Patent Application
20240161939
The present disclosure is related to solid target systems that produce high-purity radionuclide compositions using medical cyclotrons, the compositions are of suitable radionuclidic and chemical purity for use in radiopharmaceutical applications, for example, diagnostic imaging and therapy in nuclear medicine.
Radionuclides, largely used worldwide in diagnostic imaging procedures in the fields of oncology, neurology, and cardiology, are currently produced by medical cyclotron accelerators and nuclear reactors. In cyclotron production, a target coin (or simply “coin”) bearing a target metal is bombarded with subatomic particles, thereby, converting the target metal into a desired radionuclide via a nuclear reaction. The growing number of cyclotrons of different energies installed worldwide has given a strong impulse to the production of conventional and emerging radionuclides for medical applications (See, e.g., Synowiecki M. A., et al. Production of Novel Diagnostic Radionuclides in Small Medical Cyclotrons. EJNMMI Radiopharm. Chem. 2018; 3: 1-25).
In particular, the great advantage of using medical cyclotrons is the possibility to produce the medical radionuclide of interest on-site and on demand. The technological advancement in cyclotron-based production has recently encouraged the use of novel radionuclides (mainly radiometals) in medical applications for implementing the so-called personalized medicine approach. In particular, the strength of this approach relies on the possibility of selecting patients responding positively to targeted treatment by performing a preliminary diagnostic imaging using the same radiopharmaceutical with a differing radionuclide (theranostic approach) (Boschi A., Martini P., Costa V., Pagnoni A., Uccelli L. Interdisciplinary Tasks in the Cyclotron Production of Radiometals for Medical Applications. The Case of 47Sc as Example. Molecules. 2019; 24: 444; Srivastava S. C. A Bridge Not Too Far: Personalized Medicine with the Use of Theragnostic Radiopharmaceuticals. J. Postgrad. Med. Educ. Res. 2013; 47: 31-46; Qaim S. M. Medical Radionuclide Production. De Gruyter; Berlin, Germany: 2019.)
The availability of active and highly pure novel medical radionuclides is essential for the development of personalized nuclear medicine. Various copper radionuclides have been used in nuclear medicine, and they offer versatile choices for radionuclide imaging (e.g., in radiotracers) and therapy.
Copper radionuclides, including 60Cu, 61Cu, 62Cu, 64Cu, and 67Cu, offer versatile choices for applications in imaging and therapy. The short-lived 60Cu (t1/2=23.4 min), 61Cu (t1/2=3.32 h) and 62Cu (t1/2=9.76 min) decay by electron capture and β+ emission and have been used to prepare perfusion agents such as Cu-pyruvaldehyde bis(N4-methylthiosemicarbazone) (PTSM) and Cu-ethylglyoxal bis(thiosemicarbazone) ETS. The longer-lived 67Cu (t1/2=62.01 h) decays exclusively by β− emission and has been used to label monoclonal antibodies and antibody fragments for radioimmunotherapy. 64Cu has an intermediate half-life of 12.7 h and a unique decay prolife (β+: 18%, β−: 38%, and electron capture: 44%), making it useful for radiolabeling nanoparticles, antibodies, antibody fragments, peptides, and small molecules for Positron Emission Tomography (PET) imaging and radionuclide therapy. 64Cu radiopharmaceuticals can thus be used for quantitative PET imaging to calculate radiation dosimetry prior to performing targeted radiotherapy with 64Cu or its beta-emitting isotopologue 67Cu. 64Cu has been incorporated into many labelled bioconjugates based on antibodies, peptides and small molecules that target specific receptors or antigens, particularly in oncology applications.
More recently, 61Cu (t1/2=3.33 h, 61% β, Emax=1.216 MeV) has been considered a better choice for imaging at later time points of processes with slower kinetics and to achieve a higher tumor-to-background ratio in the detection of small metastases due to its longer half-life (3.33 h) compared with 60Cu and 62Cu. 61Cu is a positron-emitting radionuclide presenting decay characteristics comparable to 68Ga but with the advantage of presenting a lower maximum positron energy (Emax=1.216 MeV vs. Emax=1.899 MeV) and a substantially more practical half-life (3.33 h vs. 68 min). (McCarthy, D. W. et al. High-purity production and potential applications of copper-60 and copper-61. Nucl. Med. Biol. 1999, 26, 351-358.) The intermediate half-life and favorable decay properties allow for better image quality and possibly lower radiation dose to patients.
The cost and complexity of producing sufficient quantities of high-quality Cu radioisotopes for medical use present a major challenge in their broader adoption as radiopharmaceuticals. Ensuring the availability of suitable target coins is essential to providing high-quality cyclotron produced radioisotopes in the quantity needed for medical purposes.
A high apparent molar activity is often required when using Cu radionuclides to produce radiopharmaceuticals, e.g., radiolabeled bioconjugates using bifunctional chelators. To this end, contamination of a radiopharmaceutical composition by nonradioactive trace metals (i.e., “cold metals”) must be reduced. For example, the presence of nonradioactive carrier copper should be reduced as it will compete with the desired radionuclides for chelation, thus, interfering with radiolabeling, reducing yield, and reducing the apparent molar activity, e.g., of the radiolabeled radiopharmaceutical product. Another consideration is that the metal targets used to prepare radionuclides (e.g., enriched Ni for making radiocopper) often contain other trace metal impurities, including iron and zinc. Metal contaminants in a radiopharmaceutical composition also arise from solutions and equipment used in various production processes. Radionuclidic impurities should also be reduced. One source of such impurities is from, e.g., isotopically enriched Ni targets that often contain nickel isotopic impurities that can lead to undesired Cu isotopic impurities upon bombardment.
Accordingly, when preparing radionuclides for radiopharmaceutical applications, there is a need to reduce both radiochemical and radionuclidic contaminants that negatively influence the labelling and apparent molar activity of the final radiopharmaceutical product.
The present disclosure describes, among other things, the construction and evaluation of a radiocopper (6xCu) production system that reduces the amount of costly isotopically enriched Ni target metal leading to more cost-efficient radiocopper production; reduces radionuclidic impurities (particularly 60Co), nonradioactive Cu, and other trace metal contamination; and increases radiochemical purity, radionuclidic purity, chemical purity, and apparent molar activity of the resulting radionuclide compositions, which are suitable for use in medical applications such as production of radiotracers for medical imaging and treatment of cancer.
A first aspect of the present disclosure provides a novel coin for bombardment by subatomic particles for use in producing radionuclides, e.g., on a medical cyclotron; the coin includes a backing made up of Nb having a purity of at least 98.8%. In certain embodiments, various impurities in the Nb backing are limited to, e.g., Fe≤40 ppm; Ti≤60 ppm; Zn≤19 ppm; Cu≤5 ppm; Sn≤8 ppm; Ni<5 ppm; and Al≤5 ppm. In further embodiments, the backing has a backing surface that is free or substantially free of oxides, particularly metal oxides.
A second aspect of the present disclosure provides a coin as described in the first aspect of the disclosure described above, that also includes an electroplated coating of a target metal adhered to the backing surface. In certain embodiments, certain impurities in the target are limited, for example: Cd≤0.0005 ppm, Co≤0.005 ppm, Pb≤0.005 ppm, Cu≤0.08 ppm, and Fe≤0.15 ppm.
In certain embodiments, the target metal is Ni or Zn in naturally occurring isotopic abundance (“natural” Ni or Zn) or enriched to various levels of isotopic abundance.
A third aspect of the present disclosure provides a method for preparing a coin comprising an electroplated target metal adhered to the backing surface wherein the backing comprises material resistant to corrosion, the method comprising electroplating the target metal from a plating solution onto the backing surface; and wherein the plating solution has a pH of 9.5-10.7. In certain embodiments, the backing comprises Nb, Ag, Pt, Au, Al, or W, particularly Nb.
A fourth aspect of the present disclosure provides a method for preparing a coin according to the second aspect of the disclosure described above, the method comprising: electroplating the target metal from a plating solution onto the backing surface to form a target coating. In certain embodiments the plating solution has a pH of 9.5-10.7. In further embodiments is provided a coin prepared according to a method provided herein.
In embodiments of the third and fourth aspects, the methods further comprise one or more of the following elements: abrading the backing surface before the electroplating, wherein the plating solution comprises nitrate ions, wherein the electroplating occurs at a current of 120 to 300 μA, wherein the electroplating occurs for ≤3 hours, wherein the starting material source of the target metal used to prepare the plating solution is at least 99.9% pure, wherein the preparing the plating solution comprises ammonium ions, wherein the electroplating occurs in an electrolytic cell comprising a fixed anode, wherein the plating solution is characterized by reducing certain impurities to certain threshold levels, such as Cu≤0.1 ppm, Fe≤10 ppm, Ga, Lu, Pb, Y≤0.1 ppm; Zn, Co≤0.3 ppm; Cd, Cr, Al, Mn, Mo, Sn, Ti, and V≤1 ppm; and Family I (alkali metals) and Family II (alkaline earth metals) elements: ≤1000 ppm.
A fifth aspect of the present disclosure provides a high-purity radionuclide composition, the composition comprising a radionuclide and having a radionuclidic purity at the end of synthesis (EoB plus 90 minutes) for the radionuclide of ≥95%; and wherein the radionuclide is a Cu radionuclide, and/or the presence of certain radionuclidic impurities are limited, such as 110mAg≤0.1 Bq/g; 108mAg≤0.1 Bq/g; and 109Cd≤0.1 Bq/g. In certain embodiments, the high-purity radionuclide composition is in the form of an aqueous chloride salt solution, e.g., [61Cu]CuCl2. In certain embodiments, the radionuclide is 61Cu, 64Cu, or 68Ga. In certain embodiments, the high-purity radionuclide composition is characterized by a chemical purity for the radionuclide of ≥99.0%. In further embodiments, certain chemical impurities are limited to certain amounts, such as Fe≤2 mg/L; stable Cu isotopes are ≤1 mg/L; Zn(II)≤2 mg/L; Sn(IV)≤0.01 mg/L; Ti(IV)≤0.01 mg/L; Al(III)≤2 mg/L; As≤1 mg/L; Ni≤1 mg/L; and wherein any one of Cr, Cd, Co, and Y is ≤0.1 mg/mL. In certain embodiments, the high-purity radionuclide composition is characterized by one or more of: an activity concentration of 0.25-25 GBq/mL at calibration (EoB+8 hrs); an apparent molar activity of 10-100 MBq/nmol at calibration; and an activity at end of synthesis (EoB plus 90 minutes) of >500 MBq.
In a sixth aspect of the present disclosure, a method of making the high-purity radionuclide composition according to the fifth aspect of the present disclosure described above is provided, the method comprising: irradiating in a particle accelerator the target metal of the coin as according to the second aspect of the present disclosure described above, to produce an irradiated target material; and isolating the high-purity radionuclide composition. In certain embodiments, the method comprises the following elements: purifying the radionuclide chloride solution to reduce chemical impurities, wherein the irradiating time is up to the length of two half-lives of the radionuclide, such as one half-life.
In certain embodiments of the sixth aspect, the target metal is natural Ni, 60Ni, 61Ni, and the radionuclide of the high-purity radionuclide composition is [61Cu]CuCl2 according to one of the following reactions: natNi(d,n)61Cu and 60Ni(d,n)61Cu. In certain embodiments, the target metal is 61Ni, the radionuclide is 61Cu produced according to the following reaction: 61Ni(p,n)61Cu. In certain embodiments, the target metal is 64Zn, wherein the radionuclide is 61Cu produced according to the following reaction: 64Zn(p,α)61Cu. In certain embodiments, the target metal is 61Ni, wherein the radionuclide is 61Cu produced according to the following reaction: 60Ni(p,n)60Cu. In certain embodiments, the target metal is 62Ni, wherein the radionuclide is 62Cu produced according to the following reaction: 62Ni(p,n)62Cu. In certain embodiments, the target metal is 64Ni, wherein the radionuclide is 64Cu produced according to the following reaction: 64Ni(p,n)64Cu. In certain embodiments, the target metal is 68Zn, wherein the radionuclide is 64Cu produced according to the following reaction: 68Zn(p,αn)64Cu. In further embodiments, the target metals are natural or are enriched in the identified isotope to at least 95%, at least 97%, or at least 99%.
These and other features, aspects, and advantages of the present disclosure will become better understood with regard to the following description and accompanying drawings where:
An aspect of the present disclosure is the provision of a novel coin comprising a metal target for bombardment by subatomic particles to produce radionuclide compositions. In certain embodiments, a provided target coin is designed specifically for use in low energy, biomedical cyclotrons. In certain embodiments, a provided target coin is designed for use in biomedical cyclotrons.
In certain embodiments, the coin of the present disclosure comprises a backing. This backing has a mass and in certain embodiments has at least one backing surface upon which a targeting metal is deposited. The term “backing surface” as used herein refers to a single side of the backing that is or will be in contact with the target metal. In certain embodiments, the target metal is adhered to the backing, e.g., by electrodeposition. To describe this in another way, the target metal is adhered to the backing, for example, in the form of an electroplated coating or layer, this mass referred to herein simply as the “target” or “target metal.” After the target metal is adhered to the backing, the result is the coin.
In certain embodiments of the present disclosure, the backing comprises a chemically inert material, such as Nb, Ag, Pt, Au, Al, or W, particularly Nb. In certain embodiments of the present disclosure, the backing consists of a chemically inert material, such as Nb, Ag, Pt, Au, Al, or W, particularly Nb.
In certain embodiments, the backing is a Nb or Ag backing. In certain embodiments, the backing is a Ag backing. In certain embodiments, the backing is a Nb backing. In certain embodiments, the backing is a Pt backing. In certain embodiments, the backing is a Au backing. In certain embodiments, the backing is an Al backing. In certain embodiments, the backing is a W backing.
In certain embodiments, the backing is not a Ag backing. In certain embodiments, the backing is not a Pt backing. In certain embodiments, the backing is not a Au backing. In certain embodiments, the backing is not an Al backing. In certain embodiments, the backing is not a W backing.
In certain embodiments, the backing does not comprise Ag. In certain embodiments, the backing does not comprise Pt. In certain embodiments, the backing does not comprise Au. In certain embodiments does not comprise Al. In certain embodiments, the backing does not comprise W.
4.1.1.1 High-Purity Nb
In certain embodiments of the present disclosure, the backing is a high purity Nb backing. In certain embodiments, the purity of Nb is ≥98.8%. In certain embodiments, the purity of Nb is 299.8%. In certain embodiments, the purity of Nb is 99-99.9%. In certain embodiments, purity of Nb is 99-99.99%. In certain embodiments, of the purity of Nb is 99-99.999%.
In certain embodiments, the purity of the Nb backing is ≥98.850%, ≥98.900%, ≥98.950%, ≥990%, ≥99.050%, ≥99.100%, ≥99.150%, ≥99.200%, ≥99.250%, ≥299.300%, ≥99.350%, ≥99.400%, ≥99.450%, ≥99.500%, ≥99.510%, ≥99.520%, ≥99.530%, ≥99.540%, ≥99.550%, ≥99.560%, ≥99.570%, ≥99.580%, ≥99.590%, ≥99.600%, ≥99.610%, ≥99.620%, ≥99.630%, ≥99.640%, ≥99.650%, ≥99.660%, ≥99.670%, ≥99.680%, ≥99.690%, ≥99.700%, ≥99.710%, ≥99.720%, ≥99.730%, ≥99.740%, ≥99.750%, ≥99.760%, ≥99.770%, ≥99.780%, ≥99.790%, ≥99.800%, ≥99.810%, ≥99.820%, ≥99.830%, ≥99.840%, ≥99.850%, ≥99.853%, ≥99.856%, ≥99.859%, ≥99.862%, ≥99.865%, ≥99.868%, ≥99.871%, ≥99.874%, ≥99.877%, ≥99.880%, ≥99.883%, ≥99.886%, ≥99.889%, ≥99.892%, ≥99.895%, ≥99.898%, ≥99.901%, ≥99.904%, ≥99.907%, ≥99.910%, ≥99.913%, ≥99.916%, ≥99.919%, ≥99.922%, ≥99.925%, ≥99.928%≥99.931%, ≥99.934%, ≥99.937%, ≥99.940%, ≥99.943%, ≥99.946%, ≥99.949%, ≥99.952%, ≥99.955%, ≥99.958%, ≥99.961%, ≥99.964%, ≥99.967%, ≥99.970%, ≥99.973%, ≥99.976%, ≥99.979%, ≥99.982%, ≥99.985%, ≥99.988%, ≥99.991%, ≥99.994%, or ≥99.997%. In certain embodiments, of the purity of the Nb backing is 99.810%.
In certain embodiments, the Nb backing is characterized by limiting the amount of certain impurities, as described below.
In certain embodiments of the Nb backing, the amount of Fe in the backing is ≤30 ppm. In certain embodiments, the amount of Fe in the backing is ≤27 ppm, ≤28 ppm, ≤29 ppm, ≤30 ppm, ≤31 ppm, ≤32 ppm, ≤33 ppm, ≤34 ppm, ≤35 ppm, ≤36 ppm, ≤37 ppm, ≤38 ppm, ≤39 ppm, ≤40 ppm, ≤41 ppm, ≤42 ppm, ≤43 ppm, ≤44 ppm, ≤45 ppm, ≤46 ppm, ≤47 ppm, ≤48 ppm, ≤49 ppm, or ≤50 ppm.
In certain embodiments of the Nb backing, the amount of Ti in the backing is ≤60 ppm; for example, Ti is ≤10 ppm. In certain embodiments, the amount of Ti in the backing is ≤5 ppm, ≤6 ppm, ≤7 ppm, ≤8 ppm, ≤9 ppm, ≤10 ppm, ≤11 ppm, ≤12 ppm, ≤13 ppm, ≤14 ppm, ≤15 ppm, ≤16 ppm, ≤17 ppm, ≤18 ppm, ≤19 ppm, ≤20 ppm, ≤21 ppm, ≤22 ppm, ≤23 ppm, ≤24 ppm, ≤25 ppm, ≤26 ppm, ≤27 ppm, ≤28 ppm, ≤29 ppm, ≤30 ppm, ≤31 ppm, ≤32 ppm, ≤33 ppm, ≤34 ppm, ≤35 ppm, ≤36 ppm, ≤37 ppm, ≤38 ppm, ≤39 ppm, ≤40 ppm, ≤41 ppm, ≤42 ppm, ≤43 ppm, ≤44 ppm, ≤45 ppm, ≤46 ppm, ≤47 ppm, ≤48 ppm, ≤49 ppm, ≤50 ppm, ≤51 ppm, ≤52 ppm, ≤53 ppm, ≤54 ppm, ≤55 ppm, ≤56 ppm, ≤57 ppm, ≤58 ppm, ≤59 ppm, ≤60 ppm, ≤61 ppm, ≤62 ppm, ≤63 ppm, ≤64 ppm, ≤65 ppm, ≤66 ppm, ≤67 ppm, ≤68 ppm, ≤69 ppm, ≤70 ppm, ≤71 ppm, ≤72 ppm, ≤73 ppm, or ≤74 ppm.
In certain embodiments of the Nb backing, the amount of Zn in the backing is ≤19 ppm; e.g., Zn is ≤10 ppm. In certain embodiments, the amount of Zn in the backing is ≤5 ppm, ≤6 ppm, ≤7 ppm, ≤8 ppm, ≤9 ppm, ≤10 ppm, ≤11 ppm, ≤12 ppm, ≤13 ppm, ≤14 ppm, ≤15 ppm, ≤16 ppm, ≤17 ppm, ≤18 ppm, ≤19 ppm, ≤20 ppm, ≤21 ppm, ≤22 ppm, ≤23 ppm, ≤24 ppm, ≤25 ppm, ≤26 ppm, ≤27 ppm, ≤28 ppm, ≤29 ppm, or ≤30 ppm.
In certain embodiments of the Nb backing, the amount of Cu in the backing is ≤5 ppm; e.g., Cu is ≤3 ppm. In certain embodiments, the amount of Cu in the backing is ≤0.5 ppm, ≤1 ppm, ≤1.5 ppm, ≤2 ppm, ≤2.5 ppm, ≤3 ppm, ≤3.5 ppm, ≤4 ppm, ≤4.5 ppm, ≤5 ppm, ≤5.5 ppm, ≤6 ppm, ≤6.5 ppm, ≤7 ppm, ≤7.5 ppm, or ≤8 ppm.
In certain embodiments of the Nb backing, the amount of Sn in the backing is ≤5 ppm. In certain embodiments, the amount of Sn in the backing is ≤0.5 ppm, ≤1 ppm, ≤1.5 ppm, ≤2 ppm, ≤2.5 ppm, ≤3 ppm, ≤3.5 ppm, ≤4 ppm, ≤4.5 ppm, ≤5 ppm, ≤5.5 ppm, ≤6 ppm, ≤6.5 ppm, ≤7 ppm, ≤7.5 ppm, ≤8 ppm, ≤8.5 ppm, ≤9 ppm, ≤9.5 ppm, ≤10 ppm, ≤10.5 ppm, ≤11 ppm, ≤11.5 ppm, ≤12 ppm, ≤12.5 ppm, or ≤13 ppm.
In certain embodiments of the Nb backing, the amount of Ni in the backing is <5 ppm; e.g., Ni is <1 ppm. In certain embodiments, the amount of Ni in the backing is ≤0.2 ppm, ≤0.4 ppm, ≤0.6 ppm, ≤0.8 ppm, ≤1 ppm, ≤1.2 ppm, ≤1.4 ppm, ≤1.6 ppm, ≤1.8 ppm, ≤2 ppm, ≤2.5 ppm, ≤3 ppm, ≤3.5 ppm, ≤4 ppm, ≤4.5 ppm, ≤5 ppm, ≤5.5 ppm, ≤6 ppm, ≤6.5 ppm, ≤7 ppm, ≤7.5 ppm, or ≤8 ppm.
In certain embodiments of the Nb backing, the amount of Al in the backing is ≤5 ppm. In certain embodiments, the amount of Al in the backing is ≤0.2 ppm, ≤0.4 ppm, ≤0.6 ppm, ≤0.8 ppm, ≤1 ppm, ≤1.2 ppm, ≤1.4 ppm, ≤1.6 ppm, ≤1.8 ppm, ≤2 ppm, ≤2.5 ppm, ≤3 ppm, ≤3.5 ppm, ≤4 ppm, ≤4.5 ppm, ≤5 ppm, ≤5.5 ppm, ≤6 ppm, ≤6.5 ppm, ≤7 ppm, ≤7.5 ppm, ≤8 ppm, ≤8.5 ppm, ≤9 ppm, ≤9.5 ppm, or ≤10 ppm.
In certain embodiments of the Nb backing, the amount of Fe in the backing is ≤50 ppm (e.g., ≤30 ppm), the amount of Ti in the backing is ≤60 ppm (e.g., ≤10 ppm), the amount of Zn in the backing is ≤19 ppm (e.g., ≤10 ppm), the amount of Cu in the backing is ≤5 ppm (e.g., ≤3 ppm), the amount of Sn in the backing is ≤13 ppm (e.g., ≤5 ppm), the amount of Ni in the backing is <5 ppm (e.g., <1 ppm), and/or the amount of Al in the backing is ≤5 ppm (e.g., 1 ppm), or any combination of the above.
In certain embodiments, the Nb backing is 99.8% pure, and comprises: C≤24 ppm, H≤1 ppm, Mo≤2 ppm, Ni≤4 ppm, Si≤1 ppm, Ti≤2 ppm, Zr≤3 ppm, Fe≤1 ppm, Hf≤2 ppm, N≤14 ppm, O≤56 ppm, Ta≤785 ppm, and W≤4 ppm. In certain embodiments, the Nb backing is 99.9% pure and comprises: B≤10 ppm, Ni≤5 ppm, O≤100 ppm, Si≤100 ppm, Zr≤10 ppm, Ta≤500 ppm, H≤10 ppm, W≤100 ppm, C≤25 ppm, Ni≤20 ppm, Fe≤30 ppm, Cu≤5 ppm, Mo≤10 ppm, and Ti≤10 ppm.
4.1.1.2 Dimensions of the Backing
The backing according to the present disclosure is any two-dimensional shape without restriction and that has any thickness suitable for its intended use. In certain embodiments, the backing is a circle, an oval, or a geometric shape having from 3-10 sides, for example, a quadrilateral, such as a rectangle, square, trapezoid or parallelogram, a triangle, a composite of multiple geometric shapes, or an organic shape with irregular sides.
In certain embodiments, the backing has a circular cross-section (i.e., disc-shaped). In further such embodiments, the backing has a diameter of 35-15 mm, e.g., 28 mm, or 22 mm. Unless stated otherwise, the tolerance in diameter is ±0.1 mm.
In certain embodiments, the backing has a thickness of 0.50-3 mm or 1-2 mm. In certain embodiments the backing has a thickness of 0.75-2.25 mm, 0.88-2.13 mm, 1-2 mm, 1.13-1.88 mm, 1.25-1.75 mm, or 1.38-1.63 mm. In certain embodiments, the backing has a thickness of 0.5 mm, 0.63 mm, 0.75 mm, 0.88 mm, 1 mm, 1.13 mm, 1.25 mm, 1.38 mm, 1.5 mm, 1.63 mm, 1.75 mm, 1.88 mm, 2 mm, 2.13 mm, 2.25 mm, 2.38 mm, 2.5 mm, 2.63 mm, 2.75 mm, 2.88 mm, or 3 mm.
In certain embodiments, the backing has a thickness of 1 mm to 2.5 mm. In certain embodiments, the backing thickness is 1.5 mm.
Unless stated otherwise, the tolerance in the backing thickness values reported herein is f 0.05 mm.
In certain embodiments, the backing comprises a central disc-shaped groove. In further embodiments, the disc-shaped groove has a diameter of 10 mm and a depth of about 0.6 mm.
In certain embodiments, the surface of the backing material has a roughness (Ra) of 1.6 μm (micrometer). In certain embodiments, the surface of the backing material has an Ra of 1.5 μm. In certain embodiments, the surface of the backing material has an Ra of 1.4 μm. In certain embodiments, the surface of the backing material has an Ra of 1.3 μm. In certain embodiments, the surface of the backing material has an Ra of 1.2 μm. In certain embodiments, the surface of the backing material has an Ra of 1.1 μm. In certain embodiments, the surface of the backing material has an Ra of 1 μm. In certain embodiments, the surface of the backing material has an Ra of 0.9 μm. In certain embodiments, the surface of the backing material has an Ra of 0.8 μm. In certain embodiments, the surface of the backing material has an Ra of 0.7 μm. In certain embodiments, the surface of the backing material has an Ra of 0.6 μm. In certain embodiments, the surface of the backing material has an Ra of 0.5 μm. In certain embodiments, the surface of the backing material has an Ra of 0.4 μm. In certain embodiments, the surface of the backing material has an Ra of 0.3 μm. In certain embodiments, the surface of the backing material has an Ra of 0.2 μm. In certain embodiments, the surface of the backing material has an Ra of 0.1 μm.
Variations on the dimensions of the backing provided without tolerance values herein are according to ISO 2768 1:1989 General tolerances—Part 1: Tolerances for linear and angular dimensions without individual tolerance indications.
4.1.1.3 Backing Surface
In certain embodiments of the backing, and in particular, of the backing surface to which the target metal adheres, is free of oxides, for example, as evaluated by visual inspection. The presence of oxides is typically apparent as a discoloration that obscures the natural luster or color of the raw metal backing. In certain of these embodiments, any observed oxides are removed, e.g., by abrasion. Without being bound by theory, treatment of the backing surface with an abrasive method may further improve purity of the radionuclide product and/or to ensure sufficient adhesion of a target coating which in turn ensures target metal integrity during coin transfer and during particle bombardment.
In certain embodiments, the backing comprises Nb, wherein the backing surface is free or substantially free of oxides, particularly metal oxides. In certain embodiments, the Nb backing is new or unused, e.g., manufactured and stored to avoid exposure to oxidizing physical conditions. In certain embodiments, the backing is rolled out from a metal foil having a thickness greater than the desired thickness of the backing, thus imparting surface roughness.
In certain embodiments, the Nb backing surface has some oxidation, e.g., as observed by the presence discoloration of the natural luster or color of the raw metal surface. In related embodiments, the oxidation has been removed by physical abrasion, e.g., as described herein.
In certain embodiments, the target metal is the material to be irradiated (bombarded by, e.g., protons or deuterons) thereby producing radionuclide compositions of the present disclosure. In certain embodiments, impurities in the target metal are limited to certain levels described herein.
In certain embodiments, the target metal is electrodeposited, pressed, sintered, press-bonded, melted or physically deposited (through vapor or atomic deposition) onto the backing which acts as a stable carrier during the irradiation process. In certain embodiments, the target metal is in the form of a foil. In certain embodiments, the foil is a sheet or roll.
In certain embodiments, the electrodeposited target metal forms a target coating. In certain embodiments, the target coating covers only a portion of the backing surface, for example, the center of the backing surface but not all the way to the perimeter of the backing surface. In certain embodiments, the target coating is prepared by electroplating the target metal from a plating solution, e.g., as described herein. In certain embodiments, a target coating is prepared by electroplating a target metal from a plating solution onto a backing surface.
In certain embodiments, the deposited target is a smooth and homogenous deposit with uniform thickness (with less than 25%, 20%, 15%, 12%, 10%, or 5% variability, particularly less than 15% variability) free of observable cracks or craters.
In certain embodiments, the maximum thickness of the target coating is 0.07 mm, 0.075 mm, 0.08 mm, 0.085 mm, 0.09 mm, 0.095 mm, 0.1 mm, 0.105 mm, 0.11 mm, 0.115 mm, 0.12 mm, 0.125 mm, 0.13 mm, or 0.135 mm. In certain embodiments, the maximum thickness of the target coating is 0.1 mm.
In certain embodiments, the minimum thickness of the target coating is 0.1 mm, 0.105 mm, 0.11 mm, 0.115 mm, 0.12 mm, 0.125 mm, 0.13 mm, 0.135 mm, 0.14 mm, 0.145 mm, 0.15 mm, 0.155 mm, 0.160 mm, 0.165 mm, 0.17 mm, 0.175 mm, or 0.18 mm. In certain embodiments, the minimum thickness of the target coating is 0.14 mm.
Unless otherwise indicated, the tolerance of the thickness measurements is ±0.005 mm.
In certain embodiments, the amount of target metal deposited on the backing is 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, or 240 mg.
In certain embodiments, the amount of target metal deposited on the backing is 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, or 80 mg.
Unless otherwise indicated, the tolerance of the mass measurements is ±0.5 mg.
4.1.2.1.1 Nickel
In certain embodiments, the target metal is Ni. In certain embodiments, the target metal is natural Ni. Naturally occurring nickel is composed of five stable isotopes. 58Ni is the most abundant isotope (68.077% natural abundance). The four minor (i.e., not most abundant) stable isotopes and their corresponding natural abundance is: 60Ni (26.223%), 61Ni (1.1400), 62Ni (3.635%), and 64Ni (0.926%).
In certain embodiments, the target metal is Ni and is isotopically enriched in a minor isotope selected from 60Ni, 61Ni, 62Ni, and 64Ni, relative to the minor isotope's natural abundance in Ni.
In certain embodiments, the target metal is Ni that is isotopically enriched in the minor isotope to 95% or more.
In certain embodiments, the target metal is Ni that is enriched in 60Ni to 95%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 60Ni to 96%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 60Ni to 97%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 60Ni to 98%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 60Ni to 99%-99.99%.
In certain embodiments, the target metal is Ni that is enriched in 61Ni to 95%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 61Ni to 95%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 61Ni to 96%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 61Ni to 97%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 61Ni to 98%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 61Ni to 99%-99.99%.
In certain embodiments, the target metal is Ni that is enriched in 62Ni to 95%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 62Ni to 96%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 62Ni to 97%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 62Ni to 98%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 62Ni to 99%-99.99%.
In certain embodiments, the target metal is Ni that is enriched in 64Ni to 95%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 64Ni to 96%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 64Ni to 97%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 64Ni to 98%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 64Ni to 99%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 64Ni to 95%. In certain embodiments, the target metal is Ni that is enriched in 64Ni to 96%. In certain embodiments, the target metal is Ni that is enriched in 64Ni to 97%. In certain embodiments, the target metal is Ni that is enriched in 64Ni to 98%. In certain embodiments, the target metal is Ni that is enriched in 64Ni to 99%.
In certain embodiments, the target metal is Ni that is isotopically enriched in the minor isotope to 97% or more. In certain embodiments, the target metal is Ni that is enriched in 60Ni to 97%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 60Ni to 98%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 60Ni to 99%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 61Ni to 97%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 61Ni to 98%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 61Ni to 99%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 62Ni to 97%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 62Ni to 98%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 62Ni to 99%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 64Ni to 97%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 64Ni to 98%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 64Ni to 99%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 62Ni to 97%±1%.
In certain embodiments, the target metal is Ni that is isotopically enriched in the minor isotope to 99% or more. In certain embodiments, the target metal is Ni that is enriched in 60Ni to 99%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 61Ni to 99%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 62Ni to 99%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 64Ni to 99%-99.99%. In certain embodiments, the target metal is Ni that is enriched in 60Ni to 99%±0.5%. In certain embodiments, the target metal is Ni that is enriched in 61Ni to 99%±0.5%.
Unless stated otherwise, the tolerance associated with a given enrichment value is f 0.1%.
4.1.2.1.2 Zinc
In certain embodiments, the target metal is Zn. In certain embodiments, the target metal is isotopically enriched in 68Zn relative to natural Zn. Natural Zn is composed of five stable isotopes with 64Zn being the most abundant isotope (49.17% natural abundance). The minor isotopes along with their natural abundance are 66Zn (27.73%), 67Zn (4.04%), 68Zn (18.45%), and 70Zn (0.61%).
In certain embodiments, the target metal is Zn that is isotopically enriched in 68Zn to 95% or more, e.g., 95%-99.99%. In certain embodiments, the target metal is Zn and is isotopically enriched in 68Zn to 99% or more.
4.1.2.2 Target Coating Purity
In aspects of the provided disclosure, the target coating, i.e., the electrochemically deposited material on the backing surface, is highly pure. In certain embodiments, nuclear bombardment of the present high-purity target coating provides a radionuclide composition of higher purity than if a lower purity target coating had been used. In certain embodiments, the target coating comprises one or more of: Cd≤0.0005 ppm, Co≤0.005 ppm, Pb≤0.005 ppm, Cu≤0.08 ppm, and Fe≤0.15 ppm.
In certain embodiments, the target metal is natural Ni having a chemical purity of 95%-99.99%, e.g., 96%-99.99%, 97%-99.99%, 98%-99.99%, or 99%-99.99%.
In certain embodiments, the target metal is natural Ni having a chemical purity of ≥95%, ≥96%, ≥97%, ≥98%, ≥99%.
In certain embodiments, the target metal is “Ni having a chemical purity of 95%-99.99%, e.g., 96.%-99.99%, 97%-99.99%, 98%-99.99%, or 99%-99.99%.
In certain embodiments, the target metal is Ni that is enriched in 61Ni having a chemical purity of 95%-99.99%, e.g., 96%-99.99%, 97%-99.99%, 98%-99.99%, or 99%-99.99%.
In certain embodiments, the target metal is Ni that is enriched in 62Ni having a chemical purity of 95%-99.99%, e.g., 96%-99.99%, 97%-99.99%, 98%-99.99%, or 99%-99.99%.
In certain embodiments, the target metal is Ni that is enriched in 64Ni having a chemical purity of 95%-99.99%, e.g., 96%-99.99%, 97%-99.99%, 98%-99.99%, or 99%-99.99%.
The dimensions of the target coating of the present disclosure are not particularly limited. The dimensions can be adjusted, e.g., according to the intended use of the coin. In certain embodiments, the surface area, mass, and thickness of the target coating are selected to accommodate various kinds of irradiation processes. In certain embodiments, the surface area (e.g., based on diameter for a circular coin), mass, and/or thickness of the target coating are selected to optimize, e.g., the activity yield and/or the radionuclidic purity of the produced radionuclide compositions, for example, on the basis of knowledge of the beam properties and reaction cross-sections provided by particular cyclotrons.
4.1.3.1 Target Coating Thickness
In certain embodiments, the target coating has a thickness of 5 to 250 μm, e.g., 5 to 200 μm, 5 to 180 μm, 5 to 170 μm, 5 to 160 μm, 5 to 150 μm, 5 to 140 μm, 5 to 130 μm, 5 to 120 μm, 5 to 110 μm, 20 to 150 μm, 50 to 150 μm, 75 to 150 μm, 90 to 150 μm, 50 to 130 μm, or 70 to 100 μm.
In certain embodiments, the target coating has a thickness of 40 to 250 μm, e.g., 50 to 250 μm, 60 to 250 μm, 70 to 250 μm, 80 to 250 μm, 90 to 250 μm, 100 to 250 μm, 110 to 250 μm, 120 to 250 μm, 130 to 250 μm, 140 to 250 μm, 150 to 250 μm, 160 to 250 μm, 170 to 250 μm, 180 to 250 μm, 190 to 250 μm, 200 to 250 μm, 220 to 250 μm, 50 to 220 μm, 50 to 200 μm, 50 to 180 μm, 50 to 160 μm, 50 to 150 μm, 50 to 140 μm, 50 to 130 μm, 50 to 120 μm, 50 to 110 μm, 50 to 100 μm, 50 to 90 μm, 50 to 80 μm, 50 to 70 μm, 100, 125, 150, 175, 200, 225, or 250 μm, 100 μm, 125 μm, 150 μm, 175 μm, 200 μm, 225 μm, 250 μm.
4.1.3.2 Target Coating Mass
In certain embodiments, the target coating has a mass of 40 mg or more. In certain embodiments, the target coating has a mass of 45 mg or more. In certain embodiments, the target coating has a mass of 50 mg or more. In certain embodiments, the target coating has a mass of 60 mg or more. In certain embodiments, the target coating has a mass of 30 to 200 mg, 30 to 180 mg, 30 to 160 mg, 30 to 140 mg, 30 to 120 mg, 30 to 100 mg, 30 to 90 mg, 30 to 75 mg, 40 to 160 mg, 40 to 130 mg, 40 to 110 mg, 45 to 100 mg, 60 to 100 mg, 70 to 90 mg. In certain embodiments, the target coating has a mass of 75 to 85 mg, 65, 70, 75, 80, 85, or 90 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg. Unless otherwise stated, the tolerance in a provided mass value is ±3 mg.
In certain embodiments, electroplating occurs in an electrolytic cell with a fixed anode. In these embodiments, a thicker target coating metal deposition occurs in the center of the backing. This thicker target coating material occurs where the cyclotron beam is most intense, providing a greater effective surface area and volume for direct bombardment, which in turn enhances activation efficiency and subsequently enhanced dissolution rate of the irradiated target coating. In certain embodiments, the target coating has a variability in the thickness of the target coating across the surface of the coating by about 25%, 20%, 15%, 12%, 10%, 5%, or less. In certain embodiments, the variability is 15% or less. In certain embodiments, the variability is 10% or less. For example, in certain embodiments, the thickness of the coating is 15% thicker in the center compared to the thickness at the edges of the coating.
In certain embodiments, the target coating is 5-30% thicker at the center compared to an average thickness of the coating around the perimeter, e.g., 5%, 7%, 10% or 12% to 15%, 17%, 20%, 25%, or 30% thicker, including 5-15%, 5-20%, 10-15%, 10-17%, 10-20%, 10-25%, 12-15%, 12-17%, 15-20%, or 12-25%, particularly 10-15% thicker at the center compared to an average thickness of the coating around the perimeter.
In certain embodiments, the target coating is generally circular in shape, having a diameter of 3 cm or less, e.g., from 2.5 cm to about 0.75 cm. In certain embodiments, 95% of the target coating mass is within a radius of 2.5, 2.0, 1.5, 1.2, or 1 cm. In certain embodiments, the radius may vary by 10%, 7%, 5%, 3%, 2%, or 1%.
In certain embodiments, the target coating is electrodeposited on a surface of a backing in a circular shape that has a diameter of 1 cm. In certain embodiments, the diameter is 5 mm to 1 cm, e.g., 5 mm to 500 mm, 5 mm to 250 mm, 5 mm to 100 mm, 10 mm-50 mm, 10 mm-25 mm, 8 mm-15 mm. In certain embodiments, the target coating is a circular shape and has a diameter of 10 mm or 13 mm±1 mm.
4.2.1.1 Durability of Target Coating
In certain embodiments, the target coating material remains intact on the surface of the coin after being transferred to and from the cyclotron, such as by means of a pneumatic coin transfer system. An advantage of the present coins is that the electroplated target coating is sufficiently durable to remain adhered to the backing under conditions of direct air flow and abrupt mechanical movements incurred during coin transfer.
In certain embodiments, the target coating remains adhered to the backing during pneumatic transfer both to and from the cyclotron. Such a pneumatic system is typically fed by a compressed air connection of 6-7 bar, and at minimum, 360 SLPM flow. Such a system is “push-push”, and therefore, compressed air is typically blown on both the front and rear sides of the coin, respectively, depending on the direction of transfer. In certain embodiments, the target coating remains adhered to the backing after the coin comes to an abrupt stop as it reaches the target station or hot cell.
In certain embodiments, suitable tests that indicate target coating durability include the following, whereby the total plating mass loss for all tests combined should be negligible (e.g. <2% w/w): Visual inspection, gentle knocking/tapping on a countertop on top of white paper to check for loosening of target coating grains, gently rubbing an acid-washed Teflon spatula against the deposited target coating and checking for loosening of target coating grains, and/or placing and gently pressing down on a piece of Scotch tape against the target coating.
If there is access to the cyclotron apparatus, it is recommended to transfer the coin back/forth multiple times and ensure target coating stability (i.e., no mass loss). Such a test may be performed with or without a degrader (e.g., a 500 μm thin sheet of Al of at least the same dimensions as the target coating or greater) in place.
In a further aspect of the present disclosure, a method is provided for preparing a coin comprising a target metal according to the present disclosure as described herein, wherein the method comprises the steps of electroplating the dissolved target metal from a plating solution onto the backing surface; wherein the plating solution has a pH of 9.5-10.7.
In certain embodiments, the backing is comprised of a corrosion-resistant material. In certain embodiments, the backing comprises Nb, Ag, Pt, Au, Al, or W. In certain embodiments, the backing comprises Nb or Ag. In certain embodiments, the backing consists of Nb.
In certain embodiments, the backing comprises high-purity Nb as described herein, and is used, for example in preparing high-purity radionuclide compositions.
In further embodiments of these methods, the method further comprises a step of abrading the backing surface. The method of abrading is not particularly limited and includes any kind of mechanical abrasion. In certain embodiments, the entire area of the backing surface to be electroplated is abraded, e.g., to ensure adhesion of the target coating and/or to remove any oxides or discoloration, which may interfere with the electroplating. In certain embodiments, the abrading is performed with a vibrational tumbler. In certain embodiments, the abrading is performed with a corundum grinding stone. In certain embodiments, the abrasion is performed with a Bosh Impact 12 hand grinder (pink corundum abrasive grit size 60) at 50 rpm for a duration of roughly 45 to 60 seconds to cover a surface area of about 650-550 mm2.
An aspect of the present disclosure is that by utilizing a basic solution for the plating solution, a higher anode-cathode potential can be achieved that reduces plating times, e.g., to <3 hours compared to the 24 hours of commercially available platings. In addition, the presence of ammonia in the plating solution leads to a lower rate of hydrogen evolution, resulting in a more homogenous and uniform crystal structure and uniform micropores in structure of a target metal coating, e.g., plated layer of Ni or Zn. Without being bound by any particular theory, it is thought that this can be attributed to the chemical nature of NH3 and its tendency to receive hydrogen atoms to form NH4+.
In certain embodiments, a mass of 40 to 100 mg of target metal (e.g., natNi, 60Ni, or 61Ni) is electroplated onto a backing surface to be used in a single bombardment session. In certain embodiments, a mass of 50 to 100 mg of target metal is electroplated onto a backing surface to be used in a single bombardment session to obtain a radionuclide, e.g., of 61Cu or 68Ga, particularly 61Cu.
In an aspect of the present disclosure, a plating solution having a basic pH is provided. In certain embodiments, the pH of the plating solution is from 9 to 11, e.g., 9.5-10.7 or 10-10.4. In certain embodiments, the plating solution has a pH of 9.5-10.7. In certain embodiments, the plating solution has a pH of 10-10.4. Unless indicated otherwise, the tolerance of any pH value of the plating solution is 0.1.
In certain embodiments, preparing the plating solution comprises the step of dissolving the target metal starting material, e.g., metal powder, in nitric acid.
In certain embodiments, electroplating the target metal is from a plating solution wherein the plating solution comprises nitrate ions. In certain embodiments, the plating solution comprises or is prepared using aqueous HNO3. In certain embodiments, the plating solution does not comprise sulfate ions.
In certain embodiments, the method further comprises the step of preparing a plating solution.
In certain embodiments, preparing the plating solution comprises dissolving the target metal starting material. In certain embodiments, the plating solution is prepared by combining the target metal and a molar excess of HNO3. In certain embodiments, the HNO3 is in the form of 65% nitric acid (aqueous) and is added to the plating solution in excess of 40 grams HNO3 per gram target metal (e.g., HNO3:Ni 40 g:1 g).
In certain embodiments, a mass of 20 to 200 mg of target metal (e.g., natNi, 60Ni, or 61Ni) is dissolved in the plating solution. In certain embodiments, a mass of 50 to 100 mg of target metal is dissolved in the plating solution. In certain embodiments, the mass of target metal dissolved in the plating solution is 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg. In certain embodiments, a mass of 50 mg of target metal is dissolved in the plating solution. In certain embodiments, a mass of 100 mg of target metal is dissolved in the plating solution. Unless otherwise stated, the target mass has a tolerance of 3 mg.
In certain embodiments, preparing the plating solution comprises preparing a buffer solution by combining ammonium chloride and ammonium hydroxide in water. In certain embodiments, the plating solution is an ammonium buffer solution. In certain embodiments, the plating solution is or comprises ammonium ions. In certain embodiments, the buffer solution has a pH of 9.2-9.40, e.g., 9.28-9.30. In certain embodiments, the buffer solution has a pH of about 9.3 (at room temperature).
In certain embodiments, preparing the plating solution comprises adding a buffer solution to the plating solution comprising ammonium ions. In certain embodiments, a plating solution is prepared by contacting a metal salt with a buffer solution. In certain embodiments, a plating solution is prepared by contacting a metal nitrate with a buffer solution. In certain embodiments, a plating solution is prepared by contacting nickel nitrate with a buffer solution. In certain embodiments, a plating solution comprises a metal salt dissolved in a buffer solution. In certain embodiments, a plating solution comprises a nickel salt dissolve in a buffer solution. In certain embodiments, the plating solution comprises dissolved metal ions. In certain embodiments, the plating solution comprises dissolved metal ions for electrodeposition. In certain embodiments, the plating solution comprises ammonium ions and a dissolved metal for electrodeposition. In certain embodiments, the plating solution comprises nickel ions. In certain of these embodiments, the plating solution comprises the dissolved target metal.
In certain embodiments, the plating solution comprises natNi and/or 60Ni or a salt thereof. In certain embodiments, the plating solution comprises natNi or a salt thereof. In certain embodiments, the plating solution comprises 60Ni or a salt thereof. In certain embodiments, the plating solution comprises 61Ni or a salt thereof.
In certain embodiments, the plating solution has a pH of 8.5 to 11. In certain embodiments, the pH of the plating solution is 8 to 10.8. In certain embodiments, the pH is 8.10 to 10.6, 8.2 to 10.5, 8.3 to 10.4, 8.5 to 10.3, 8.6 to 10.25, 8.7 to 10.2, 8.5 to 10.15, 8.5 to 10.1, 8.5 to 10, 8.5 to 9.9, 8.5 to 9.80, 8.5 to 9.6, 8.5 to 9.50, 8.5 to 9.4, 8.5 to 9.3, 8.5 to 9.2, 8.5 to 9.1, or 8.5 to 9. In certain embodiments, the plating solution has a pH of 9, 9.50, 10, 10.05, 10.10, 10.15, 10.20, 10.25, 10.30, 10.35, 10.40, 10.50, 10.60, or 10.70, 9, 10, 10.05, 10.10, 10.15, 10.20, 10.25, 10.30, 10.35, or 10.40.
In certain embodiments, the step of preparing the plating solution further comprises adjusting the pH of the plating solution, e.g., after addition of the buffer, by adding an effective amount of NH4OH to achieve a particular pH value for the plating solution.
In further embodiments, the step of adjusting the pH of the plating solution further adding NH4OH, e.g., dropwise, to the plating solution until a desired pH is reached.
An aspect of the present disclosure is the provision of a high-purity plating solution for use in the production of high-purity radionuclide compositions. Frequent sources of trace metals are the target metal starting material itself, especially enriched nickel, reagents and instruments used. Iron is common and requires careful consideration to be reduced from the environment in which the plating solution is prepared. Reagents are selected to reduce impurities.
In certain embodiments of the provided methods, the target metal is selected from those described in this disclosure. In certain embodiments, the target metal used to prepare the plating solution (i.e., target metal source material) is in the form of a metal salt, oxide or elemental metal. In certain of these embodiments, metal oxide or metal (e.g., rod, granules, powder) is at least 98% pure, based on trace metals analysis. In certain embodiments, the target metal source material is at least 99.9% pure based on trace metals analysis. In certain embodiments, the target metal source material is at least 99.99% pure based on trace metals analysis. In certain embodiments, the target metal source material comprises no more than 150 ppm sum trace metal impurities.
In certain embodiments, the method of preparing a coin further comprises a method of purifying the plating solution prior to the electroplating step. In certain embodiments, purifying the plating solution is according to known methods to reduce dissolved Cu, Zn, Fe, Co, Sn, Ti, and/or Al from the plating solution. In certain embodiments, purifying is according to known methods to reduce Cu, Zn, Fe, Sn, Ti, and/or Al from the plating solution. In certain embodiments, purifying is according to known methods to reduce Cu, Zn, and/or Fe from the plating solution. In certain embodiments, purifying is according to known methods to reduce Cu from solutions.
In certain embodiments, the plating solution comprises Cu≤0.1 ppm, Cu≤0.2 ppm, Cu≤0.3 ppm, Cu≤0.4 ppm, Cu≤0.5 ppm, Cu≤0.6 ppm, Cu≤0.7 ppm, Cu≤0.8 ppm, Cu≤0.9 ppm, Cu≤10 ppm, Cu≤10.1 ppm, Cu≤10.2 ppm, Cu≤10.3 ppm, Cu≤10.4 ppm, Cu≤10.5 ppm, Cu≤10.6 ppm, Cu≤10.7 ppm, Cu≤10.8 ppm, Cu≤10.9 ppm, Cu≤11 ppm, Cu≤12 ppm, Cu s 13 ppm, Cu s 14 ppm, Cu 15 ppm, Cu≤16 ppm, Cu 17 ppm, Cu≤18 ppm, Cu≤19 ppm, or Cu≤20 ppm. In certain embodiments, the plating solution comprises Cu≤0.1 ppm. In certain embodiments, the plating solution comprises Cu≤0.2 ppm. In certain embodiments, the plating solution comprises Cu≤0.3 ppm. In certain embodiments, the plating solution comprises Cu≤0.4 ppm. In certain embodiments, the plating solution comprises Cu≤0.5 ppm. In certain embodiments, the plating solution comprises Cu≤0.6 ppm. In certain embodiments, the plating solution comprises Cu≤0.7 ppm. In a particular embodiment, the plating solution comprises Cu≤0.1 ppm.
In certain embodiments of the provided methods, the plating solution comprises Fe≤10 ppm. In certain embodiments, the plating solution comprises Fe≤1 ppm, Fe≤5 ppm, Fe≤10 ppm, Fe≤15 ppm, Fe≤20 ppm, Fe≤25 ppm, Fe≤30 ppm, Fe≤32 ppm, or Fe≤35 ppm. In certain embodiments, the plating solution comprises Fe≤1 ppm. In certain embodiments, the plating solution comprises Fe≤5 ppm. In certain embodiments, the plating solution comprises Fe≤10 ppm. In certain embodiments, the plating solution comprises Fe≤15 ppm. In certain embodiments, the plating solution comprises Fe≤20 ppm. In certain embodiments, the plating solution comprises Fe≤25 ppm. In certain embodiments, the plating solution comprises Fe≤30 ppm. In certain embodiments, the plating solution comprises Fe≤32 ppm. In certain embodiments, the plating solution comprises Fe≤35 ppm.
In certain embodiments of the provided methods, the below identified elements are limited to the provided thresholds. That is, in certain embodiments, the plating solution comprises one or more of the following:
In certain embodiments, the highest grades of reagents should be used, to avoid trace metal contamination of the target coating, as more than a tenth of a microgram per 100 mg of target metal (that is, 1 ppm of the target metal) is already a significant contamination that may render the coin unusable for production of high-purity radionuclides. In the case of the production of radiocopper it is not accepted to add more than 0.1 ppm of cold Cu as this would reduce the purity of the prepared radionuclide composition.
In certain embodiments of the provided methods of preparing the plating solution, the maximum level of impurities allowed to be added by this process to the target metal starting material (refer to trace metal analysis of supplied starting material) are:
In certain embodiments of the provided methods of preparing the plating solution impart only very small amounts of impurities to the solution. In these embodiments, the maximum level of impurities added by this process to the target metal starting material (e.g., natNi and enriched Ni isotopes) in comparison to the trace metal analysis of supplied starting material are limited to:
In certain embodiments of the provided methods of preparing the plating solution, the maximum level of impurities tolerated by this process to the target metal (e.g., natZn and xxZn isotopes) starting material (refer to trace metal analysis of supplied starting material) are one or more of the following:
In certain embodiments, the electroplating occurs at a current of 100 to 380 μA. In certain embodiments, the electroplating occurs at a current of 100 to 360 μA, of 100 to 340 μA, of 100 to 320 μA, of 100 to 300 μA, of 100 to 280 μA, of 100 to 260 μA, of 100 to 240 μA, of 100 to 220 μA, of 100 to 210 μA, of 100 to 200 μA, of 100 to 180 μA, of 100 to 170 μA, of 100 to 160 μA, of 120 to 380 μA, of 140 to 380 μA, of 160 to 380 μA, of 180 to 380 μA, of 200 to 380 μA, of 220 to 380 μA, of 240 to 380 μA, of 260 to 380 μA, of 280 to 380 μA, of 300 to 380 μA, of 320 to 380 μA, of 120 to 350 μA, of 120 to 320 μA, of 120 to 300 μA, of 120 to 280 μA, of 120 to 260 μA, of 120 to 240 μA, of 120 to 220 μA, of 120 to 200 μA. In certain embodiments, the electroplating occurs at a current of 120 to 180 μA, of 130 to 170 μA, of 140 to 170 μA, of 150 to 170 μA. In certain embodiments, the electroplating occurs at a current of 155 to 165 μA. In certain embodiments, the electroplating occurs at a current of 140, 145, 150, 155, 160, 165, 170, 175, or 180 μA. In certain embodiments, the electroplating occurs at a current of 140 μA. In certain embodiments, the electroplating occurs at a current of 145 μA. In certain embodiments, the electroplating occurs at a current of 150 μA. In certain embodiments, the electroplating occurs at a current of 155 μA. In certain embodiments, the electroplating occurs at a current of 160 μA. In certain embodiments, the electroplating occurs at a current of 165 μA. In certain embodiments, the electroplating occurs at a current of 170 μA. In certain embodiments, the electroplating occurs at a current of 175 μA. In certain embodiments, the electroplating occurs at a current of 180 μA. Unless indicated otherwise, the tolerance of any provided current value is f 0.3 μA.
In certain embodiments, the electroplating occurs at a voltage of 2.5-6.5 V. In certain embodiments, the electroplating occurs at a voltage of 3.5-6 V. In certain embodiments, the electroplating occurs at a voltage of 3.25, 3.50, 3.75, 4.0, 4.25, 4.50, 4.75, 5.0, 5.25, 5.50, 5.75, or 6 V, or within a range defined by any two of these values. For example, the electroplating occurs at a voltage of 4.25-5.25 V or from 4.5-5.5 V. In certain embodiments, the electroplating occurs at a voltage of 5.5 V. Unless indicated otherwise, the tolerance of any provided voltage value is ±0.2 V.
In certain embodiments, the electroplating occurs at a temperature of 15-30° C. In certain embodiments, the electroplating occurs at a temperature of 20-25° C. Unless indicated otherwise, the tolerance of any provided temperature value is ±0.5° C.
In certain embodiments, the electroplating occurs in a cycle time of ≤5 hours. In certain embodiments, the electroplating occurs in a cycle time of ≤4 hours. In certain embodiments, the electroplating occurs in a cycle time of ≤3 hours. In certain embodiments, the electroplating occurs in a cycle time of ≤2 hours. In certain embodiments, the electroplating occurs in a cycle time of ≤90 minutes. In these embodiments a cycle can comprise plating a single coin, two coins, three coins or more in a batch process.
In certain embodiments, the electroplating occurs under one or more conditions selected from: a voltage of 3.5-5.5 V; temperature of 20-25° C.; and a cycle time of ≤3 hours. In certain embodiments, the electroplating occurs under two or more conditions selected from: a voltage of 3.5-5.5 V; temperature of 20-25° C.; and a cycle time of ≤3 hours. In certain embodiments, the electroplating occurs under all three conditions selected from: a voltage of 3.5-5.5 V; temperature of 20-25° C.; and a cycle time of ≤3 hours.
In certain embodiments, the electroplating occurs with a plating solution volume of 30, 25, 20, 15, 12, 10, 7, or 5 mL or less, in particular 10 mL or less.
In certain embodiments, the electroplating occurs in an electrolytic cell comprising a fixed anode. In certain embodiments, the anode is selected from a graphite anode and a platinum anode. In certain embodiments, the anode is 99.999% trace metal free by weight. In certain embodiments, the anode is a platinum anode. In certain embodiments, the platinum anode is in the form of a wire or foil.
An aspect of the disclosure provided herein is the provision of a method of making a high-purity radionuclide composition. The method comprises: irradiation of the target metal of the coin in a particle accelerator according to the present disclosure to produce an irradiated target coating; and isolation of the produced high-purity radionuclide composition.
In certain embodiments, the coin comprises a high-purity Nb backing as described herein. In further embodiments, the coin comprises a target coating prepared as described herein.
An overview of a production process for preparing a copper radionuclide xCu (e.g., 60Cu, 61Cu, 62Cu, or 64Cu) is given below:
In certain embodiments of the method of producing high-purity radionuclides, isolating comprises dissolving the irradiated target coating in aqueous HCl solution to obtain a radionuclide chloride solution, such as a [xCu]CuCl2 aqueous solution. In certain of these embodiments, the aqueous HCl solution is a 10 M HCl solution.
Highly pure compositions comprising positron emitting isotopes of copper suitable for medical use, e.g., in diagnostic imaging or through a Positron Emission Tomography (PET) scan, such as 60Cu, 61Cu, 62Cu, and 64Cu, can be produced by the deuteron or proton bombardment of a coin prepared according to the present disclosure (e.g., highly pure Nb backing with a target coating comprising stable nickel or zinc isotopes) through a particle accelerator. Certain embodiments of the nuclear reactions and corresponding production routes possible using a small hospital cyclotron are as listed in Table 1 below:
60Cu
60Ni(p,n)60Cu
61Cu
60Ni(d,n)61Cu
61Ni(p,n)61Cu
64Zn(p,α)61Cu
62Cu
62Ni(p,n)62Cu
64Cu
64Ni(p,n)64Cu
68Zn(p,αn)64Cu
67Cu
68Zn(p,2p)67Cu
70Zn(p,α)67Cu
In various of these embodiments, the radionuclide is a Cu radionuclide. In certain embodiments, the radionuclide is 61Cu. In certain embodiments, the radionuclide is prepared according to natNi(d,n)61Cu. In certain embodiments, the radionuclide is prepared according to 60Ni(d,n)61Cu. In certain embodiments, the radionuclide is prepared according to 61Ni(p,n)61Cu.
In certain embodiments, the radionuclide is 64Cu. In certain embodiments, the radionuclide is prepared according to 64Ni(p,n)64Cu.
In certain embodiments, the radionuclide is 67Cu. In certain embodiments, the radionuclide is prepared according to 68Zn(p,2p)67Cu or 70Zn(p,α)67Cu.
4.4.1.1 Bombardment Time
In certain embodiments of the method of producing high-purity radionuclides, the irradiation occurs for one half-life of the radionuclide. In certain of these embodiments, the irradiation is from 60-220 minutes. In certain embodiments, the irradiation is from 30-200 minutes. In certain embodiments, the irradiation is from 50-180 minutes. In certain embodiments, the irradiation is from 60-180 minutes. In certain embodiments, the irradiation is from 80-180 minutes. In certain embodiments, the irradiation is from 90-180 minutes. In certain embodiments, the irradiation is from 100-180 minutes. In certain embodiments, the irradiation is from 110-180 minutes. In certain embodiments, the irradiation is from 120-180 minutes. In certain embodiments, the irradiation is from 30-160 minutes. In certain embodiments, the irradiation is from 30-140 minutes. In certain embodiments, the irradiation is from 30-120 minutes. In certain embodiments, the irradiation is from 30-110 minutes. In certain embodiments, the irradiation is from 30-100 minutes. In certain embodiments, the irradiation is from 30-90 minutes. In certain embodiments, the irradiation is from 30-80 minutes. In certain embodiments, the irradiation is from 30-70 minutes. In certain embodiments, the irradiation is from 30-60 minutes. In certain embodiments, the irradiation is 30, 45, 60, 75, 90, 105, 120, 135, 150, or 165 minutes. In certain embodiments, the irradiation is 30 minutes. In certain embodiments, the irradiation is 45 minutes. In certain embodiments, the irradiation is 60 minutes. In certain embodiments, the irradiation is 30 minutes. In certain embodiments, the irradiation is 75 minutes. In certain embodiments, the irradiation is 90 minutes. In certain embodiments, the irradiation is 105 minutes. In certain embodiments, the irradiation is 120 minutes. In certain embodiments, the irradiation is 135 minutes. In certain embodiments, the irradiation is 150 minutes. In certain embodiments, the irradiation is 165 minutes. In certain embodiments, the irradiation is 200 minutes. In certain embodiments, the irradiation is 220 minutes.
4.4.1.2 Bombardment Particles
In certain embodiments of the method of producing high-purity radionuclides, irradiation comprises: bombarding the target metal with protons, deuterons, or alpha particles. In certain embodiments, the bombardment beam is selected from protons, deuterons, alpha particles, and photons. In certain embodiments, the bombardment beam is selected from protons, deuterons, electrons, and photons. In certain embodiments, the bombardment beam is selected from protons and deuterons. In certain embodiments, the bombardment beam is selected from protons and deuterons. In certain embodiments, the bombardment beam comprises deuterons. In certain embodiments, the bombardment beam comprises protons. In certain embodiments, the bombardment beam comprises alpha particles. In certain embodiments, the bombardment beam comprises photons.
4.4.1.3 Deuteron Bombardment Energy
In certain embodiments of the method of producing high-purity radionuclides, the target metal is bombarded with deuterons having a beam energy≤9, 3-9, or 8-9 MeV. In certain embodiments, the beam energy is 1-10 MeV, 3-9 MeV, 5-9 MeV, 6-9 MeV, 7-9 MeV, 8-9 MeV, 8.1 MeV, 8.2 MeV, 8.3 MeV, 8.4 MeV, 8.5 MeV, 8.6 MeV, 8.7 MeV, 8.8 MeV, or 8.9 MeV.
4.4.1.4 Deuteron Bombardment Current
In certain embodiments of producing high-purity radionuclides, the target metal is bombarded with deuterons with beam current≤100 μA, e.g., 10-100 μA, 10-60 μA, 10-50 μA, 20-60 μA, 30-60 μA, 40-60 μA, 20-50 μA, 30-50 μA, 35-50 μA, 40-60 μA, 40-55 μA, 40-50 μA, or 40-45 μA.
In certain of these embodiments, the target metal comprises natNi, 60Ni, or 61Ni. In these embodiments, the high-purity radionuclide composition comprises 61Cu.
In certain embodiments of the method of producing high-purity radionuclides, the target metal is bombarded with deuterons having one or both of a beam energy≤9 MeV and/or a beam current≤100 μA.
4.4.1.5 Proton Bombardment Energy
In certain embodiments, the target metal is bombarded with protons having a beam energy of 7-20 MeV, e.g., 7-18 MeV, 7-16 MeV, 7-14 MeV, 7-12 MeV, 7-10 MeV, 8-18 MeV, 9-18 MeV, 10-18 MeV, 11-18 MeV, 12-18 MeV, 13-18 MeV, 8-16 MeV, 9-15 MeV, 10-14 MeV, 11-14 MeV, 12-14 MeV, 13-14 MeV, 13.1 MeV, 13.2 MeV, 13.3 MeV, 13.4 MeV, 13.5 MeV, 13.6 MeV, 13.7 MeV, 13.8 MeV, or 13.9 MeV.
4.4.1.6 Proton Bombardment Current
In certain embodiments, the target metal is bombarded with protons having a beam current of 10-150 μA, e.g., 10-140 μA, 10-130 μA, 10-120 μA, 10-110 μA, 10-100 μA, 10-90 μA, 10-80 μA, 20-150 μA, 30-150 μA, 50-150 μA, 60-150 μA, 70-150 μA, 80-150 μA, 90-150 μA, 100-150 μA, 110-150 μA, 75 μA, 80 μA, 85 μA, 90 μA, or 100 μA.
In certain of these embodiments, the target metal comprises 61Ni and the radionuclide is a 61Cu radionuclide. In certain of these embodiments, the target metal comprises 60Ni and the radionuclide is a 60Cu radionuclide. In certain of these embodiments, the target metal comprises 64Ni and the radionuclide is a 64Cu radionuclide. In certain of these embodiments, the target metal comprises 64Zn and the radionuclide is a 61Cu radionuclide. In certain of these embodiments, the target metal comprises 68Zn and the radionuclide is a 64Cu radionuclide.
In certain embodiments, the radionuclide is prepared according to natNi(d,n)61Cu.
In certain embodiments, the radionuclide is prepared according to 60Ni(d,n)61Cu.
In certain embodiments, the radionuclide is prepared according to 61Ni(p,n)61Cu.
In certain embodiments, the radionuclide is prepared according to 64Zn(p,α)61Cu.
In certain embodiments, the radionuclide is 64Cu. In certain embodiments, the radionuclide is prepared according to 64Ni(p,n)64Cu, e.g., on a particle accelerator such as a medical cyclotron.
In certain embodiments, the radionuclide is prepared according to 68Zn(p,αn)64Cu.
In certain embodiments, separation and purification of the high-purity radionuclide (for example, as a [xCu]CuCl2 aqueous solution) is accomplished using a cassette-based FASTlab platform. In certain embodiments, a TBP (tributylphosphate-based) resin is used, e.g., (1 mL) (particle size 50-100 μm; pre-packed, Triskem®). In certain embodiments, a weakly basic resin is used, e.g., (tertiary amine; TK201) (2 mL) (particle size 50-100 μm; pre-packed, Triskem®). In certain embodiments, the resin is pre-conditioned with H2O (7 mL) and HCl (10M, 7 mL). In certain embodiments, cassette reagent vials were prepared using concentrated HCl (Optima Grade, Fischer Scientific), NaCl (ACS, Fischer Scientific) and/or milli-Q water (Millipore system, 18 MΩ-cm resistivity), e.g., 6M HCl (2×4.2 mL), 5M NaCl in 0.05 M HCl (4.2 mL). In certain embodiments, the obtained 61Cu was then purified with two subsequent ion exchange resins in a FASTlab synthesis unit. In certain embodiments the acid-adjusted dissolution solution (approx. 7 mL) was loaded over both columns in series and directed into a “Ni collection fraction”. In certain embodiments a TBP resin is implemented as a guard column as it quantitatively retained Fe3+ ions, while the Cu2+ and Co2+ complexes were quantitatively retained on the tertiary amine (TK201) resin. In certain embodiments, both columns are used and washed with 6M HCl (4 mL) to maximize Ni recovery for future recycling. In certain embodiments, the TK201 column was washed with HCl, e.g., 4.5M (5.5 mL) to elute most cobalt salts into the waste stream. In certain embodiments, the TK201 column is washed with HCl, e.g., 5M NaCl in 0.05M (4 mL) to decrease residual acid on the resin and further remove any residual cobalt salts. In certain embodiments, the TK201 column was washed with HCl, e.g., of 0.05M (3 mL) to quantitatively elute the [61Cu]CuCl2.
In a further aspect of the present disclosure is the provision of a radionuclide composition, e.g., of [61Cu]CuCl2. In various embodiments, a radionuclide composition is produced by the bombardment of a target metal by subatomic particles, e.g., irradiated with protons, deuterons, electrons, or alpha particles, particularly protons or deuterons.
In certain embodiments, the radionuclide composition is in the form of an aqueous solution, e.g., an aqueous solution that comprises a radionuclide in a salt, such as [61Cu]CuCl2. In certain embodiments, a radioactive composition is dissolved in a HCl solution.
In various embodiments, the radionuclide composition is in the form of a lyophilized halide salt. In various embodiments, the radionuclide composition is in the form of a lyophilized chloride salt.
The term “radionuclidic purity” refers to the ratio of the radionuclide, expressed as a percentage of total radioactivity content of a radionuclide containing composition. As reported herein, unless otherwise specified, radionuclidic purity is determined by high resolution gamma spectroscopy (e.g., high-purity germanium (HPGe) detector) on a sample after expiration, e.g. >8 hours or >3 weeks) and is then extrapolated (e.g., using the TENDLE-2019 database according to procedures well known in the art), and reported herein as the value at the end of synthesis (EoB+2 hours) of the radionuclide.
Radionuclidic purity at “end of synthesis” or “EoS” refers to a measurement at the time the final radionuclide composition is obtained, e.g., after dissolution and optional purification. Unless otherwise stated, EoS is EoB plus 90 minutes.
Various methods for purifying produced copper radioisotopes are known to those of skill in the art, see for example, INTERNATIONAL ATOMIC ENERGY AGENCY, Production of Emerging Radionuclides towards Theranostic Applications: copper-61, Scandium-43 and -44, and Yttrium-86, IAEA-TECDOC-1955, IAEA, Vienna (2021) and the references cited therein. For example, trialkylphosphate and ion exchange-based purification schemes relevant to Cu, such as either 61Cu or 64Cu purification, are generally applicable.
In various embodiments, the radionuclide composition has a radionuclidic purity at end of synthesis (EoB plus 90 minutes) of ≥95.0%. In certain embodiments, the high-purity composition comprises a 6xCu radionuclide, e.g., 61Cu, 64Cu, or 67Cu. In certain embodiments, the high-purity composition comprises 64Cu, for example, for use as a diagnostic agent. In other embodiments, the high-purity composition comprises 67Cu for use as a therapeutic agent. In certain embodiments, the high-purity composition comprises 61Cu, for example, for use in radiolabeling a radiotracer for medical use, such as in diagnostic imaging.
In various embodiments, the high-purity composition comprises 61Cu and has a radionuclidic purity at end of synthesis of ≥97.0%.
In certain embodiments, the radionuclide composition, e.g., a high-purity radionuclide, comprising 61Cu, 64Cu, or 67Cu, particularly 61Cu, is characterized by one or more of the following purity requirements:
Considering radiocobalt impurities, the 64Ni(p,α) reaction produces 61Co (t½=1.649 h), with other radiocobalt impurities (e.g., 55Co, etc.) arising largely from the small quantities of other (A≠64) Ni isotopes in the isotopically enriched starting material. In the context of 61Cu, however, among other reactions on other Ni isotopes, the dominant 61Ni(p,α) and 60Ni(d,α) reactions will give rise to long lived 58Co (t½=70.86 d) producing 0.05% and 0.11% of 58Co relative activity compared with 61Cu, respectively. As such, efficient purification of the radionuclide composition from radiocobalt by-products may prove to be even more important in the context of 61Cu purification. In considering QC of 61Cu, Section 2.6 of the IAEA Radioisotopes and Radiopharmaceuticals Reports No. 1 [INTERNATIONAL ATOMIC ENERGY AGENCY, Cyclotron produced radionuclides: Emerging positron emitters for medical applications: 64Cu and 124I, Radioisotopes and Radiopharmaceuticals Reports 1, IAEA, Vienna (2016) 63, incorporated herein in its entirety] presents in great detail on 64Cu radionuclidic purity, and apparent molar activity.
In certain embodiments, the high-purity radionuclide composition is produced via the deuteron irradiation of natural nickel or 60Ni, or via the proton irradiation of 61Ni, wherein the composition comprises one or more of the following:
In certain embodiments, the high-purity radionuclide composition is produced via the deuteron irradiation of natural nickel or 60Ni, or via the proton irradiation of 61Ni, wherein the composition comprises two or more of the following:
In certain embodiments, the high-purity radionuclide composition is produced via the deuteron irradiation of natural nickel or 60Ni, or via the proton irradiation of 61Ni, wherein the radionuclide is not a Cu radionuclide and the composition comprises one or more of the following:
The term “chemical purity,” as used herein, is understood to represent the molar percent of the identified or desired radionuclide to all metals in the sample. The radionuclide compositions prepared by the disclosed methods herein exhibit high chemical purity, which facilitates the production of radiopharmaceuticals with high radiochemical purity.
Radiochemical purity, as understood herein, is the ratio or percent of radioactivity from the desired radionuclide in the radiopharmaceutical to the total radioactivity of the sample that includes the radiopharmaceutical. Non-radioactive isotopes of metals (“cold” metals) will not contribute to the total radioactivity of a sample, but they can compete with the desired radionuclide for inclusion in the radiopharmaceutical, e.g., competing for chelation sites in the radiopharmaceutical.
In certain embodiments, the radionuclide composition according to the present disclosure has a chemical purity of ≥99.0% by mole. In certain embodiments, the radionuclide composition is prepared according to the methods provided herein.
In certain embodiments, the radionuclide composition is an aqueous solution and is characterized by one or more of the following:
In certain embodiments, the radionuclide composition is an aqueous solution and is characterized by comprising Fe≤2 mg/L. In some embodiments, the radionuclide composition is an aqueous solution characterized by comprising Fe≤2 mg/L, ≤1.9 mg/L, ≤1.8 mg/L, ≤1.7 mg/L, ≤1.6 mg/L, ≤1.5 mg/L, ≤1.4 mg/L, ≤1.3 mg/L, ≤1.2 mg/L, ≤1.1 mg/L, ≤1 mg/L, ≤0.9 mg/L, ≤0.8 mg/L, ≤0.7 mg/L, ≤0.6 mg/L, ≤0.5 mg/L, ≤0.4 mg/L, ≤0.3 mg/L, ≤0.2 mg/L, or ≤0.1 mg/L.
In certain embodiments, the radionuclide composition is an aqueous solution and is characterized by the sum of 69Cu and 65Cu≤1 mg/L. In certain embodiments, the radionuclide composition is an aqueous solution and is characterized by the sum of 69Cu and 65Cu≤1 mg/L, ≤1 mg/L, ≤0.9 mg/L, ≤0.8 mg/L, ≤0.7 mg/L, ≤0.6 mg/L, ≤0.5 mg/L, ≤0.4 mg/L, ≤0.3 mg/L, ≤0.2 mg/L, ≤0.1 mg/L≤0.09 mg/L, ≤0.08 mg/L, ≤0.07 mg/L, ≤0.06 mg/L, ≤0.05 mg/L, ≤0.04 mg/L, ≤0.03 mg/L, ≤0.02 mg/L, or ≤0.01 mg/L.
In certain embodiments, the radionuclide composition is an aqueous solution and is characterized by comprising Ni≤1 mg/L, ≤1 mg/L, ≤0.9 mg/L, ≤0.8 mg/L, ≤0.7 mg/L, ≤0.6 mg/L, ≤0.5 mg/L, ≤0.4 mg/L, ≤0.3 mg/L, ≤0.2 mg/L, ≤0.1 mg/L≤0.09 mg/L, ≤0.08 mg/L, ≤0.07 mg/L, ≤0.06 mg/L, ≤0.05 mg/L, ≤0.04 mg/L, ≤0.03 mg/L, ≤0.02 mg/L, or ≤0.01 mg/L.
In certain embodiments, the radionuclide composition is an aqueous solution and is characterized by comprising Zn≤2 mg/L, ≤1.9 mg/L, ≤1.8 mg/L, ≤1.7 mg/L, ≤1.6 mg/L, ≤1.5 mg/L, ≤1.4 mg/L, ≤1.3 mg/L, ≤1.2 mg/L, ≤1.1 mg/L, ≤1 mg/L, ≤0.9 mg/L, ≤0.8 mg/L, ≤0.7 mg/L, ≤0.6 mg/L, ≤0.5 mg/L, ≤0.4 mg/L, ≤0.3 mg/L, ≤0.2 mg/L, or ≤0.1 mg/L.
In certain embodiments, the radionuclide composition is an aqueous solution and is characterized by comprising Sn≤0.1 mg/L, ≤0.09 mg/L, ≤0.08 mg/L, ≤0.07 mg/L, ≤0.06 mg/L, ≤0.05 mg/L, ≤0.04 mg/L, ≤0.03 mg/L, ≤0.02 mg/L, ≤0.01 mg/L, ≤0.009 mg/L, ≤0.008 mg/L, ≤0.007 mg/L, ≤0.006 mg/L, ≤0.005 mg/L, ≤0.004 mg/L, ≤0.003 mg/L, ≤0.002 mg/L, or ≤0.001 mg/L.
In certain embodiments, the radionuclide composition is an aqueous solution and is characterized by comprising Ti≤0.1 mg/L, ≤0.09 mg/L, ≤0.08 mg/L, ≤0.07 mg/L, ≤0.06 mg/L, ≤0.05 mg/L, ≤0.04 mg/L, ≤0.03 mg/L, ≤0.02 mg/L, ≤0.01 mg/L, ≤0.009 mg/L, ≤0.008 mg/L, ≤0.007 mg/L, ≤0.006 mg/L, ≤0.005 mg/L, ≤0.004 mg/L, ≤0.003 mg/L, ≤0.002 mg/L, or ≤0.001 mg/L.
In certain embodiments, the radionuclide composition is an aqueous solution and is characterized by comprising Al 2 mg/L, ≤1.9 mg/L, ≤1.8 mg/L, ≤1.7 mg/L, ≤1.6 mg/L, ≤1.5 mg/L, ≤1.4 mg/L, ≤1.3 mg/L, ≤1.2 mg/L, ≤1.1 mg/L, ≤1 mg/L, ≤0.9 mg/L, ≤0.8 mg/L, ≤0.7 mg/L, ≤0.6 mg/L, ≤0.5 mg/L, ≤0.4 mg/L, ≤0.3 mg/L, ≤0.2 mg/L, or ≤0.1 mg/L.
In certain embodiments, the radionuclide composition is an aqueous solution and is characterized by comprising As≤1 mg/L, ≤0.9 mg/L, ≤0.8 mg/L, ≤0.7 mg/L, ≤0.6 mg/L, ≤0.5 mg/L, ≤0.4 mg/L, ≤0.3 mg/L, ≤0.2 mg/L, ≤0.1 mg/L≤0.09 mg/L, ≤0.08 mg/L, ≤0.07 mg/L, ≤0.06 mg/L, ≤0.05 mg/L, ≤0.04 mg/L, ≤0.03 mg/L, ≤0.02 mg/L, ≤0.01 mg/L, ≤0.009 mg/L, ≤0.008 mg/L, ≤0.007 mg/L, ≤0.006 mg/L, ≤0.005 mg/L, ≤0.004 mg/L, ≤0.003 mg/L, ≤0.002 mg/L, or ≤0.001 mg/L.
In certain embodiments, the radionuclide composition is an aqueous solution and is characterized by comprising Cr≤0.1 mg/L≤0.09 mg/L, ≤0.08 mg/L, ≤0.07 mg/L, ≤0.06 mg/L, ≤0.05 mg/L, ≤0.04 mg/L, ≤0.03 mg/L, ≤0.02 mg/L, ≤0.01 mg/L, ≤0.009 mg/L, ≤0.008 mg/L, ≤0.007 mg/L, ≤0.006 mg/L, ≤0.005 mg/L, ≤0.004 mg/L, ≤0.003 mg/L, ≤0.002 mg/L, or ≤0.001 mg/L.
In certain embodiments, the radionuclide composition is an aqueous solution and is characterized by comprising Cd≤0.1 mg/L≤0.09 mg/L, ≤0.08 mg/L, ≤0.07 mg/L, ≤0.06 mg/L, ≤0.05 mg/L, ≤0.04 mg/L, ≤0.03 mg/L, ≤0.02 mg/L, ≤0.01 mg/L, ≤0.009 mg/L, ≤0.008 mg/L, ≤0.007 mg/L, ≤0.006 mg/L, ≤0.005 mg/L, ≤0.004 mg/L, ≤0.003 mg/L, ≤0.002 mg/L, or ≤0.001 mg/L.
In certain embodiments, the radionuclide composition is an aqueous solution and is characterized by comprising Co≤0.1 mg/L≤0.09 mg/L, ≤0.08 mg/L, ≤0.07 mg/L, ≤0.06 mg/L, ≤0.05 mg/L, ≤0.04 mg/L, ≤0.03 mg/L, ≤0.02 mg/L, ≤0.01 mg/L, ≤0.009 mg/L, ≤0.008 mg/L, ≤0.007 mg/L, ≤0.006 mg/L, ≤0.005 mg/L, ≤0.004 mg/L, ≤0.003 mg/L, ≤0.002 mg/L, or ≤0.001 mg/L.
In certain embodiments, the radionuclide composition is an aqueous solution and is characterized by comprising Y≤0.1 mg/L≤0.09 mg/L, ≤0.08 mg/L, ≤0.07 mg/L, ≤0.06 mg/L, ≤0.05 mg/L, ≤0.04 mg/L, ≤0.03 mg/L, ≤0.02 mg/L, ≤0.01 mg/L, ≤0.009 mg/L, ≤0.008 mg/L, ≤0.007 mg/L, ≤0.006 mg/L, ≤0.005 mg/L, ≤0.004 mg/L, ≤0.003 mg/L, ≤0.002 mg/L, or ≤0.001 mg/L.
In certain embodiments, trace metal analysis is conducted by ICP-MS, e.g., >3 weeks.
In certain embodiments, the sum of impurities in the radionuclide composition is ≤15 μg/GBq.
In certain embodiments, the radionuclide composition is characterized by Cu≤1.5 μg/GBq, e.g., ≤1.0 μg/GBq; or ≤0.5 μg/GBq.
In certain embodiments, the radionuclide composition is characterized by Al≤3.0 μg/GBq, e.g., ≤2.5 μg/GBq; or ≤2 μg/GBq.
In certain embodiments, the radionuclide composition is characterized by Co≤2 μg/GBq, e.g., ≤1.5 μg/GBq; or ≤1 μg/GBq.
In certain embodiments, the radionuclide composition is characterized by Fe≤4 μg/GBq, e.g., ≤3.5 μg/GBq; or ≤3 μg/GBq.
In certain embodiments, the radionuclide composition is characterized by Pb≤3 μg/GBq, e.g., ≤2.5 μg/GBq; or ≤2 μg/GBq.
In certain embodiments, the radionuclide composition is characterized by Ni≤3 μg/GBq, e.g., ≤2.50 μg/GBq; or ≤2 μg/GBq.
In certain embodiments, the radionuclide composition is characterized by Zn≤2 μg/GBq, e.g., ