional lutetium.

[0058] Still refer to Figure 2 and 3 , at box 16 and box 30, once the crucible 190 is cooled, the resulting lutetium composition is collected. Once the crucible 190 is cooled to a temperature of, for example, 150° C. or less, such as 100° C. or less, 80° C. or less, or 50° C. or less, the lutetium composition is dissolved in an acid to remove it from the crucible 190 and transfer it to a chromatographic separation device. The crucible 190 can be cooled passively (e.g., by removing the heat applied by the heating element 170 and waiting for a period of time) or actively cooled. In fact, similar to the lutetium composition collected at box 16, the lutetium composition collected at box 30 can be chromatographically separated to further enrich the lutetium in the composition or sample, as described in more detail below.

[0059] Still refer to Figure 2 and 3, each of the first average temperature of the first sublimation / distillation cycle, the second average temperature of the second sublimation / distillation cycle, and the third average temperature of the third sublimation / distillation cycle can be 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 680°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 about 625°C, 470°C to about 630°C, 800°C to 2000°C, greater than 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, the sublimation and / or distillation temperature (e.g., the temperature in the environment) 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, 710°C, 711°C, 712°C, 713°C, 714°C, 715°C, 716°C, 717°C, 718°C, 719°C, 720°C, 721°C, 722°C, 723°C, 724°C, 725°C, 726°C, 727°C, 728°C, 729°C, 730°C, 731°C, 732°C, 733°C ℃, 725℃, 750℃, 775℃, 800℃, 850℃, 900℃, 950℃, 1000℃, 1100℃, 1200℃, 1300℃, 1400℃, 1500℃, 1600℃, 1700℃, 1800℃, 1900℃, 2000℃, any range with any two of these values ​​as endpoints, or any value in a range with 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℃.

[0060] Furthermore, according to various embodiments, the ambient pressure at any of the above temperatures and temperature ranges and during any of the first, second, and third sublimation / distillation phases may be in the range of 2000 Torr to 1×10 -8 , 1520 Torr to 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 -7Torr, 100 Torr to 1×10 -6 Pallet, 1 pallet to 1×10 -6 Tray, 1×10 -1 Torr up to 1×10 -6 Tray, 1×10 -3 Torr or less, 1×10 -5 Torr or less, 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 with any two of these values ​​as endpoints, or any value within a range with any two of these values ​​as endpoints.

[0061] At boxes 18 and 30, the sublimation / distillation process produces 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 recovered solid composition entering the process. Yield and purity can be measured in a variety of ways. For example, in some embodiments, the process reduces the ytterbium mass of the initial or recovered solid composition by 10:1 to 10000:1, 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 with any two of these values ​​as endpoints, or a value within a range with any two of these values ​​as endpoints. In other words, after sublimation / distillation is completed, the ytterbium in the sample is 10 to 10000 times less than before the process (i.e., than the ytterbium present in the initial or recovered solid composition). In some embodiments, in the recovered lutetium composition (i.e., the contents subjected to acid dissolution in the crucible), the ytterbium may be 1wt.% to 90wt.%, relative to the total remaining mass, and then separated as described below in the chromatographic process. In other embodiments, the collected amount of ytterbium collected from sublimation / distillation is 90wt.% to 99.999wt.% of the ytterbium present in the initial or recovered solid composition. Purification steps are also performed to remove other trace metals and contaminants. For example, materials such as metals, metal oxides or metal ions such as K, Na, Ca, Fe, Al, Si, Ni, Cu, Pb, La, Ce, Lu (non-radioactive), Eu, Sn, Er and Tm can be removed. In other words, the methods described herein include sublimating, distilling, or a combination thereof, a sample comprising Yb-176 and Lu-177 to remove at least a portion of the Yb-176 from the sample and form a sample enriched in Lu-177.

[0062] It has been observed that purifications of 100:1 reduction in 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 and including about 40,000:1 purification. However, in order to meet the purity requirements of certain pharmaceutical products, further reductions in Yb may be required. Therefore, additional purification may be performed prior to use in pharmaceutical applications. Such purification may be achieved using chelating agents and / or chromatographic separations.

[0063] As described herein, any of the above lutetium compositions or lutetium-rich samples may be subjected to chromatographic separation 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. Exemplary methods for lutetium purification may be as described in US7,244,403 and 9,816,156, both of which are incorporated herein by reference in their entirety. 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 method may include dissolving the lutetium and ytterbium composition 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 materials, chromatographic columns, HPLC chromatographic columns, ion exchange columns, and the like.

[0064] 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-filled or dried ion exchange column, and the lutetium is eluted with an additional wash of dilute HCl. US7,244,403 generally describes this point, that the solution that is easy to handle is usually 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 strongly basic anion exchange resin with a cross-linking degree of about 8%. First, the HCl solution is passed through the column to form an HCl-treated column, then the 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 preparation steps help to elute a sterile, pyrogen-free product. The resin can then be dried before applying the lutetium solution. In some embodiments, the anion exchange resin is in powder form, typically with a particle size of 100 mesh to 200 mesh. In order to accelerate the flow of the solution through the column, sterile gas pressure can be applied to the head of the column. This can be achieved by injecting a sterile gas (preferably air) into the upper end of the column to push the Lu-177 solution through the column. The purity of the Lu-177 recovered from such a process may be higher than that before column chromatography by anion exchange column.

[0065] In another aspect, the method can include purifying lutetium from a composition that also includes ytterbium using a cation exchange resin (e.g., to further separate any ytterbium remaining in the lutetium composition). As an illustrative example, and as generally described in US9,816,156, the method includes loading a first column containing 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, thereby using an NH4Cl 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 also containing a cation exchange material. A gradient of water and a chelating agent is then applied to the column at the inlet of the first column, starting from 100% H2O to 0.2M chelating agent, so as to elute lutetium from the first and second columns. Illustrative examples of chelating agents include, but are not limited to, alpha-hydroxyisobutyrate [HIBA], citric acid, citrate, butyric acid, butyrate, EDTA, EGTA, and ammonium ions. The method may also include determining the radioactive dose at the outlet of the second column to identify the elution of the Lu-177 compound; and collecting the first Lu-177 eluate from the outlet of the second column into a container, and then protonating the chelating agent to inactivate it to form a complex with Lu-177. The method may also include loading the final column containing the cation exchange material by continuously delivering the acidic lutetium eluate to the inlet of the final column, washing away the chelating agent with a dilute mineral acid having a concentration of less than about 0.1M, washing the cation exchange material of the final column with various concentrations of mineral acid ranging from about 0.01 to 2.5M to remove trace amounts of other metal ions from the lutetium solution; and eluting the Lu-177 ions from the final column by a high concentration of mineral acid of about 1M to 12M. Finally, the eluate containing lutetium of higher purity than that applied to the column may be collected, and the solvent and the mineral acid may be removed by evaporation.

[0066] In another aspect, the method may include dissolving a lutetium composition (which may include some residual 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 comprising 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 lutetium purity of the purified chelated lutetium fraction is higher than the lutetium purity in the dissolved lutetium / ytterbium solution. High purity lutetium may be obtained using this chromatographic method. For example, the purified lutetium obtained after chromatographic separation and post-treatment may include Lu-177 having an isotopic purity greater than 99%. This includes Lu-177 having an isotopic purity greater than 99.9%, greater than 99.99%, greater than 99.999%, or greater than 99.9999%.

[0067] Using previous techniques, an ytterbium metal or metal oxide target is irradiated to form Lu-177. The target is then dissolved in an acid, a chelating agent is added, and the solution is neutralized with a base to form the chelated metal, chromatographically separated, and the purified metal is then decomplexed / dechelated from the chelating agent. However, due to the limitations of chromatography, starting with an impure lutetium source (i.e., an irradiated ytterbium oxide target), the efficiency of chromatography is very low, and only a small amount of purified lutetium is obtained per chromatography cycle, even at a preparative scale. As described above, using purified lutetium after distillation / sublimation has surprising benefits in producing higher purity rare earth metals (particularly lutetium), which are not available by distillation or chromatography alone on a larger scale and in a shorter time.

