Purification process for preparation of non-carrier added copper-64

Abstract

To provide a purification process for the preparation of non-carrier added copper-64.SOLUTION: There are provided compositions comprising high levels of high specific activity copper-64, and process for preparing the compositions. The compositions comprise from about 2 Ci to about 15 Ci of copper-64 and have specific activities up to about 3800 mCi copper-64 per microgram of copper. The processes for preparing the compositions comprise: bombarding a nickel-64 target with a low energy, high current proton beam; and purifying the copper-64 from other metals by a process comprising ion exchange chromatography or a process comprising a combination of extraction chromatography and ion exchange chromatography.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present disclosure relates to compositions containing high levels of high specific activity copper-64 and processes for preparing the compositions. [Background technology]

[0002] Diagnostic nuclear medicine uses two imaging techniques, single photon emission computed tomography (SPECT) and positron emission tomography (PET), often in combination with computed tomography (CT) or magnetic resonance imaging (MRI). Of the two imaging techniques, PET provides higher resolution images and quantitative information. The increasing capabilities of PET have increased the demand for radiopharmaceuticals that can be imaged using this technology, thereby necessitating the production of commercial quantities of PET-capable radioactive precursors for routine clinical use.

[0003] Common clinically used PET isotopes include oxygen-15( 15 O), nitrogen-13( 13 N), carbon-11( 11 C), fluorine-18( 18 F), and gallium-68 ( 68 However, each of these isotopes has a relatively short half-life, which requires them to be produced in close proximity to the PET imaging device and incorporated into the imaging agent before excessive radioactive decay or drug degradation occurs. 68 While generator systems for Ga are available, they are difficult to acquire and can severely limit the number of doses that can be prepared per day. To address the limitations of short half-life radionuclides, PET isotopes with relatively long half-lives are being investigated for the development of new diagnostic PET agents.

[0004] Copper-64( 64Cu) is a "non-standard isotope" that can be used in diagnostic nuclear medicine. It is a radionuclide with excellent properties for PET imaging. Its mean positron energy of 278.2 keV provides high-resolution images, and its moderate half-life (12.7 hours) is long enough to allow its production, purification, incorporation into carrier molecules (e.g., peptides, small molecules, antibodies, etc.), and distribution to medical facilities as end-use products.

[0005] On a commercial scale 64 Due to the widespread availability of Cu, large amounts 64 Cu (i.e., Ci or GBq amounts) is in a highly pure and chemically useful form (e.g., 64 Cu) and must be isolated. 64 Preparation of copper chloride isotopically enriched nickel-64( 64 Ni) target, 64 Cu was purified using ion exchange chromatography. 64 The highest reported production of Cu was 1.5 Ci reported at the end of irradiation (EOB). This amount is sufficient to prepare a patient dose, but taking into account decay and yield losses during manufacturing (i.e., formulation, sterilization, distribution, quality control, packaging, and shipping), the highest reported production of Cu at the EOB of -1.5 Ci is 1.5 Ci. 64 Cu can yield 50 patient doses in a best case scenario (assuming an average patient dose of 4 mCi, 32 hours for manufacturing and shipping, and a 15% yield loss). The theoretical number of patient doses is calculated based on the available 64 This can be significantly improved by increasing the copper chloride precursor. 64 Cu must be a high purity chemical and radionuclide.

[0006] 64 The specific activity of Cu chloride (i.e., per mass of total Cu) 64 The activity of Cu is a measure of its chemical purity and is often expressed in units of mCi / μg or Ci / mmol. 64The highest reported specific activity of Cu copper chloride was 348 mCi / μg Cu. While this is sufficient for radiolabeling, improvements in specific activity can improve the purity and reactivity of the radioactive precursor, thereby reducing the required amount of carrier molecule needed to produce the radiolabeled pharmaceutical. This could have implications for patient safety and enhance the diagnostic capabilities of radiopharmaceuticals. 64 Improvements in Cu specific activity can be made by increasing the amount of radioactive precursor produced, limiting the potential for trace metal contaminant contamination, and creating a robust purification process.

[0007] 64 When Cu is widely available, it can enhance the capabilities of existing PET centers and also provide in-house 68 Ge / 68 It also enables PET studies to be performed in medical centers that do not have Ga generators and / or do not rely on local cyclotrons. Described herein are purified radionuclides with improved chemical and radionuclide purity and specific activities favorable to supply the PET and commercial clinical needs of medical centers. 64 This is a method for producing Cu. Summary of the Invention [Means for solving the problem]

[0008] Among the various aspects of the present disclosure are high levels of erythropoietin with high purity and high specific activity. 64 There are compositions containing Cu and processes for preparing the compositions.

[0009] One aspect of the present disclosure is a dose of about 2 Ci to about 15 Ci at the end of irradiation (EOB). 64 A composition containing Cu is provided. The composition is obtained from a single target during a single cyclotron run. The composition has a maximum concentration of about 3800 mCi. 64 In some embodiments, the composition has a specific activity of: 64 Cu is [ 64 Cu]CuCl2, including solutions of hydrochloric acid.

[0010] A further aspect of the present disclosure is 64 From Ni 64 The present invention encompasses a process for preparing Cu, the process comprising: (a) 64 (b) irradiating a cyclotron target comprising Ni with a proton beam to produce an irradiated target; and (b) stripping the irradiated target with a volume of HCl having a molar concentration of about 6 M to about 12.1 M. 64 Ni and 64 (c) forming a stripper solution containing Cu; and (d) separating the stripper solution by ion exchange chromatography. 64 Purifying Cu, wherein the ion exchange chromatography comprises: (i) 64 Cu binds to the ion exchange resin, 64 (ii) passing the stripping solution through a column containing an ion exchange resin such that Ni passes through the column as flow-through; (iii) washing the column with a volume of HCl having a molar concentration of about 3 M to about 6 M; and (iv) adding a volume of HCl having a molar concentration of about 0.5 M to about 3 M; 64 Cu is eluted from the ion exchange resin, 64 and collecting the eluate containing Cu.

[0011] Another aspect of the present disclosure is a method for manufacturing a semiconductor device comprising: 64 From Ni 64 and further comprising an additional process for preparing Cu. 64 Cu is purified by a combination of extraction chromatography and ion exchange chromatography. The process comprises: (a) 64 (b) irradiating a cyclotron target comprising Ni with a proton beam to produce an irradiated target; and (b) stripping the irradiated target with a volume of HCl having a molar concentration of about 6 M to about 12.1 M. 64 Ni, 64 Cu, 61 forming a stripper solution containing Co and other metals; and (c) extracting the Co and other metals from the stripper solution by chromatography. 64Purifying Cu, wherein the chromatography comprises: (i) passing a stripping solution through a first column comprising an extraction resin connected in series with a second column comprising an ion exchange resin, such that one or more other metals bind to the extraction resin in the first column; 64 Cu and 61 Co binds to the ion exchange resin in the second column, 64 (ii) washing the first and second columns with a volume of HCl having a molarity of about 6 M to about 12.1 M to obtain Ni as a second flow-through fraction; 64 (iii) washing the second column with a volume of HCl having a molar concentration of about 3 M to about 6 M to remove Ni as a first waste fraction. 61 (iv) washing the second column with a volume of NaCl having a molar concentration of about 3M to about 6M in HCl having a molar concentration of about 0.01M to about 3M, or with a volume of HCl having a molar concentration of about 3M to about 6M, to obtain the remaining Co as a second waste fraction. 61 (v) adding a volume of HCl having a molar concentration of about 0.01 M to about 3 M to the second column; 64 As a product fraction containing Cu 64 and eluting Cu.

[0012] Other aspects and iterations of the present disclosure are detailed below. [Brief explanation of the drawings]

[0013] [Figure 1] FIG. 1 shows a schematic diagram of a purification process involving ion exchange chromatography. [Figure 2A] Various embodiments of the purification process are presented, including a combination of extraction chromatography and ion exchange chromatography. [Figure 2B] Same as above. [Figure 2C] Same as above. [Figure 3]1 is a plot of proton energy as a function of proton beam radius. DETAILED DESCRIPTION OF THE INVENTION

[0014] High level of specific activity 64 Provided herein are compositions comprising Cu, and processes for preparing the compositions. The processes disclosed herein produce high levels of Cu from a single target during one continuous cyclotron irradiation (i.e., cyclotron run). 64 Cu can be produced by these processes. 64 The Cu has high specific activity and high chemical and radionuclide purity. Preferably, the Cu produced by the processes disclosed herein 64 The Cu composition also has low levels of metallic impurities such as cobalt, iron, nickel, and lead.

[0015] (I) Composition Disclosed herein 64 Cu composition has high specific activity 64 Contains Cu. Generally, 64 Cu composition is up to about 15 Ci 64 Contains Cu, up to approximately 3800mCi 64 It has a specific activity of Cu / μgCu. 64 The Cu composition may be prepared by the processes described below in sections (II) and (III).

[0016] 64 Cu activity (Ci or Bq) can be measured by gamma spectroscopy (e.g., high purity germanium (HPGe) detector), dose calibrator, or similar means. Specific activity (mCi 64 Cu / μgCu) can be determined by measuring the mass of Cu by various methods, including inductively coupled plasma optical emission spectroscopy (ICP-OES), inductively coupled plasma mass spectroscopy (ICP-MS), or titration.

[0017] Generally, the compositions disclosed herein provide from about 2 Ci to about 15 Ci at end of beam (EOB). 64 Contains Cu. 64 The level of Cu can be determined at EOB or at a later time point. 64 It is understood that the level of Cu activity will decrease over time. In some embodiments, the composition contains from about 2 Ci to about 3 Ci, from about 3 Ci to about 4 Ci, from about 4 Ci to about 5 Ci, from about 5 Ci to about 6 Ci, from about 6 Ci to about 7 Ci, from about 7 Ci to about 8 Ci, from about 8 Ci to about 9 Ci, from about 9 Ci to about 10 Ci, from about 10 Ci to about 11 Ci, from about 11 Ci to about 12 Ci, from about 12 to about 13 Ci, from about 13 to about 14, or from about 14 to about 15 Ci. 64 In other embodiments, the composition may contain about 4.0-4.5 Ci, about 4.5-5.0 Ci, about 5.0-5.5 Ci, about 5.5-6.0 Ci, about 6.0-6.5 Ci, about 6.5-7.0 Ci, about 7.0-7.5 Ci, about 7.5-8.0 Ci, about 8.0-8.5 Ci, about 8.5-9.0 Ci, about 9.0-12.0, about 12.0-15.0, about 4.0-5.5 Ci, about 5.5-7.0 Ci, about 6.0-7.5 Ci, about 7.0-8.5 Ci, about 7.5-9.0 Ci, or about 9.0-15.0 Ci. 64 It may contain Cu.

[0018] In other embodiments, the composition is about 2 Ci to about 5 Ci at EOB. 64 Cu, approximately 5 Ci to approximately 9 Ci during EOB 64 In a further embodiment, the composition may contain about 2 Ci to about 5 Ci of Cu after about 2-4 hours of irradiation (EOB). 64 Cu, or after about 6 hours of irradiation (EOB) about 5 Ci to about 9 Ci 64 Cu, or after about 8 to 12 hours of irradiation (EOB) about 4 Ci to about 15 Ci 64 It may contain Cu.

[0019] Each of the compositions disclosed herein may be produced during a single cyclotron run and / or obtained from a single cyclotron irradiation.

[0020] Disclosed herein64 The radionuclide purity of the Cu composition is generally greater than about 98.5%, greater than about 99%, greater than about 99.5%, or greater than about 99.9% (referenced at 6:00 AM the day after irradiation).

[0021] In the compositions disclosed herein 64 The specific activity of Cu is approximately 3800 mCi at EOB. 64 Cu / μg Cu. One skilled in the art will appreciate that the specific activity of a composition will decrease over time. In various embodiments, the specific activity is about 100 mCi 64 Cu / μgCu ~ approx. 500mCi 64 Cu / μgCu, approximately 500mCi 64 Cu / μgCu ~ approx. 1000mCi 64 Cu / μgCu, approximately 1000mCi 64 Cu / μgCu ~ approx. 1500mCi 64 Cu / μgCu, approximately 1500mCi 64 Cu / μgCu ~ approx. 2500mCi 64 Cu / μgCu, approximately 2500mCi 64 Cu / μgCu ~ approx. 3000mCi 64 Cu / μgCu, or approximately 3000mCi 64 Cu / μgCu ~ approx. 3800mCi 64 In some embodiments, the specific activity may be in the range of about 350 μg Cu / μg Cu. 64 Cu / μgCu ~ approx. 2300mCi 64 In a further embodiment, the specific activity may be in the range of about 350 μg Cu / μg Cu at EOB. 64 Cu / μgCu ~ approx. 500mCi 64 Cu / μgCu, approximately 500 at EOB 64 Cu / μgCu ~ approx. 1000mCi 64 Cu / μgCu, or approximately 1000 at EOB 64 Cu / μgCu ~ approx. 2300mCi 64 Cu / μgCu.

[0022] Generally, the methods disclosed herein 64The Cu composition contains low levels of metal contaminants. The metal contaminants may be radioactive or non-radioactive. The metal contaminants may include calcium, cobalt, copper, gold, iron, lead, mercury, nickel, and zinc. For example, the 2M HCl eluate described in Example 5 below contains 0 ppm Au, 0 ppm Hg, <0.02 ppm Co, <0.2 ppm Fe, <0.4 ppm Pb, <0.5 ppm Ni, <0.6 ppm Cu, and <1.5 ppm Zn. Generally, the Cu compositions disclosed herein contain low levels of metal contaminants. 64 The Cu composition comprises less than about 6 ppm total, less than about 5 ppm total, less than about 4 ppm total, or less than about 3 ppm total of cobalt, copper, gold, iron, lead, mercury, nickel, and zinc.

[0023] Disclosed herein 64 The Cu composition is 64 The solution may include a solution of hydrochloric acid (HCl) such that the solution contains CuCuCl. The HCl solution may include about 0.005 M to about 3.0 M HCl. In some embodiments, the HCl solution may include HCl at a molar concentration of about 0.01 M to about 2.0 M, about 0.02 M to about 1.0 M, or 0.04 M to about 0.06 M. In certain embodiments, 64 The Cu composition may comprise a solution of about 0.05M HCl.

[0024] In some embodiments, the compositions disclosed herein can further comprise at least one bifunctional chelating agent such that copper can be complexed with the bifunctional chelating agent. The bifunctional chelating agent can be a macrocyclic compound, a bridged macrocyclic compound, a bicyclic compound, or an acyclic compound. Suitable bifunctional chelating agents include 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7-triacetinoic acid (NOTA), 1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid (TETA), 5-(8-methyl-3,6,10,13,16,19-hexaaza-bicyclo[6.6.6]icosan-1-ylamino)-5-oxopentanoic acid (MeCO Sar), 5-((8-amino-3,6,10,13,16,19-hexazabicyclo(6.6.6)eicos-1-yl)amino)-5-oxopentanoic acid (sar-COH), di- and trimethylthiazolyl-1,4,7-triazacyclononane (TACN), diethylenetriaminepentaacetic acid (DTPA), 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (PCTA), analogs, or derivatives thereof. In certain embodiments, the bifunctional chelator can be DOTA. The bifunctional chelator can be linked to a cell targeting agent, such as a peptide, protein, antibody, or fragment thereof.

[0025] Process for producing (II) copper-64 - Purification by ion exchange chromatography In this specification, 64 From Ni 64 A process for preparing Cu is also provided, 64 Cu has high specific activity, high chemical purity, and high radionuclide purity. 64 The Ni nucleus captures a proton, followed by the following reaction: 64 Ni+p→ 64 When a neutron is emitted, as shown in Cu+n, 64 Cu is formed. 64Proton-induced production of Cu occurs in a cyclotron. The process disclosed herein is "non-carrier added" in that no inactive materials or carriers are intentionally added during the production process.

[0026] The process disclosed herein provides high yields and high specific activities in a single cyclotron run. 64 Cu can be produced. In other words, 64 High yields and high specific activity compositions containing Cu can be obtained from a single cyclotron target during a single cyclotron run. Depending on various parameters, approximately 40 Ci of Cu can be obtained using the process disclosed herein. 64 Similar high yields as with Cu can be achieved.

[0027] The generation process is 64 Ni target was irradiated with a proton beam, resulting in 64 Cu is produced, and cobalt-61( 61 Co) is produced as a by-product. The next step in the process involves stripping the metal from the irradiated target with a strong acid (e.g., 6 M to about 12.1 M HCl) to form a stripping solution. The final step in the production process is to separate the metal by ion exchange chromatography. 64 The ion exchange chromatography process involves purifying Cu by (i) 64 Cu binds to the ion exchange resin, 64 (ii) passing the stripping solution through a column containing an ion exchange resin such that Ni passes through the column as flow-through; (ii) washing the column with a volume of HCl having a molar concentration of about 3 M to about 6 M; and (iii) adding a volume of HCl having a molar concentration of about 0.5 M to about 3 M to the column to remove Ni from the ion exchange resin. 64 Cu is eluted, 64 and collecting the eluate containing Cu. Figure 1 provides a schematic representation of the process iteration.

[0028] (a) Target irradiation 64 Via Ni target 64Proton-induced production of Cu occurs in a cyclotron. Suitable cyclotrons include low-energy cyclotrons (e.g., in the energy range of 3-20 MeV) and medium-energy cyclotrons (e.g., in the range of 15-30 MeV). The cyclotron target can be curved or flat. As detailed in Example 3 below, the present disclosure demonstrates that the cyclotron target can be irradiated with a high current of approximately 12 MeV to 13 MeV protons.

[0029] The cyclotron target may include a copper base layer that is electroplated with gold to a thickness of about 50 μm. The gold-plated cyclotron target is then enriched with 64 It can be plated with Ni. 64 Ni is about 98%, about 99%, about 99.6%, or about 99.9% 64 It can be enriched in Ni. 64 The target mass of Ni can range from about 40 mg to about 60 mg, from about 45 mg to about 55 mg, from about 48 mg to about 52 mg, or about 50 mg. The plating area is about 3.0 cm. 2 ~Approx. 5.0cm 2 , approximately 3.2 cm 2 ~Approx. 4.8cm 2 , approximately 3.6 cm 2 ~Approx. 4.4cm 2 , about 3.8cm 2 ~ approx. 4.2cm 2 , or 4.0 cm 2 The range may be: 64 The Ni plating layer may have a thickness of about 8 μm to about 20 μm, about 10 μm to about 18 μm, about 12 μm to about 16 μm, or about 14 μm.

[0030] In the process disclosed herein, 64 The Ni target area is 64The target is irradiated with low-energy protons to produce Cu. Typically, the cyclotron proton beam is adjusted to have an energy of less than about 20 MeV relative to the target. In some embodiments, the energy of the proton beam at the target can range from about 5 MeV to about 20 MeV, about 7 MeV to about 17 MeV, about 10 MeV to about 15 MeV, about 11 MeV to about 14 MeV, about 10 MeV to about 14 MeV, about 11 MeV to about 12 MeV, or about 12 MeV to about 13 MeV. In certain embodiments, the actual proton beam energy at the target is about 12 MeV.

[0031] The proton beam current can range up to about 250 μA. In some embodiments, the proton beam current can range from about 10 μA to about 30 μA, from about 30 μA to about 100 μA, from about 100 μA to about 175 μA, or from about 175 μA to about 250 μA. In certain embodiments, the proton beam current can range from about 190 μA to about 230 μA, or from about 200 μA to about 225 μA.

[0032] The proton beam strikes the target area at an angle. In some embodiments, the proton beam angle can range from about 1° to about 20°, from about 2° to about 10°, from 2° to about 8°, from about 3° to about 6°, or about 4°. In other embodiments, the proton beam angle can be tangential to the target area.

[0033] In some embodiments, the target radius of the proton beam can range from about 24 cm to about 32 cm, about 26 cm to about 30 cm, about 27 cm to about 29 cm, or about 28 cm. In certain embodiments, the target radius of the proton beam can be about 27.9 cm. In some embodiments, the proton beam can impact about 20-25%, about 15-30%, or about 10-35% of the entire target surface. In other embodiments, the total area covered by the beam can be less than about 1 cm. 2 ~Approx. 16cm 2 , about 2 cm 2 ~about 8cm 2 , about 3cm 2 ~approx. 6cm 2 , or about 3.5 cm 2 ~about 4.5cm2 In yet another embodiment, the total area covered by the beam can be in the range of about 3.0 cm 2 , about 3.5cm 2 , about 4.0cm 2 , about 4.5cm 2 , about 5.0cm 2 , or approximately 6.0 cm 2 It could be.

[0034] The irradiation time can range from about 0.5 hours to about 24 hours. In some embodiments, the irradiation time can range from 0.5 hours to about 8 hours, from about 8 hours to about 16 hours, or from about 16 hours to about 24 hours. In other embodiments, the irradiation time can range from 1 hour to about 8 hours, from about 2 hours to about 8 hours, from about 4 hours to about 8 hours, from about 5 hours to about 8 hours, or from about 5 hours to about 7 hours. In certain embodiments, the irradiation time can range from about 1 hour to about 6 hours, from about 2 hours to about 6 hours, from about 3 hours to about 6 hours, from about 4 hours to about 6 hours, or from about 5 hours to about 6 hours. In other embodiments, the irradiation time can be less than 8 hours, less than 7.5 hours, less than 7 hours, less than 6.5 hours, less than 6 hours, less than 5.5 hours, less than 5.0 hours, less than 4.5 hours, or less than 4 hours. In further embodiments, the irradiation time can be about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, or about 8 hours. In certain embodiments, the irradiation time can range from about 2 hours to about 4 hours, or the irradiation time can be about 6 hours.

[0035] In certain embodiments, 50 mg 64 A cyclotron target containing Ni is irradiated with a proton beam having an energy of about 12 MeV and a beam current of 200 μA or 225 μA for about 1 hour, 2 hours, 3 hours, 4 hours, or 6 hours.

[0036] The irradiated target has a concentration of approximately 2 Ci to 15 Ci at the end of irradiation (EOB). 64 The irradiated target may also contain unreacted Cu, which is also produced during the irradiation process. 64 Ni and 61In various embodiments, the irradiated target contains about 2 Ci to about 3 Ci, about 3 Ci to about 4 Ci, about 4 Ci to about 5 Ci, about 5 Ci to about 6 Ci, about 6 Ci to about 7 Ci, about 7 Ci to about 8 Ci, or about 8 Ci to about 9 Ci. 64 Cu, about 9 Ci to about 10 Ci, about 10 Ci to about 11 Ci, about 11 Ci to about 12 Ci, about 12 to about 13 Ci, about 13 to about 14 Ci, or about 14 to about 15 Ci 64 Generally, longer exposure times result in higher levels of 64 For example, an irradiation time of about 2 to about 4 hours results in about 2 Ci to about 5 Ci of Cu at EOB. 64 Cu, and the irradiation time of about 6 hours resulted in about 5 Ci to about 9 Ci at EOB. 64 Cu, and the irradiation time of about 12 hours resulted in about 7 Ci to about 15 Ci at EOB. 64 Generally, the processes disclosed herein can produce about 1 Ci / hr to about 1.5 Ci / hr of irradiation with a proton beam having an energy of about 12 MeV and a current of up to about 225 μA.

[0037] (b) Detachment of the irradiated target The next step in the process is 64 Ni, 64 Cu, 61 This method involves stripping Co and other metals from the irradiated target. The metals are stripped from the target with a strong acid having a pKa of less than 1. Suitable strong acids include hydrochloric acid, nitric acid, hydrobromic acid, and sulfuric acid. In some embodiments, the irradiated target is stripped with HCl having a molar concentration of about 6 M to about 12.1 M (concentrated HCl). For example, the irradiated target can be stripped with about 6 M HCl, about 7 M HCl, about 8 M HCl, about 9 M HCl, about 10 M HCl, about 11 M HCl, or about 12.1 M HCl. In a specific embodiment, the irradiated target is stripped with about 9 M HCl.

[0038] Stripping can include adding a volume of strong acid to a chamber or holding vessel containing the irradiated target, and the target is heated to a temperature of about 65°C to about 100°C. In certain embodiments, stripping is performed at a temperature of about 75°C. After about 3 to 5 minutes, the acid can be removed and saved as a first stripping solution. The target can be contacted with the strong acid several more times, and the resulting solution can be combined with the first stripping solution. The chamber holding the target can then be washed with strong acid, and the wash solution can be combined with the stripping solution from the final stripping solution. In certain embodiments, the irradiated target can be exposed three times to about 3 mL of strong acid (e.g., 9 M HCl) to produce approximately 9 mL of stripping solution.

[0039] In some embodiments, the stripping solution can be evaporated to dryness or a small volume, and the residue can be reconstituted in HCl at the desired molarity (eg, 9M) for column chromatography.

[0040] In certain embodiments, the stripping comprises contacting the irradiated target with several aliquots of 9 M HCl at a temperature of about 65° C. to about 100° C. and collecting the aliquots as a stripping solution. The chamber holding the irradiated target can be washed with 9 M HCl, and the wash solution can be combined with the stripping solution.

[0041] (c) by ion exchange chromatography 64 Purification of Cu This process uses ion exchange chromatography to separate the metals from other metals in the stripping solution. 64The method further includes isolating Cu. Generally, ion exchange chromatography utilizes a strong anion exchange resin. Strong anion exchange resins generally contain quaternary ammonium groups. For example, the strong anion exchange resin may contain trialkylammonium chloride (e.g., trialkylbenzylammonium or trimethylbenzylammonium) surface groups or dialkyl 2-hydroxyethylammonium chloride (e.g., dimethyl-2-hydroxyethylbenzylammonium) surface groups. Examples of suitable strong anion exchange resins containing trimethylbenzylammonium groups include AG® 1-X8 (available from Bio-Rad) and Dowex® 1x8 resin. In certain embodiments, the strong anion exchange resin may be AG® 1-X8, 100-200 mesh, chloride form.

[0042] Various column sizes and bed volumes are available to separate the metals from other metals in the stripper solution. 64 This process can be used to purify Cu using about 4.5 g of strong anion ion exchange resin in a column with an internal diameter of about 1 cm. 64 Generated from Ni target material 64 It has been developed to effectively isolate Cu. Without departing from the scope of the present disclosure, it is understood that the amount of strong anion exchange resin can range from about 4.0 g to about 5.0 g, and the inner diameter of the column can range from about 0.7 cm to about 1.25 cm. Similarly, the volume of eluate passing through the column will vary depending on the size and volume of the column, and / or 64 This may vary depending on the amount of Ni target material. Generally, the ion exchange column is equilibrated with HCl (e.g., 9M HCl) prior to the chromatographic process.

[0043] (i) 64 Extraction of Ni The ion exchange separation process involves passing the stripper solution through the prepared ion exchange column, as well as an additional 1 mL of 9 M HCl, which is used to wash the holding vessel. The stripper solution can be added in multiple smaller aliquots (e.g., 3 × 3 mL, 2 × 4.5 mL, etc.), or the stripper solution can be added all at once. Ni in the stripper solution does not bind to the strong anion exchange resin and passes through the column, while Cu and Co and other metals bind to the strong anion exchange resin. The column flow-through can be collected as the Ni recovery fraction. The column can be washed with an additional volume of HCl having the same molar concentration as the stripper solution to completely remove any remaining Ni from the column. For example, the column can be washed with approximately 10 mL of 9 M HCl. The 10 mL can be added in multiple smaller aliquots (e.g., 5 × 2 mL, 3 × 3.333 mL, etc.), or the 10 mL can be added all at once. The column flow-through from the wash solution can be collected and combined with the original Ni recovery fraction. The combined Ni recovery fractions are 64 The nickel may be further processed to recover the nickel, which may then be recycled and used to plate additional cyclotron targets. Nickel recovery processes are well known to those skilled in the art. On average, the nickel present in the stripper solution 64 Approximately 82% of the Ni can be recovered from the Ni recovery fraction. In various embodiments, 64 Ni percentage starting 64 It can range from about 40% to about 99% of Ni.

[0044] (ii) 61 Removal of Co The ion exchange purification process involves adding a volume of HCl having a molar concentration of about 3M to about 6M to an ion exchange column, 61The method further includes eluting Co. In various embodiments, a volume of 3M HCl, 4M HCl, 5M HCl, or 6M HCl can be added to the ion exchange column. In certain embodiments, a volume of 4M HCl can be added to the ion exchange column. For example, about 10 mL of 4M HCl can be added to the column. The eluate can be added in smaller aliquots (e.g., 5 x 2 mL, 3 x 3.33 mL, etc.) or as a bolus. The column eluate is primarily 61 Co-containing waste fractions can be recovered.

[0045] (iii) 64 Cu isolation The purification process involves adding a volume of HCl having a molar concentration of about 0.5M to about 3M to an ion exchange column; 64 In certain embodiments, a volume of 0.5 HCl, 1 M HCl, 2 M HCl, or 3 M HCl can be added to the ion exchange column. 64 Cu can be eluted from the ion exchange column with a volume of 2 M HCl. For example, about 8 mL to about 20 mL of 2 M HCl can be added to the column. The eluate can be added in smaller aliquots (e.g., 4 x 2 mL, 4 x 5 mL, etc.) or as a bolus. 64 The Cu-containing eluate is collected as a product of the process. On average, 64 Approximately 80% of Cu is 64 In various embodiments, the Cu-containing eluate may be recovered. 64 recovered in the eluate containing Cu 64 The percentage of Cu can range from about 60% to about 100%. 64 Cu is 64 Cu]CuCl2.

[0046] 64The final eluate containing Cu can be evaporated to dryness (or a smaller volume), and the resulting residue can be reconstituted in a volume of HCl having a molarity of about 0.001 M to about 1 M. In various embodiments, the residue can be reconstituted in HCl having a molarity of about 0.005 M to about 0.5 M, about 0.010 M to about 0.2 M, about 0.025 M to about 0.1 M, or about 0.04 M to about 0.06 M. In specific embodiments, the residue can be reconstituted in 0.05 M HCl to 64 A final product containing Cu may be formed.

[0047] Prepared by the process disclosed herein 64 The Cu composition is described above in section (I).

[0048] (iv) Exemplary Ion Exchange Chromatography Purification Process The 9M HCl stripping solution was passed through an ion exchange column. 64 Cu and 61 Co binds to the resin, 64 Ni flows through the column. The column 64 The column is washed with 9M HCl to remove Ni. The initial column flow-through and the 9M HCl wash can be combined as the Ni recovery fraction. The column is washed with 4M HCl to remove Ni, which is the waste fraction. 61 Co is eluted. Finally, 64 Cu is eluted from the column with 2M HCl.

[0049] Process for producing (III) copper-64 - Purification by extraction chromatography and ion exchange chromatography Another aspect of the present disclosure is to separate hydroxybenzoates from other metals in the stripping solution by a combination of extraction chromatography and ion exchange chromatography. 64 The process includes an additional process for purifying Cu, the process comprising: (a) 64 (b) irradiating a cyclotron target comprising Ni with a proton beam to produce an irradiated target; and (b) stripping the irradiated target with a volume of HCl having a molar concentration of about 6 M to about 12.1 M.64 Ni, 64 Cu, 61 forming a stripper solution containing Co and other metals; and (c) extracting the Co and other metals from the stripper solution by chromatography. 64 Purifying Cu, wherein the chromatography comprises: (i) passing the stripping solution through a first column comprising an extraction resin connected in series with a second column comprising an ion exchange resin, such that one or more metals (e.g., cationic iron) bind to the extraction resin in the first column; 64 Cu and 61 Co binds to the ion exchange resin in the second column; 64 (ii) washing the first and second columns with a volume of HCl having a molar concentration of about 6 M to about 12.1 M to remove residual Ni; 64 (iii) washing the second column with a volume of HCl having a molar concentration of about 3 M to about 6 M to remove Ni as a first waste fraction. 61 (iv) washing the second column with a volume of NaCl having a molar concentration of about 3 M to 6 M in HCl having a molar concentration of about 0.01 M to about 3 M to elute the Co remaining as a second waste fraction. 61 Co can be eluted or collected as a second waste fraction by washing the second column with an additional volume of HCl having a molarity of about 3 M to about 6 M. 61 (v) adding a volume of HCl having a molar concentration of about 0.01 M to about 3 M to the second column; 64 As a product fraction containing Cu 64 2A, 2B, and 2C present schematic diagrams or some embodiments of a dual chromatography purification process.

[0050] (a) Target irradiation Suitable cyclotrons and cyclotron targets are described above in section (II)(a). The cyclotron target may include a copper base layer that is electroplated with gold to a thickness of about 50 μm. The gold-plated cyclotron target is then coated with concentrated 64 It can be plated with Ni. 64 Ni is about 98%, about 99%, about 99.6%, or about 99.9% 64 It can be enriched in Ni. 64 The target mass of Ni can range from about 675 mg to about 825 mg, from about 700 mg to about 800 mg, from about 720 mg to about 780 mg, or about 750 mg. The plating area is about 17.3 cm. 2 ~Approx. 28.8cm 2 , approx. 18.4cm 2 ~approx. 27.6cm 2 , approx. 20.7cm 2 ~Approx. 25.3cm 2 , approx. 21.8cm 2 ~approx. 24.2cm 2 , approx. 22.0cm 2 ~Approx. 24.0cm 2 , or approximately 23.0 cm 2 The range may be: 64 The Ni plating layer may have a thickness of about 21 μm to about 53 μm, about 26 μm to about 48 μm, about 32 μm to about 42 μm, or about 37 μm.

[0051] In the process disclosed herein, 64 The Ni target area is 64 The target is irradiated with low-energy protons to produce Cu. Typically, the cyclotron proton beam is adjusted to have an energy of less than about 20 MeV relative to the target. In some embodiments, the energy of the proton beam at the target can range from about 5 MeV to about 20 MeV, about 7 MeV to about 18 MeV, about 9 MeV to about 16 MeV, about 10 MeV to about 15 MeV, about 11 MeV to about 14 MeV, about 12 MeV to about 13 MeV, or about 12 MeV to about 14 MeV. In certain embodiments, the actual proton beam energy at the target is about 12 MeV.

[0052] The proton beam current can range up to about 408 μA. In some embodiments, the proton beam current can range from about 100 μA to about 150 μA, from about 150 μA to about 200 μA, from about 200 μA to about 250 μA, from about 250 μA to about 300 μA, from about 300 μA to about 350 μA, or from about 350 μA to about 410 μA, from about 405 μA to about 410 μA, or about 408 μA. In certain embodiments, the proton beam current can range from about 325 μA to about 375 μA, or from about 350 μA to about 408 μA.

[0053] The proton beam strikes the target area at an angle. In some embodiments, the proton beam angle can range from about 1° to about 20°, from about 2° to about 10°, from 2° to about 8°, from about 3° to about 6°, or about 5°. In other embodiments, the proton beam angle can be tangential to the target area.

[0054] In some embodiments, the beam impingement has an elliptical shape with a minor axis and a major axis. The minor axis can range from about 25.8 mm to about 34.2 mm, about 27.9 mm to about 32.1 mm, about 28.8 mm to about 31.2 mm, or about 30.0 mm. The major axis can range from about 84.4 mm to about 63.6 mm, about 79.2 mm to about 68.8 mm, about 77.0 mm to about 71.0 mm, or about 74.0 mm. In certain embodiments, the minor and major axes of the elliptical beam impingement can be about 30.0 mm and 74.0 mm, respectively. In some embodiments, the proton beam can impinge on about 70-80%, about 60-90%, or about 55-95% of the entire target surface. In other embodiments, the total area covered by the beam is about 14.0 cm. 2 ~Approx. 30.0cm 2 , approx. 28.0cm 2 ~Approx. 16.0cm 2 , approx. 26.0cm 2 ~Approx. 18.0cm 2 , or approximately 25.0 cm 2 ~Approx. 20.0cm 2 , or 23.0 cm 2 The range may be:

[0055] The irradiation time can range from about 0.5 hours to about 24 hours. In some embodiments, the irradiation time can range from 0.5 hours to about 8 hours, from about 8 hours to about 20 hours, or from about 20 hours to about 24 hours. In other embodiments, the irradiation time can range from 1 hour to about 24 hours, from about 2 hours to about 24 hours, from about 4 hours to about 24 hours, from about 5 hours to about 24 hours, or from about 5 hours to about 23 hours. In certain embodiments, the irradiation time can range from about 1 hour to about 19 hours, from about 2 hours to about 19 hours, from about 3 hours to about 19 hours, from about 4 hours to about 19 hours, or from about 5 hours to about 19 hours. In other embodiments, the irradiation time can be less than 19 hours, less than 18 hours, less than 17.5 hours, less than 17 hours, less than 16.5 hours, less than 16 hours, less than 15.5 hours, or less than 15 hours. In further embodiments, the irradiation time can be about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, or about 15 hours. In certain embodiments, the irradiation time can range from about 1 hour to about 12 hours, or the irradiation time can be about 12 hours.

[0056] In some embodiments, about 750 mg 64 The Ni-containing target may be irradiated with a proton beam having an energy of about 12 MeV to about 14 MeV and a beam current of about 350 μA to about 408 μA for about 10 hours, 12 hours, 14 hours, 16 hours, or 19 hours. In certain embodiments, about 750 mg of Ni each may be irradiated with a proton beam having an energy of about 12 MeV to about 14 MeV and a beam current of about 350 μA to about 408 μA for about 10 hours, 12 hours, 14 hours, 16 hours, or 19 hours. 64 Two targets containing Ni can be simultaneously irradiated for about 10 hours, 12 hours, 14 hours, or 19 hours with a proton beam having an energy of about 12 MeV to about 14 MeV and a beam current incident on each target of about 350 μA to about 408 μA.

[0057] The irradiated target has a concentration of approximately 58 Ci to 80 Ci at the end of irradiation (EOB). 64 The irradiated target may also contain unreacted Cu, which is produced during the irradiation process. 64 Ni and 61In various embodiments, the irradiated target contains about 38 Ci to about 52 Ci, about 43 Ci to about 59 Ci, about 48 Ci to about 66 Ci, about 52 Ci to about 72 Ci, about 56 Ci to about 77 Ci, or about 58 Ci to about 80 Ci. 64 Generally, longer exposure times result in higher levels of 64 For example, an irradiation time of about 12 to about 16 hours results in about 43 Ci to about 72 Ci of Cu at EOB. 64 An irradiation time of about 19 hours can result in about 58 Ci to about 80 Ci of Cu at EOB. 64 Generally, the processes disclosed herein can produce about 3.3 Ci / hr to about 3.8 Ci / hr of irradiation with a proton beam having an energy of about 13 MeV and a current of about 350 μA or about 408 μA.

[0058] (b) Detachment of the irradiated target The next step in the process involves stripping the metal from the irradiated target. The metal is stripped from the target with a strong acid having a pKa of less than 1. Suitable strong acids include hydrochloric acid, nitric acid, hydrobromic acid, and sulfuric acid. In some embodiments, the irradiated target is stripped with HCl having a molar concentration of about 6 M to about 12.1 M. For example, the irradiated target can be stripped with about 6 M HCl, about 7 M HCl, about 8 M HCl, about 9 M HCl, about 10 M HCl, about 11 M HCl, or about 12.1 M HCl. In a specific embodiment, the irradiated target is stripped with about 9 M HCl.

[0059] Stripping can include adding a volume of strong acid to a chamber or holding vessel containing the irradiated target, and the target is heated to a temperature of about 65°C to about 100°C. In certain embodiments, stripping is performed at a temperature of about 75°C. After about 3 to 5 minutes, the acid can be removed and saved as a first stripping solution. The target can be contacted with the strong acid several more times, and the resulting solution can be combined with the first stripping solution. The chamber holding the target can then be washed with strong acid, and the wash solution can be combined with the stripping solution from the final stripping solution. In certain embodiments, the irradiated target and holding chamber can be contacted several times with aliquots (e.g., 5 to 10 mL) of strong acid (e.g., HCl) to produce approximately 20 mL to 40 mL of a final stripping solution.

[0060] In certain embodiments, stripping comprises contacting the irradiated target with several aliquots of 9M HCl at a temperature of about 65° C. to about 100° C. and collecting the aliquots as a stripping solution. The chamber holding the irradiated target may be washed with 9M HCl, and the wash solution may be combined with the stripping solution. The stripping solution may comprise: 64 Ni, 64 Cu, 61 It contains Co and may contain other metals (eg, Fe).

[0061] (c) by extraction chromatography and ion exchange chromatography 64 Purification of Cu The final step in the process is to separate the cesium from the other metals in the stripper solution using two chromatography columns. 64 The process involves passing the stripping solution through two columns connected in series, the first containing an extraction resin and the second containing an ion exchange resin.

[0062] Extraction chromatography resins generally comprise a macroporous polymer that retains organic complexed compounds or extracts within the pore structure of the polymer. Suitable extraction chromatography extractants include tributyl phosphate (TBP), carbamoyl-methylphosphine oxide (CMPO), di-(2-ethylhexyl)-phosphoric acid (DEHPA), and dipentyl pentylphosphonate (DP[PP]). In some embodiments, the extraction chromatography extractant can be a mixture of CMPO and TBP (e.g., TRU resin; TrisKem). In certain embodiments, the extraction chromatography extractant is TBP. An example of a suitable impregnated macroporous polymer (i.e., resin) containing TBP is TrisKem TBP resin. In certain embodiments, the extraction resin can be TBP resin, 100-150 mesh, and in the chloride form.

[0063] The ion exchange column contains a weak anion exchange resin. Weak anion exchange resins generally contain a polystyrene or polyacrylic ester frame containing primary, secondary, or tertiary amino groups as functional groups. Suitable weak anion functional groups include diethylaminoethyl (DEAE) and dimethylaminoethyl (DMAE). Examples of suitable weak anion exchange resins containing tertiary ammonium groups include AmberLite™ FPA53 (available from DuPont) and TrisKem TK201 resin. In a specific embodiment, the weak anion exchange resin is TK201 resin, 50-100 mesh, in the chloride form.

[0064] Various column sizes and bed volumes are available to separate the metals from other metals in the stripper solution. 64 This process can be used to purify Cu using two different columns containing an extraction resin and a weak anion exchange resin connected in series to extract approximately 750 mg of Cu. 64 Generated from Ni target material 64This column was developed to effectively isolate Cu. The first column contains approximately 300 mg of extraction resin in a column having an internal diameter of 0.5 cm. It is understood that the amount of extraction resin can range from approximately 270 mg to approximately 330 mg, and the internal diameter of the column can range from approximately 0.4 cm to approximately 0.6 cm without departing from the scope of this disclosure. The second column uses approximately 2.7 g of weak anion exchange resin in a column having an internal diameter of approximately 1 cm. It is understood that the amount of weak anion exchange resin can range from approximately 2.4 g to approximately 3.0 g, and the internal diameter of the column can range from approximately 0.7 cm to approximately 1.25 cm without departing from the scope of this disclosure. Similarly, the volume of eluate passing through the column depends on the size and volume of the column, and / or 64 This may vary depending on the amount of Ni target material. Generally, the column containing the extraction resin and ion exchange resin is equilibrated with HCl (e.g., 9M HCl) prior to the chromatographic process.

[0065] (i) cationic Fe and 64 Extraction of Ni The separation process involves adding a stripping solution to a prepared extraction column connected in series with a prepared ion exchange column. In this process, the stripping solution volume comprises about 20 mL to about 40 mL. The stripping solution can be added in multiple smaller aliquots (e.g., 4 x 10 mL, 2 x 10 mL, etc.), or the stripping solution can be added all at once. Fe in the stripping solution binds to the extractant (e.g., TBP) in the first column. Ni in the stripping solution does not bind to the chromatography resin and passes freely through both columns, while Cu and Co and other metals bind to the ion exchange column. The column flow-through volume can be collected as the Ni recovery fraction.

[0066] The column may be washed with an additional volume of HCl having the same molarity as the stripping solution to completely remove any residual Ni from the column. For example, the column may be washed with about 8 mL to about 10 mL of 9 M HCl. For example, the column may be washed with about 8 mL of 9 M HCl. A volume of HCl may be added in multiple smaller aliquots (e.g., 4 x 2 mL, 2 x 4 mL, etc.), or a volume of HCl may be added all at once. The column flow-through from the 9 M HCl wash may be collected and combined with the original Ni recovery fraction. The combined Ni recovery fraction may be 64 It may be further processed to recover Ni, which may then be recycled and used to plate additional cyclotron targets. Nickel recovery processes are well known to those skilled in the art. On average, 64 In tracer studies mimicking Cu purification, approximately 98% of the target Ni present in the simulated stripper solution can be recovered from the Ni recovery fraction. In various embodiments, the percentage of Ni recovered in the recovery fraction can range from about 40% to about 99% of the starting Ni.

[0067] (ii) 61 Removal of Co The separation process involves adding a volume of HCl having a molar concentration of about 3M to about 6M to a second column containing an ion exchange resin; 61 The method further includes eluting Co (and metals other than Cu). In various embodiments, a volume of 3M HCl, 4M HCl, 5M HCl, or 6M HCl can be added to the ion exchange column. In certain embodiments, a volume (e.g., about 10 mL to about 20 mL) of 4M HCl can be added to the ion exchange column. For example, about 10 mL of 4M HCl can be added to the ion exchange column. The eluate can be added in smaller aliquots (e.g., 5 x 2 mL, 3 x 3.33 mL, etc.), or the eluate can be added all at once. The ion exchange column eluate is primarily 61 Co-containing waste fraction can be recovered as a first waste fraction.

[0068] The ion exchange column is washed with an additional volume (e.g., about 8 mL to about 10 mL) of NaCl having a molarity of about 3 M to about 6 M in HCl having a molarity of about 0.01 M to about 3 M to remove residual 61 Co can be eluted. In certain embodiments, a volume (e.g., 8 mL) of 5 M NaCl in 0.05 M HCl can be added to the ion exchange column. The eluate can be added in smaller aliquots (e.g., 4 x 2 mL, 2 x 4 mL, etc.), or the eluate can be added all at once. 61 The ion exchange column eluate from the 5M NaCl eluate containing Co was collected and 61 It may be combined with the first waste fraction containing Co.

[0069] Alternatively, the ion exchange column may be washed with an additional volume (e.g., about 8 mL to about 10 mL) of HCl having a molarity of about 3 M to about 6 M to remove residual HCl. 61 Co can be eluted. In certain embodiments, a volume (e.g., 8 mL) of 4 M HCl can be added to the ion exchange column. The eluate can be added in smaller aliquots (e.g., 4 x 2 mL, 2 x 4 mL, etc.), or the eluate can be added all at once. 61 The ion exchange column eluate from the 5M HCl eluate containing Co was collected and 61 It may be combined with the first waste fraction containing Co.

[0070] (iii) 64 Cu isolation The separation process involves adding a volume of HCl having a molar concentration of about 0.01M to about 3M to the ion exchange column, 64 In certain embodiments, a volume of 0.05 HCl, 1 M HCl, 2 M HCl, or 3 M HCl can be added to the ion exchange column. 64Cu can be eluted from the ion exchange column with a volume of 0.05 M HCl. For example, about 10 mL of 0.05 M HCl can be added to the ion exchange column. The eluate can be added in smaller aliquots (e.g., 5 x 2 mL, 4 x 2.5 mL, etc.), or the eluate can be added all at once. 64 The Cu-containing effluent is recovered as the product of the process. 64 Tracer studies mimicking Cu purification have shown that approximately 89% of the Cu present in the simulated stripper solution can be recovered in the Cu-containing eluate. 64 recovered in the eluate containing Cu 64 The percentage of Cu can range from about 60% to about 100%. 64 Cu is 64 Cu]CuCl2.

[0071] 64 The final eluate containing Cu can be evaporated to dryness (or a smaller volume), and the resulting residue can be reconstituted in a volume of HCl having a molarity of about 0.001 M to about 1 M. In various embodiments, the residue can be reconstituted in HCl having a molarity of about 0.005 M to about 0.5 M, about 0.010 M to about 0.2 M, about 0.025 M to about 0.1 M, or about 0.04 M to about 0.06 M. In specific embodiments, the residue can be reconstituted in 0.05 M HCl to 64 A final product containing Cu may be formed.

[0072] Prepared by this process 64 The Cu composition is described above in section (I).

[0073] (iv) Exemplary Extraction and Ion Exchange Chromatography Purification Process The 9M HCl stripper solution is passed through a first column containing an extraction resin connected in series with a second column containing a weak anion exchange resin. The Fe in the stripper solution binds to the extraction resin in the first column, 64 Cu and 61 The Co binds to the ion exchange resin in the second column.64 Ni flows through both columns. The first and second columns are 64 The ion exchange column is washed with 4M HCl to remove Ni. The initial column flow-through and the 9M HCl wash can be combined as the Ni recovery fraction. 61 Co was eluted and then the remaining Co was eluted with 5M NaCl in 0.05M HCl or further with 4M HCl. 61 Co is eluted. Finally, 64 Cu is eluted from the ion exchange column with 0.05 M HCl.

[0074] (IV) Specific Compositions and Methods of the Disclosure Accordingly, the present disclosure relates, inter alia, to the following non-limiting compositions and methods:

[0075] In the first composition, Composition 1, the present disclosure provides about 2 Ci to about 15 Ci of copper-64( 64 Cu), up to approximately 3800mCi 64 A composition having a specific activity of Cu / μgCu is provided.

[0076] In another composition, Composition 2, the present disclosure provides a cyclotron having a concentration of about 2 Ci to about 15 Ci at the end of bombardment (EOB) of a single cyclotron run. 64 A composition comprising Cu is provided.

[0077] In another composition, Composition 3, the present disclosure provides about 2 Ci to about 5 Ci of cyclotron activity at EOB for a single cyclotron run of about 2 hours or about 4 hours. 64 A composition comprising Cu is provided.

[0078] In another composition, Composition 4, the present disclosure provides about 5 Ci to about 9 Ci of cyclotron activity at EOB for a single cyclotron run of about 6 hours. 64 A composition comprising Cu is provided.

[0079] In another composition, composition 5, the present disclosure provides up to about 15 Ci at EOB for a single cyclotron run of about 12 hours. 64A composition comprising Cu is provided.

[0080] In another composition, Composition 6, the present disclosure provides a composition as provided in any one of Compositions 1-5, wherein the composition comprises about 140 mCi 64 Cu / μgCu ~ approx. 3800mCi 64 It has a specific activity of Cu / μgCu.

[0081] In another composition, Composition 7, the present disclosure provides a composition as provided in any one of Compositions 1-6, wherein the composition comprises about 350 mCi 64 Cu / μgCu ~ approx. 2300mCi 64 It has a specific activity of Cu / μgCu.

[0082] In another composition, composition 8, the present disclosure provides a composition as provided in any one of compositions 3-7, wherein the single cyclotron operation includes irradiating a nickel-64 target with a beam of protons having an energy of about 12 MeV to about 14 MeV.

[0083] In another composition, composition 9, the present disclosure provides a composition as provided in any one of compositions 1-8, wherein the composition has a total trace metal content of less than about 5 parts per million (ppm), and the trace metals are cobalt, copper, gold, iron, lead, mercury, nickel, and zinc.

[0084] In another composition, composition 10, the present disclosure provides a composition as provided in any one of compositions 1-9, wherein the composition includes a solution of hydrochloric acid (HCl).

[0085] In another composition, composition 11, the present disclosure provides a composition as provided in composition 10, wherein the solution comprises about 0.001 M to about 3 M HCl.

[0086] In another composition, composition 12, the present disclosure provides a composition as provided in composition 10 or 11, wherein the solution comprises about 2 M HCl.

[0087] In another composition, composition 13, the present disclosure provides a composition as provided in any one of compositions 10-12, wherein the solution comprises about 0.05 M HCl.

[0088] In another composition, composition 14, the present disclosure provides a composition as provided in any one of compositions 10-13, 64 Cu is 64 Cu]CuCl2.

[0089] In another composition, composition 15, the present disclosure provides a composition as provided in any one of compositions 1-14, wherein the composition comprises: 64 It further comprises a chelating agent or bifunctional chelating agent in which Cu is coordinated.

[0090] In another composition, composition 16, the present disclosure provides a composition as provided in composition 15, wherein the chelating agent or bifunctional chelating agent is a macrocyclic compound, a bridged macrocyclic compound, a bicyclic compound, or an acyclic compound.

[0091] In another composition, composition 17, the present disclosure provides a composition as provided in composition 15 or 16, wherein the bifunctional chelator is DOTA.

[0092] In another composition, composition 18, the present disclosure provides: (i) up to about 3800 mCi 64 Cu / μgCu specific activity of about 2 Ci to about 15 Ci 64 providing a solution comprising (i) Cu, and (ii) HCl;

[0093] In another composition, composition 19, the present disclosure provides a composition as provided in composition 18, wherein the specific activity of the solution is about 350 mCi 64 Cu / μgCu ~ approx. 2300mCi 64 Cu / μgCu.

[0094] In another composition, composition 20, the present disclosure provides a composition as provided in composition 18 or 19, wherein HCl has a concentration of about 0.001M to about 3M.

[0095] In another composition, composition 21, the present disclosure provides a composition as provided in any one of compositions 18-20, wherein the HCl has a concentration of about 0.5M.

[0096] In another composition, composition 22, the present disclosure provides a composition as provided in any one of compositions 18-21, 64 Cu is 64 Cu]CuCl2.

[0097] In another composition, composition 23, the present disclosure provides a composition as provided in any one of compositions 18-22, wherein the solution has a total trace metal content of less than about 5 ppm, and the trace metals are cobalt, copper, gold, iron, lead, mercury, nickel, and zinc.

[0098] In another composition, Composition 24, the present disclosure provides a composition as provided in any one of Compositions 18-23, wherein the solution comprises: 64 It further comprises a chelating agent or bifunctional chelating agent in which Cu is coordinated.

[0099] In another composition, composition 25, the present disclosure provides a composition as provided in composition 25, wherein the chelating agent or bifunctional chelating agent is a macrocyclic compound, a bridged macrocyclic compound, a bicyclic compound, or an acyclic compound.

[0100] In another composition, composition 26, the present disclosure provides a composition as provided in composition 24 or 25, wherein the bifunctional chelator is DOTA.

[0101] In the first process, Process 1, the present disclosure provides nickel-64 ( 64Ni) to Copper-64( 64 Cu), the process comprising: (a) 64 (b) irradiating a cyclotron target comprising Ni with a proton beam to produce an irradiated target; and (b) stripping the irradiated target with a volume of hydrochloric acid (HCl) having a molar concentration of about 6 M to about 12.1 M. 64 Ni and 64 forming a stripper solution containing Cu; and (c) 64 purifying Cu from the stripper solution by ion exchange chromatography, comprising: (i) 64 Cu binds to the ion exchange resin, 64 (ii) passing the stripping solution through a column containing an ion exchange resin such that Ni passes through the column as flow-through; (ii) washing the column with a volume of HCl having a molar concentration of about 3 M to about 6 M; and (iii) adding a volume of HCl having a molar concentration of about 0.5 M to about 3 M to the column to remove Ni from the ion exchange resin. 64 Cu is eluted, 64 and collecting the eluate containing Cu.

[0102] In another process, Process 2, the present disclosure provides a process as provided in Process 1, wherein the cyclotron target is about 4.0 cm 2 Approximately 50 mg of material was plated within an area of 64 Contains Ni.

[0103] In another process, Process 3, the present disclosure provides a process as provided in Process 1 or 2, wherein the proton beam has an energy of about 10 MeV to about 14 MeV and a current of about 100 μA to about 250 μA.

[0104] In another process, Process 4, the present disclosure provides a process as provided in any one of Processes 1-3, wherein the proton beam has an energy of about 12 MeV and a current of up to about 225 μA.

[0105] In another process, Process 5, the present disclosure provides a process as provided in any one of Processes 1-4, wherein the irradiation proceeds for about 1 hour to about 6 hours.

[0106] In another process, Process 6, the present disclosure provides a process as provided in any one of Processes 1-5, wherein after irradiation, the irradiated target has about 2 Ci to about 12 Ci of ion at the end of irradiation (EOB). 64 Contains Cu.

[0107] In another process, Process 7, the present disclosure provides a process as provided in Process 6, wherein after about 2 hours to about 4 hours of irradiation, the irradiated target receives about 2 Ci to about 5 Ci of ion beam radiation at EOB. 64 Contains Cu.

[0108] In another process, Process 8, the present disclosure provides a process as provided in Process 6, wherein after about 6 hours of irradiation, the irradiated target has about 5 Ci to about 9 Ci of ion beam radiation at EOB. 64 Contains Cu.

[0109] In another process, Process 9, the present disclosure provides a process as provided in any one of Processes 1 to 8, wherein the ablation of the irradiated target is carried out at a temperature of about 65°C to about 100°C.

[0110] In another process, Process 10, the present disclosure provides a process as provided in any one of Processes 1-9, wherein stripping includes contacting the irradiated target three times with aliquots of 9 M HCl for about 3-5 minutes each time, and collecting the aliquots as stripping solutions.

[0111] In another process, Process 11, the present disclosure provides a process as provided in any one of Processes 1-10, wherein the irradiated target is washed with an additional aliquot of 9 M HCl and then added to the stripping solution.

[0112] In another process, Process 12, the present disclosure provides a process as provided in any one of Processes 1 to 11, wherein the ion exchange resin is a strong anion exchange resin containing trimethylbenzylammonium chloride groups.

[0113] In another process, Process 13, the present disclosure provides a process as provided in any one of Processes 1-12, wherein the flow-through from the stripping solution passing through the column comprises: 64 It is collected as the Ni recovery fraction.

[0114] In another process, Process 14, the present disclosure provides a process as provided in any one of Processes 1 to 13, wherein after passing the stripping solution through the column, an additional volume of 9M HCl is added to the column, and the flow-through is 64 It is combined with the Ni recovery fraction.

[0115] In another process, Process 15, the present disclosure provides a process as provided in Process 14, with an average of about 82% of the target 64 Ni is 64 It is recovered in the Ni recovery fraction.

[0116] In another process, Process 16, the present disclosure provides a process as provided in any one of Processes 1-15, wherein washing comprises adding 4 M HCl to the column to elute cobalt, which is collected as a waste fraction.

[0117] In another process, Process 17, the present disclosure provides a process as provided in any one of Processes 1 to 16, 64 Cu is eluted from the column with 2M HCl.

[0118] In another process, Process 18, the present disclosure provides a process as provided in any one of Processes 1 to 17, wherein an average of about 80% of the cellulose present in the stripper solution is 64 Cu is64 It is recovered in the eluate containing Cu.

[0119] In another process, Process 19, the present disclosure provides a process as provided in any one of Processes 1 to 18, 64 The Cu-containing eluate was evaporated to dryness and reconstituted in 0.05 M HCl, whereby 64 A final product containing Cu is formed.

[0120] In another process, Process 20, the present disclosure provides a process as provided in Process 19, 64 The final product containing Cu is about 2 Ci to about 12 Ci. 64 Contains Cu.

[0121] In another process, Process 21, the present disclosure provides a process as provided in Process 19 or 20, 64 The final product containing Cu is approximately 3800 mCi 64 It has a specific activity of Cu / μgCu.

[0122] In another process, Process 22, the present disclosure provides a process as provided in any one of Processes 19-21, 64 The final product containing Cu was approximately 350 mCi 64 Cu / μgCu ~ approx. 2300mCi 64 It has a specific activity of Cu / μgCu.

[0123] In another process, Process 23, the present disclosure provides a process as provided in any one of Processes 19-22, 64 The final product containing Cu has a total trace metal content of less than about 5 ppm, the trace metals being cobalt, copper, gold, iron, lead, mercury, nickel, and zinc.

[0124] In another process, Process 24, the present disclosure provides nickel-64 ( 64 Ni) to Copper-64( 64Cu), 64 Cu is purified by a combination of extraction chromatography and ion exchange chromatography. The process comprises: (a) 64 (b) irradiating a cyclotron target comprising Ni with a proton beam to produce an irradiated target; and (b) stripping the irradiated target with a volume of HCl having a molar concentration of about 6 M to about 12.1 M. 64 Ni, 64 Cu, 61 forming a stripping solution containing Co and one or more trace metals; and (c) extracting the Co from the stripping solution by chromatography. 64 Purifying Cu, wherein the chromatography comprises: (i) passing a stripping solution through a first column comprising an extraction resin connected in series with a second column comprising an ion exchange resin, such that one or more other trace metals bind to the extraction resin in the first column; 64 Cu and 61 Co binds to the ion exchange resin in the second column, 64 (ii) washing the first and second columns with a volume of HCl having a molarity of about 6 M to about 12.1 M to obtain Ni as a second flow-through fraction; 64 (iii) washing the second column with a volume of HCl having a molar concentration of about 3 M to about 6 M to remove Ni as a first waste fraction. 61 (iv) washing the second column with a volume of NaCl having a molar concentration of about 3 M to 6 M in HCl having a molar concentration of about 0.01 M to about 3 M to elute the Co remaining as a second waste fraction. 61 The second column is washed with an additional volume of HCl having a molar concentration of about 3 M to about 6 M to elute Co, which remains as a second waste fraction. 61 (v) adding a volume of HCl having a molar concentration of about 0.01 M to about 3 M to the second column; 64 As a product fraction containing Cu 64 and eluting Cu.

[0125] In another process, Process 25, the present disclosure provides a process as provided in Process 24, wherein the cyclotron target in (a) is about 23.0 cm 2 Approximately 750 mg of plating was carried out within the area of 64 Contains Ni.

[0126] In another process, Process 26, the present disclosure provides a process as provided in Process 24 or 25, wherein the proton beam in (a) has an energy of about 10 MeV to about 15 MeV and a current of about 350 μA to about 408 μA.

[0127] In another process, Process 27, the present disclosure provides a process as provided in any one of Processes 24-26, wherein the proton beam has an energy of about 13 MeV and a current of about 350 μA to about 408 μA.

[0128] In another process, Process 28, the present disclosure provides a process as provided in any one of Processes 24-27, wherein the irradiation (a) proceeds for about 12 hours to about 24 hours, and the irradiated target receives about 46 Ci to about 82 Ci of ion beam radiation at the end of irradiation (EOB). 64 Contains Cu.

[0129] In another process, Process 29, the present disclosure provides a process as provided in Process 28, wherein after about 16 hours to about 20 hours of irradiation in (a), the irradiated target produces about 75 Ci of ion at EOB. 64 Contains Cu.

[0130] In another process, Process 30, the present disclosure provides a process as provided in Process 28, wherein after about 19 hours of irradiation in (a), the irradiated target produces about 62 Ci to about 73 Ci at EOB. 64 Contains Cu.

[0131] In another process, Process 31, the present disclosure provides a process as provided in any one of Processes 24-30, wherein the stripping in (b) includes contacting the irradiated target with 9M HCl, and the stripping in (b) is conducted at a temperature of about 65°C to about 100°C.

[0132] In another process, Process 32, the present disclosure provides a process as provided in any one of Processes 24-31, wherein the extraction resin in the first column in (c)(i) comprises tributyl phosphate as a functional group, and the ion exchange resin in the second column in (c)(i) comprises a tertiary amine as a functional group.

[0133] In another process, Process 33, the present disclosure provides a process as provided in any one of Processes 24-32, wherein the wash in (c)(ii) comprises 9M CHI.

[0134] In another process, Process 34, the present disclosure provides a process as provided in any one of Processes 24-33, wherein the first and second flow-through fractions are: 64 The Ni fractions are combined as Ni recovery fractions.

[0135] In another process, Process 35, the present disclosure provides a process as provided in Process 34, with an average of about 98% of the target 64 Ni is 64 It is recovered in the Ni recovery fraction.

[0136] In another process, Process 36, the present disclosure provides a process as provided in any one of Processes 24-35, wherein the washing in (c)(iii) comprises 4 M HCl and the washing in (c)(iv) comprises 0.05 M HCl or 5 M NaCl in an additional 4 M HCl.

[0137] In another process, Process 37, the present disclosure provides a process as provided in any one of Processes 24-36, 64 Cu is eluted in (c)(v) with 0.05M HCl.

[0138] In another process, Process 38, the present disclosure provides a process as provided in any one of Processes 24 to 37, wherein an average of about 89% of the cellulose present in the stripper solution is removed. 64 Cu is 64 It is recovered in the product fraction containing Cu.

[0139] In another process, Process 39, the present disclosure provides a process as provided in any one of Processes 24-38, 64 The product fraction containing Cu ranged from about 2 Ci to about 15 Ci. 64 Contains Cu, up to approximately 3800mCi 64 It has a specific activity of Cu / μgCu.

[0140] In another process, Process 40, the present disclosure provides a process as provided in any one of Processes 24-39, 64 The Cu-containing product fraction has a total trace metal content of less than about 5 ppm, the trace metals being cobalt, copper, gold, iron, lead, mercury, nickel, and zinc.

[0141] definition The features, structures, steps, or characteristics disclosed herein in connection with one embodiment may be combined in any suitable manner in one or more alternative embodiments.

[0142] As used in this specification and claims, unless clearly indicated to the contrary, the indefinite articles "a" and "an" should be understood to mean "at least one."

[0143] In the claims, as well as in the foregoing specification, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "consisting of," and the like, are to be understood to be open-ended, i.e., to mean inclusive, but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0144] The terms "about" and "substantially" preceding a numerical value mean ±10% of the recited numerical value.

[0145] Where a range of values ​​is provided, each value between the upper and lower limits of the range is specifically contemplated and described herein.

[0146] As used herein, the term "carrier" refers to an inactive material intentionally added to a particular radioactive substance to ensure that the radioactivity behaves normally in all subsequent chemical and physical processes.

[0147] The term "non-carrier-added" refers to preparations of radioisotopes that are "free" of stable isotopes of the element in question. More precisely, it is a preparation of high specific activity radioisotopes to which no isotope carrier has been intentionally added and which were not produced by irradiation of a stable isotope of the same element. [Example]

[0148] The following examples illustrate various non-limiting embodiments of the present disclosure.

[0149] Example 1: Separation of metals via ion exchange chromatography According to the literature, irradiated Ni targets are typically dissolved in 6 M hydrochloric acid (HCl), and the resulting solution is purified via anion exchange chromatography. After the nickel is completely eluted from the column, the eluate is changed to low molar HCl (often ≦0.5 M) or water, and the copper is collected as it leaves the column. However, copper prepared in this manner 64 Cu typically appears as Co elutes from the resin at 4M HCl or below. 61 It contains Co. Therefore, to obtain a better separation of Co and Cu, test separations of various metals were carried out using solutions of 6M, 4M, and 2M HCl to elute Ni, Co, and Cu, respectively.

[0150] Solutions containing 5.0 mg / mL Ni and 25 μg / mL each of Co, Cu, Fe, Zn, Hg, and Pb in 6 M HCl were prepared to mimic the crude mixture. A glass Econo column (0.7 cm × 20 cm) was dry-packed with 4.5 g of AG1-X8 resin (16 cm bed height, 6 mL bed volume). The resin was pretreated by washing the column with 30 mL of Chelex-treated HO, followed by 30 mL of 6 M HCl. This wash cycle was repeated again, resulting in a final wash with 6 M HCl. The column was gravity-drained, and each wash was considered complete when droplet formation ceased.

[0151] The column was loaded with 10 mL of metal solution (50 mg Ni, 250 μg of each added metal), and the flow-through was collected in 2 × 5 mL fractions (loading fractions). The column was eluted as follows: 5 × 2 mL aliquots of 6 M HCl (6 M fraction), 5 × 2 mL aliquots of 4 M HCl (4 M fraction), 5 × 2 mL aliquots of 2 M HCl (2 M fraction), and 1 × 5 mL aliquot of 0.5 M HCl (0.5 M fraction). Each eluate and aliquot of the initial crude mixture were analyzed by inductively coupled plasma-optical emission spectroscopy (ICP-OES). Table 1 presents the amount of metal present in each fraction as a percentage of that present in the initial crude mixture. [Table 1]

[0152] As expected, Ni was present in the loading fraction and the 6M HCl fraction. The majority of Cu was present in the 2M HCl fraction, with a small amount (9.6%) in the 4M HCl fraction. Co was observed in the loading, 6M HCl, and 4M HCl fractions, with no co-elution with Cu in the 2M HCl fraction. Therefore, Ni and Co were well separated from Cu, with 80.6% of the total Cu collected in the 2M HCl fraction without co-elution with either Ni or Co. The only other test metals present in the 2M HCl fraction were small amounts of Pb and Fe.

[0153] Example 2: Varying Molar Concentration of Starting Acid To determine whether the early breakthrough of Co as well as Pb breakthrough in the 2M HCl fraction could be reduced, the molarity of the starting acid was increased to 9M HCl.

[0154] A solution containing 5.0 mg / mL Ni and 25 μg / mL each of Co, Cu, Fe, Zn, Hg, and Pb in 9 M HCl was prepared. A column containing 4.5 g of AG1-X8 resin was prepared as described in Example 1 above. The column resin was pretreated with 30 mL of Chelex-treated HO, followed by 30 mL of 9 M HCl. This wash cycle was repeated again, resulting in a final wash with 9 M HCl. The prepared column was loaded with 10 mL of Ni solution (50 mg Ni, 250 μg of each added metal) and collected in 2 × 5 mL fractions. The column was then eluted, and fractions were collected as follows: 5 × 2 mL fractions of 9 M HCl, 5 × 2 mL fractions of 4 M HCl, 5 × 2 mL fractions of 2 M HCl, and 1 × 5 mL fraction of 0.5 M HCl. Samples of the eluate and the initial crude mixture were analyzed via ICP-OES. These data are presented in Table 2. [Table 2]

[0155] The use of 9 M HCl as the starting acid concentration improved the overall separation process by shifting the elution profiles of Co and Pb. Most of the Co eluted in the 4 M HCl fraction (rather than in the previous fractions), and most of the Pb eluted in the loading fraction and the 9 M HCl fraction (rather than in the 4 M HCl fraction). The 2 M HCl fraction contained primarily Cu with a low percentage of Fe, as well as traces of Co and Pb.

[0156] Example 3: Adjusting the CS-30 Cyclotron to Reduce Proton Beam Energy Copper-64 can be produced by irradiating enriched nickel-64 with low-energy protons (e.g., less than 14 MeV). At higher beam energies, 61 Co and stable 63 Cu production increases, 64 The production of Cu is reduced, and therefore via the (p,n) reaction 64 From Ni 64 Cu production is best performed with 12 MeV protons.

[0157] Generally, the CS-30 cyclotron has the potential to accelerate proton beams up to approximately 30 MeV, 64 It is assumed that cyclotrons are not suitable for the production of Cu. It is generally understood that cyclotrons cannot achieve beam energies lower than half the maximum energy. Therefore, the lowest energy achievable with the CS-30 cyclotron is theoretically about 15 MeV.

[0158] The output energy of the cyclotron is given by the equation E=(rqB) 2 / 2m, where E is the particle energy, r is the radius into which the target is inserted, q is the charge on the particle of interest, B is the magnetic field, and m is the mass of the particle being accelerated. As the proton is being accelerated, its mass and charge are 1.672x10 -27 kg, and 1.602x10 -19C. The magnetic field used in the CS-30 cyclotron is 1.847 T. Figure 3 shows the proton energy as a function of proton beam radius. This plot predicts a target radius of approximately 27.9 cm to achieve a beam energy of approximately 12 MeV.

[0159] Therefore, to produce the desired proton beam energy of 12 MeV, the target location was adjusted within the cyclotron so that the proton beam struck the target at a smaller radius of about 27.9 cm.

[0160] Initial beam impacts using the CS-30 curved target showed that the proton beam was very far along one edge of the target, all the way to the edge, leaving most of the target surface free of beam and the opposite edge completely missing. Only about 25% of the total target surface had beam, half of which was on the unusable edge. This arrangement resulted in much of the beam being lost and therefore inadequate. This was rectified by replacing the flat target with a curved target. Using the flat target allowed the beam to impact about one-fifth of the total target area (e.g., about one-fifth from the edge of the target). The total area covered by the beam was 4 cm 2 Beam collisions from a flat target were acceptable. The tuning parameters of the CS-30 were determined to give the best beam collisions at the new radius of 27.9 cm. Therefore, by using a flat target, the target radius can be reduced and the proton beam energy can be reduced to approximately 12 MeV.

[0161] Example 4: Target irradiation of enriched nickel-64 Using a CS-30 cyclotron tuned as described in Example 3 above, 64 Cu was generated. 64 Ni (approximately 99% isotopically enriched) was electroplated onto a flat target of a CS-30 cyclotron, which contained a copper base layer electroplated with gold to a thickness of approximately 50 μm. The plating area was approximately 4.0 cm. 2The targets were irradiated with a beam energy of approximately 12 MeV, a beam current of 200 μA or 225 μA, and irradiation times of 1 to 6 hours. The targets were stripped with 9 M HCl, and the resulting solutions were analyzed by HPGe gamma spectroscopy to determine the rf at end of bombardment (EOB). 64 The Cu yield was determined. Table 3 shows the results of the preliminary run. [Table 3]

[0162] Example 5: Purification of Copper-64 from Irradiated Nickel-64 Targets A flat CS-30 cyclotron target electroplated with 50 μm of gold was used, with a mass of approximately 50 mg and a diameter of 4.0 cm. 2 The plating area is targeted, and the concentration 64 The targets were plated with Ni. The targets were irradiated for 1 to 6 hours with a beam energy of approximately 12 MeV and a beam current of approximately 200 μA or 225 μA. The irradiated targets were stripped using three 3.0 mL aliquots of 9 M HCl. During this time, the target stripping cell was heated to 75°C, and each aliquot was held for 3 to 5 minutes. After the hold period, 3 mL aliquots were removed and placed in a holding container. The aliquots were collected together as one approximately 9 mL stripping solution.

[0163] 64 Cu was isolated and purified by anion exchange chromatography essentially as described in Example 2 above. To this end, a glass ion exchange column (internal diameter = 1.0 cm, length = 20 cm) was washed with nitric acid, rinsed with high resistivity water, and packed with 4.5 g of AG1-X8 resin (chloride form), 100-200 mesh (8 cm bed height, 6 mL bed volume). The column resin was pretreated by washing with Chelex-treated 18.2 MΩ.cm resistivity water, followed by two washes with 9 M HCl.

[0164] 9 mL of the stripping solution was loaded onto the pretreated ion exchange column, along with an additional 1 mL of 9 M HCl used to wash the container holding the stripping solution. The 10 mL load volume was eluted from the column by gravity at approximately 1 mL per minute as the load fraction. Gravity filtration was used for all solutions passing through the column. The column was then washed with another 10 mL of 9 M HCl, and the eluate was combined with the load fraction. The combined fraction (approximately 20 mL) was 64 It contained Ni recovery fraction. 64 After the Ni recovery fraction was collected from the column, 10 mL of 4 M HCl was added to the column. The eluate containing cobalt was collected separately as a waste fraction. After the 4 M HCl fraction was collected from the column, 8 mL of 2 M HCl was added to the column. The 2 M HCl eluate was collected in a separate vial. 64 The 2M HCl eluate, which contained the Cu product, was evaporated to dryness and reconstituted in 0.05M HCl to a target radioactivity concentration of approximately 1.25 Ci / mL.

[0165] Aliquots of the stripper solution and eluate were analyzed by gamma spectroscopy and / or dose calibrators to determine: 64 The Cu activity was determined and the metal content was determined via ICP-OES. 64 The Cu yield ranged from 674 mCi (1 hour irradiation at 200 μA) to 8,706 mCi (6 hours irradiation at 200 μA). 64 The average yield of Cu was 67132.6 mCi (sd = 1189.1) in the 2 M HCl eluate (relative to the stripper) over 15 runs. 64 The average recovery of Cu was approximately 80% (sd = 20%) in 0.05M HCl. 64 After reconstitution of Cu, the resulting [ 64 The specific activity of Cu]CuCl2 averaged 965.8 mCi at EOB as measured by a volumetric calibrator. 64 Cu / μgCu (sd=658), and an average of 1,724.2 mCi at EOB as measured by the HPGe detector.64 The Cu content was determined via ICP-OES. Further analysis showed no statistically significant differences between the dose calibrator and the HPGe detector. The dose calibrator method was preferred as it is easier to use during manufacturing. 64 Ni) in the recovered fraction 64 The average recovery rate of Ni was approximately 82%.

[0166] Below we present a detailed analysis of the purified products from three representative runs. For these runs, the target was irradiated for 6 hours with a beam energy of approximately 12 MeV and a beam current of 200 or 225 μA. The total activity was 64 The values ​​were measured using a dose calibrator calibrated for Cu. Table 4 shows the values ​​collected after the purification process. 64 Table 4 also shows the activity of Cu per total activity of the stripper solution (as determined by the dose calibrator). 64 The refinery process yield as a quantity of Cu is shown. [Table 4] Table 5 presents the levels of trace metals in the 2M HCl eluate. [Table 5]

[0167] Table 6 shows the results of the 0.05M HCl solution 64 The specific activity of the Cu product is presented. [Table 6]

[0168] Example 6. Separation of metals via extraction and ion exchange chromatography Test separations of various metals were carried out using a combination of extraction and ion exchange chromatography to more effectively separate Cu from masses of Ni, Co, Fe, and other transition metals up to 750 mg.

[0169] A polyethylene (PE) column (0.7 cm x 20 cm) was vacuum packed with 2.7 g of TK201 resin (approximately 5 cm to 6 cm bed height, approximately 1 mL to 2 mL bed volume) using 20 mL of 0.05 M HCl. A PE frit was securely placed on top of the packed resin bed. The vacuum PE column containing the TK201 resin was washed under vacuum with 20 mL of 0.05 M HCl. The packed PE column was capped and stored at 4.4 °C.

[0170] A prepackaged PE column containing 2.7 g of TK201 resin and a 2 mL PE column containing 300 mg of TBP resin, both stored at 4.4°C in 0.05 M HCl, were pretreated by washing each column with 10 mL of high resistance water (HRW) followed by 10 mL of 9 M HCl. The HRW and 9 M HCl were passed through each column at a flow rate of 1 mL / min using a syringe pump. Each wash was considered complete when droplet formation ceased.

[0171] A solution containing 25.0 mg / mL Ni, 20.4 μg / mL Co, 8.6 μg / mL Cu, 8.1 μg / mL Fe, and 10.3 μg / mL Pb was prepared in 9 M HCl to simulate the stripping solution for the irradiated target.

[0172] The serially connected PE columns were loaded with 30 mL of metal solution (746 mg Ni, 259 μg Cu, 611 μg Co, 244 μg Fe, and 309 μg Pb) using a syringe pump at a flow rate of 1 mL / min, and the flow-through was collected in a single 30 mL fraction (loading fraction). The two columns were eluted with two 4 mL aliquots of 9 M HCl (9 M fraction), and the flow-through was collected. The ion-exchange column was then eluted as follows: two 5 mL aliquots of 4 M HCl (4 M fraction), two 4 mL aliquots of 5 M NaCl in 0.05 M HCl (5 M NaCl fraction), and two 5 mL aliquots of 0.05 M HCl (0.05 M fraction). Each eluate and aliquot of the initial mixture were analyzed by inductively coupled plasma optical emission spectroscopy (ICP-OES). Table 7 presents the amount of metal present in each fraction as a percentage of the starting amount in the simulated stripper mixture. [Table 7]

[0173] As expected, Ni was present in the loading fraction and the 9 M HCl wash fraction (98.4%). Cu was measured only in the 0.05 M HCl fraction (86.5%). Co was observed in the loading, 9 M HCl, 4 M HCl, and 5 M NaCl fractions, with no co-elution of Cu in the 0.05 M HCl fraction. Therefore, Ni and Co were well separated from Cu, with 86.5% of the total Cu collected in the 0.05 M HCl fraction without co-elution of either Ni or Co. In one embodiment, for example, the following items are provided: (Item 1) Approximately 2 Ci to 15 Ci of copper-64( 64 Cu), up to approximately 3800mCi 64 Compositions with a specific activity of Cu / μgCu. (Item 2) 2. The composition of claim 1, wherein the composition is obtained from a single cyclotron run. (Item 3) The composition has a concentration of about 2 Ci to about 5 Ci at the end of bombardment (EOB) of a single cyclotron run of about 2 hours to about 4 hours. 64 3. The composition according to item 1 or 2, comprising Cu. (Item 4) The composition has a concentration of about 5 Ci to about 9 Ci at the end of bombardment (EOB) of a single cyclotron run of about 6 hours. 64 3. The composition according to item 1 or 2, comprising Cu. (Item 5) The composition has a concentration of about 4 Ci to about 15 Ci at the end of bombardment (EOB) of a single cyclotron run of about 8 hours to about 12 hours. 64 3. The composition according to item 1 or 2, comprising Cu. (Item 6) The composition contains about 140 mCi 64 Cu / μgCu ~ approx. 3800mCi 64 6. The composition according to any one of items 1 to 5, having a specific activity of Cu / μgCu. (Item 7) The composition contains about 350 mCi 64 Cu / μgCu ~ approx. 2300mCi 64 7. The composition according to any one of items 1 to 6, having a specific activity of Cu / μgCu. (Item 8) 8. The composition of any one of items 1 to 7, wherein the composition has a total trace metal content of less than about 5 parts per million (ppm), and the trace metals are cobalt, copper, gold, iron, lead, mercury, nickel, and zinc. (Item 9) 9. The composition according to any one of items 1 to 8, wherein the composition comprises a solution of hydrochloric acid (HCl) having a molar concentration of about 0.001 M to about 3 M. (Item 10) 10. The composition of claim 9, wherein the molar concentration of the HCl is about 0.05M. (Item 11) The aforementioned 64 Cu is [ 64 11. The composition of claim 9 or 10, wherein the composition is present as Cu]CuCl. (Item 12) The composition comprises 6412. The composition of any one of items 1 to 11, further comprising a chelating agent or a bifunctional chelating agent in which Cu is coordinated, wherein the chelating agent or the bifunctional chelating agent is a macrocyclic compound, a bridged macrocyclic compound, a bicyclic compound, or an acyclic compound. (Item 13) 13. The composition of claim 12, wherein the bifunctional chelating agent is DOTA. (Item 14) Nickel-64( 64 Ni) to Copper-64( 64 Cu), comprising: (a) 64 irradiating a cyclotron target comprising Ni with a proton beam to produce an irradiated target; (b) stripping the irradiated target with a volume of hydrochloric acid (HCl) having a molar concentration of about 6 M to about 12.1 M; 64 Ni, 64 Cu, 61 forming a stripper solution comprising Co and one or more other metals; (c) the above 64 purifying Cu from the stripper solution, (i) passing the stripping solution through a first column comprising an extraction resin connected in series with a second column comprising an ion exchange resin, such that the one or more other metals bind to the extraction resin in the first column; 64 Cu and 61 Co is bound to the ion exchange resin in the second column; 64 passing Ni through the first and second columns as a first flow-through fraction; (ii) washing the first and second columns with a volume of HCl having a molar concentration of about 6 M to about 12.1 M to remove any remaining 64 eluting Ni as a second flow-through fraction; (iii) washing the second column with a volume of HCl having a molarity of about 3 M to about 6 M; 61 eluting Co as a first waste fraction; (iv) washing the second column with a volume of sodium chloride (NaCl) having a molar concentration of about 3 M to about 6 M in HCl having a molar concentration of about 0.01 M to about 3 M to obtain a residual 61 eluting Co as a second waste fraction, or washing the second column with a volume of HCl having a molar concentration of about 3M to about 6M to remove residual Co. 61 eluting Co as a second waste fraction; (v) adding a volume of HCl having a molar concentration of about 0.01 M to about 3 M to the second column; 64 As a product fraction containing Cu, 64 and purifying by eluting Cu. (Item 15) Item 15. The process of item 14, wherein the proton beam in (a) has an energy of about 12 MeV to about 14 MeV. (Item 16) The irradiation in (a) proceeds for about 1 hour to about 6 hours, and the irradiated target has a concentration of about 2 Ci to about 12 Ci at the end of irradiation (EOB). 64 16. The process of claim 14 or 15, comprising Cu. (Item 17) After about 2 to about 4 hours of irradiation in (a), the irradiated target has about 2 Ci to about 5 Ci of ion beam radiation at EOB. 64 16. The process of claim 14 or 15, comprising Cu. (Item 18) After about 6 hours of irradiation in (a), the irradiated target has about 5 Ci to about 9 Ci at EOB. 64 16. The process of claim 14 or 15, comprising Cu. (Item 19) After about 8 to about 12 hours of irradiation in (a), the irradiated target has about 4 Ci to about 15 Ci at EOB. 64 16. The process of claim 14 or 15, comprising Cu. (Item 20) 20. The process of any one of items 14 to 19, wherein the stripping in (b) comprises contacting the irradiated target with 9M HCl, and the stripping in (b) is carried out at a temperature of about 65°C to about 100°C. (Item 21) 22. The process according to any one of items 14 to 20, wherein the extraction resin in the first column in (c)(i) contains tributyl phosphate as a functional group, and the ion exchange resin in the second column in (c)(i) contains a tertiary amine as a functional group. 22. The process of any one of items 14 to 21, wherein the washing in (c)(ii) comprises 9M HCl. (Item 23) the first and second flow-through fractions being: 64 23. The process of any one of items 14 to 22, wherein the Ni recovery fractions are combined as Ni recovery fractions. (Item 24) The target 64 At least 90% of Ni is 64 24. The process of claim 23, wherein the Ni is recovered in the Ni recovery fraction. (Item 25) 25. The process of any one of items 14 to 24, wherein the washing in (c)(iii) comprises 4 M HCl and the washing in (c)(iv) comprises 5 M NaCl in 0.05 M HCl, or the washing in (c)(iv) comprises 4 M HCl. (Item 26) The aforementioned 64 26. The process of any one of items 14 to 25, wherein Cu is eluted in (c)(v) with 0.05 M HCl. (Item 27) The above-mentioned compound present in the stripping solution 64 At least 80% of Cu 64 27. The process of any one of items 14 to 26, wherein Cu is recovered in the product fraction containing Cu. (Item 28) 64 The product fraction containing Cu is about 2 Ci to about 15 Ci 64Contains Cu, up to approximately 3800mCi 64 28. The process according to any one of items 14 to 27, having a specific activity of Cu / μgCu. (Item 29) 64 29. The process of any one of items 14 to 28, wherein the product fraction containing Cu has a total trace metal content of less than about 5 ppm, the trace metals being cobalt, copper, gold, iron, lead, mercury, nickel, and zinc. (Item 30) 64 in the product fraction containing Cu 64 Cu is [ 64 30. The process of any one of items 14 to 29, wherein the compound is present as Cu]CuCl. (Item 31) Prepared by the process according to any one of items 14 to 30 64 A composition comprising Cu.

Claims

1. A composition for use as a radioactive precursor, comprising 2 Ci to 15 Ci of 64 Cu and having a specific activity of about 100 up to about 3800 mCi 64 Cu / μg Cu, where about means ±10% of the stated value.

2. The composition described in claim 1, wherein the composition is obtained from a single cyclotron operation.

3. The composition of claim 1 or claim 2, wherein the composition has a total trace metal content of less than about 6 parts per million (ppm), the trace metals being cobalt, copper, gold, iron, lead, mercury, nickel, and zinc, where about means ±10% of the stated value.

4. The composition of claim 3, wherein the composition has a total trace metal content of less than about 5 parts per million (ppm), the trace metals being cobalt, copper, gold, iron, lead, mercury, nickel, and zinc, where about means ±10% of the stated value.

5. The composition of claim 4, wherein the composition has a total trace metal content of less than about 3 parts per million (ppm), the trace metals being cobalt, copper, gold, iron, lead, mercury, nickel, and zinc, where about means ±10% of the stated value.

6. A composition described in any one of claims 1 to 5, wherein the composition has a total trace metal content of 0 ppm Au, 0 ppm Hg, <0.02 ppm Co, <0.2 ppm Fe, <0.4 ppm Pb, <0.5 ppm Ni, and <1.5 ppm Zn.

7. A composition described in any one of claims 1 to 6, wherein the composition comprises a solution of hydrochloric acid (HCl) having a molar concentration of about 0.001 M to about 3 M, where about means ±10% of the stated value.

8. The composition of claim 7, wherein the molar concentration of HCl is about 0.05 M, where about means ±10% of the stated value.

9. The composition of claim 7 or 8, wherein the 64 Cu is present as [ 64 Cu]CuCl 2 .

10. The composition of claim 1, further comprising a chelating agent or bifunctional chelating agent in which the 64 Cu is coordinated, wherein the chelating agent or bifunctional chelating agent is a macrocyclic compound, a bridged macrocyclic compound, a bicyclic compound, or an acyclic compound.

11. The composition of claim 10, wherein the bifunctional chelating agent is DOTA.

12. The composition of any one of claims 1 to 11, wherein the radionuclide purity of the 64 Cu is greater than 98.5%.

13. The composition of claim 12, wherein the radionuclide purity of the 64 Cu is greater than 99%.

14. The composition of claim 13, wherein the radionuclide purity of the 64 Cu is greater than 99.5%.

15. The composition of claim 14, wherein the radionuclide purity of the 64 Cu is greater than 99.9%.

16. The composition of any one of claims 1 to 15, wherein the composition comprises chemical and radionuclide purity suitable for positron emission tomography (PET).

17. The composition of claim 1, wherein the copper-64 is a non-carrier-added compound.

18. A composition according to any one of claims 1 to 17, wherein no inactive materials or carriers are intentionally added during the formation of the composition.

19. The composition of any one of claims 1 to 18, wherein the composition has a specific activity of about 100 64 Cu / μg Cu to about 500 mCi 64 Cu / μg Cu, where about means ±10% of the stated value.

20. The composition of any one of claims 1 to 18, wherein the composition has a specific activity of about 500 mCi 64 Cu / μg Cu to about 1000 mCi 64 Cu / μg Cu, where about means ±10% of the stated value.

21. The composition of any one of claims 1 to 18, wherein the composition has a specific activity of about 1000 mCi 64 Cu / μg Cu to about 1500 mCi 64 Cu / μg Cu, where about means ±10% of the stated value.

22. The composition of any one of claims 1 to 18, wherein the composition has a specific activity of about 1500 mCi 64 Cu / μg Cu to about 2500 mCi 64 Cu / μg Cu, where about means ±10% of the stated value.

23. The composition of any one of claims 1 to 18, wherein the composition has a specific activity of about 2500 mCi 64 Cu / μg Cu to about 3000 mCi 64 Cu / μg Cu, where about means ±10% of the stated value.

24. The composition of any one of claims 1 to 18, wherein the composition has a specific activity of about 3000 64 Cu / μg Cu to about 3800 mCi 64 Cu / μg Cu, where about means ±10% of the stated value.

25. A composition for use in the preparation of a radiopharmaceutical, comprising 4 Ci to 15 Ci of 64 Cu and having a specific activity of up to about 3800 mCi 64 Cu / μg of Cu, where about means ±10% of the stated value.

26. The composition of claim 25, wherein the composition comprises chemical and radionuclide purity suitable for positron emission tomography (PET).

27. ​​The composition described in claim 25 or 26, wherein the composition is obtained from a single cyclotron operation.

28. The composition of any one of claims 25 to 27, wherein the composition has a total trace metal content of less than about 6 parts per million (ppm), the trace metals being cobalt, copper, gold, iron, lead, mercury, nickel, and zinc, where about means ±10% of the stated value.

29. The composition of claim 28, wherein the composition has a total trace metal content of less than about 5 parts per million (ppm), the trace metals being cobalt, copper, gold, iron, lead, mercury, nickel, and zinc, where about means ±10% of the stated value.

30. The composition of claim 29, wherein the composition has a total trace metal content of less than about 3 parts per million (ppm), the trace metals being cobalt, copper, gold, iron, lead, mercury, nickel, and zinc, where about means ±10% of the stated value.

31. The composition of any one of claims 25 to 30, wherein the composition has a total trace metal content of 0 ppm Au, 0 ppm Hg, <0.02 ppm Co, <0.2 ppm Fe, <0.4 ppm Pb, <0.5 ppm Ni, and <1.5 ppm Zn.

32. The composition of any one of claims 25 to 31, wherein the composition comprises a solution of hydrochloric acid (HCl) having a molar concentration of about 0.001 M to about 3 M, where about means ±10% of the stated value.

33. The composition of claim 32, wherein the molar concentration of HCl is about 0.05 M, where about means ±10% of the stated value.

34. The composition of claim 32, wherein the 64 Cu is present as [ 64 Cu]CuCl 2 .

35. The composition of any one of claims 25 to 34, further comprising a chelating agent or bifunctional chelating agent in which the 64Cu is coordinated, wherein the chelating agent or bifunctional chelating agent is a macrocyclic compound, a bridged macrocyclic compound, a bicyclic compound, or an acyclic compound.

36. The composition of claim 35, wherein the bifunctional chelating agent is DOTA.

37. The composition of any one of claims 25 to 36, wherein the radionuclide purity of the 64 Cu is greater than 98.5%.

38. The composition of claim 37, wherein the radionuclide purity of the 64 Cu is greater than 99%.

39. The composition of claim 38, wherein the radionuclide purity of the 64 Cu is greater than 99.5%.

40. The composition of claim 39, wherein the radionuclide purity of the 64 Cu is greater than 99.9%.

41. The composition of any one of claims 25 to 40, wherein the copper-64 is a non-carrier additive.

42. A composition described in any one of claims 25 to 41, wherein no inactive materials or carriers are intentionally added during the production of the composition.

43. The composition of any one of claims 25-42, wherein the composition has a specific activity of about 100 64 Cu / μg Cu to about 500 mCi 64 Cu / μg Cu, where about means ±10% of the stated value.

44. The composition of any one of claims 25-42, wherein the composition has a specific activity of about 500 64 Cu / μg Cu to about 1000 mCi 64 Cu / μg Cu, where about means ±10% of the stated value.

45. The composition of any one of claims 25-42, wherein the composition has a specific activity of about 1000 mCi 64 Cu / μg Cu to about 1500 mCi 64 Cu / μg Cu, where about means ±10% of the stated value.

46. ​​The composition of any one of claims 25-42, wherein the composition has a specific activity of about 1500 mCi 64 Cu / μg Cu to about 2500 mCi 64 Cu / μg Cu, where about means ±10% of the stated value.

47. The composition of any one of claims 25-42, wherein the composition has a specific activity of about 2500 64 Cu / μg Cu to about 3000 mCi 64 Cu / μg Cu, where about means ±10% of the stated value.

48. The composition of any one of claims 25-42, wherein the composition has a specific activity of about 3000 64 Cu / μg Cu to about 3800 mCi 64 Cu / μg Cu, where about means ±10% of the stated value.

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