[0068] The initial dissolution of lutetium in acid can be carried out using hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, persulfuric 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 can be 0.01M to 6M and / or the concentration of the base is 0.01M to 6M. This includes concentrations of 1M to 6M and 2M to 6M. A chelating agent is then added with a base (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, NH4OH or alkylammonium hydroxide) to neutralize the acid and produce chelated lutetium. At this point, the chelated Lu-177 does contain other impurities. For example, it will contain Yb, and it may contain K, Na, Ca, Fe, Al, Si, Ni, Cu, Pb, La, Ce, Lu (except Lu-177), Eu, Sn, Er and Tm. HPLC is then performed. HPLC can be performed on an appropriate column and eluted with an appropriate mobile phase, and the column and mobile phase may vary in different method development scenarios. As an example, the column can be a cation exchange column, an anion exchange column, a reverse phase C18 column, etc., and the mobile phase can be any mobile phase that determines the separation.

[0069] For further purification, the chelated Lu-177 was then applied to a high performance liquid chromatography (HPLC) system (reverse phase C18 column, containing 12-14 vol% methanol), from which the chelated Lu-177 was eluted with a higher purity than when applied to the column. The chelated Lu-177 was acidified with HCl to release it from the chelating agent in the form of a chloride salt.

[0070] The mobile phase can be water-based or organic solvent-based. Illustrative examples include, but are not limited to, water, alcohols, alkanes, ethers, esters, acids, bases, and aromatic compounds. In various embodiments, the mobile phase can include water, methanol / water, methanol / trifluoroacetic acid / water, and / or methanol mobile phase.

[0071] After chelated lutetium is purified by HPLC, a dechelating process is performed to obtain purified lutetium as a lutetium solution and / or ionic material. In some embodiments, dechelating includes contacting the purified chelated lutetium fraction with an acid, wherein the acid is hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, persulfuric 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 can be 0.01M to 6M and / or the concentration of the base is 0.01M to 6M. This includes concentrations of 1M to 6M and 2M to 6M.

[0072] As mentioned above, the method described herein can be used to separate lutetium and ytterbium. However, it can be used to separate any rare earth and / or actinide metals in which there is a difference in boiling point / sublimation point, and then further purified using chromatography in the presence of various chelating agents. Among the above-mentioned chelating agents, rare earth elements that can be chelated and purified 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 chromatographically separating rare earth elements from a mixture of at least two metal ions, wherein at least one metal ion is cerium, dysprosium, erbium, europium, gadolinium, holmium, lanthanum, lutetium, neodymium, praseodymium, samarium, yttrium, or yttrium.

[0073] As used herein, the terms "approximately," "about," "substantially," and similar terms are intended to have a broad meaning consistent with common and accepted usage by those of ordinary skill in the art to which the subject matter of the present disclosure belongs. Those skilled in the art who read the present disclosure should understand that these terms are intended to allow description of certain features described and claimed without limiting the scope of these features to the precise numerical values ​​or ideal geometries provided. Therefore, these terms should be interpreted as indicating that insubstantial or insignificant modifications or changes to the subject matter described and claimed are considered to be within the scope of the disclosure described in the appended claims.

[0074] As used herein, the term "coupling" and its variants refer to two components being directly or indirectly connected to each other. Such connection may be static (e.g., permanent or fixed) or removable (e.g., removable or releasable). Such connection may be achieved by directly connecting the two components to each other, by connecting the two components to each other using a separate intermediate component and by connecting any other intermediate components to each other, or by connecting the two components to each other using an intermediate component that is integrally formed as a single entity with one of the two components. If "coupling" or its variants are modified by additional terms (e.g., direct coupling), the general definition of "coupling" above will be modified by the ordinary language meaning of the additional terms (e.g., "direct coupling" means that the two components are connected together without any separate intermediate component), resulting in a narrower definition than the general definition of "coupling" above. Such coupling may be mechanical, electrical, optical, or fluidic.

[0075] References to element positions herein (e.g., "top," "bottom," "above," "below") are only used to describe the orientation of the various elements in the figures. It should be noted that the orientation of the various elements may be different according to other exemplary embodiments, and such variations are intended to be encompassed in the present disclosure.

[0076] Although the drawings and description may show a specific order of method steps, the order of these steps may be different from that depicted and described, unless otherwise specified above. In addition, unless otherwise specified above, two or more steps may be performed simultaneously or partially simultaneously. Such variations may depend on the selected software and hardware systems and the designer's choice. All such variations are within the scope of the present disclosure. Similarly, software implementation of the method can be implemented by standard programming techniques, wherein rule-based logic and other logic are used to implement various connection steps, processing steps, comparison steps and decision steps.

[0077] Although specific embodiments have been illustrated and described herein, it will be appreciated that various other changes and modifications may be made without departing from the spirit and scope of the claimed subject matter. In addition, although various aspects of the claimed subject matter have been described herein, these aspects need not be used in combination. Therefore, the appended claims are intended to cover all such changes and modifications within the scope of the claimed subject matter.

Claims

1. A method, comprising: subliming or distilling an ytterbium composition from an initial solid composition comprising ytterbium and lutetium at a first average temperature in the range of 400° C. to 2000° C. in an inert or reduced pressure environment for a first sublimation / distillation period to leave a lutetium composition comprising a higher weight percent of lutetium than that present in the initial solid composition, collecting the ytterbium composition; retaining the ytterbium composition for a waiting period to form a decayed ytterbium composition, wherein the waiting period is longer than the first sublimation / distillation period; and After the waiting period, the refined ytterbium composition is sublimated or distilled from the decayed ytterbium composition in an inert or reduced pressure environment at a second average temperature in the range of 400°C to 2000°C for a second sublimation / distillation period to leave a waste composition.

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

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

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

5. The method of claim 4, further comprising subliming or distilling the ytterbium composition from the recovered solid composition in an inert or reduced pressure environment at a third average temperature in the range of 400°C to 2000°C for a third sublimation / distillation period, leaving a subsequent lutetium composition comprising a higher weight percentage of lutetium than that present in the recovered solid composition.

6. The method according to claim 1, wherein: The refined ytterbium composition comprises 0.01 wt% or less Lu-175.

7. The method according to claim 1, wherein: The waste composition comprises Lu-175 and at least one of one or more 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. The method according to claim 7, wherein: The waste composition comprises 10 mg or more of ytterbium oxide, and the method further comprises dissolving the ytterbium oxide to form dissolved ytterbium oxide and metallizing the dissolved ytterbium.

9. The method according to claim 1, wherein: The ytterbium composition comprises Yb-176 and Yb-175, and during the waiting period, Yb-175 partially decays into Lu-175 to form the decayed ytterbium composition, and the refined ytterbium composition is sublimated or distilled from the decayed ytterbium composition to separate Yb-176 and Lu-175.

10. The method according to claim 9, wherein: The refined ytterbium composition comprises Yb-176 and the waste composition comprises Lu-175.

11. The method according to claim 1, wherein: The waiting period is at least 1 week.

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

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

14. The method according to claim 1, wherein: The reduced pressure is 1×10 -3 or lower, and the first average temperature is in the range of 450°C to 1500°C.

15. The method according to claim 1, wherein: The first average temperature is less than 700°C.

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

17. The method of claim 1, further comprising subjecting the lutetium composition to a chromatographic separation to further enrich the lutetium in the lutetium composition.

18. The method of claim 17, further comprising 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 comprising chelated lutetium and ytterbium, and chromatographing the chelated lutetium solution, collecting a purified chelated lutetium fraction, and dechelating the lutetium to obtain purified lutetium.

19. The method according to claim 1, wherein: The initial solid composition is contained in a crucible of a sublimation / distillation apparatus, and subliming or distilling ytterbium from the initial solid composition includes heating the crucible so that the ytterbium composition is sublimated, distilled, or sublimed and distilled from the initial solid composition and collected on a collecting base of the sublimation / distillation apparatus.

20. The method according to claim 1, wherein: The refined ytterbium composition comprises a higher weight percentage of ytterbium than that present in the decayed ytterbium composition.

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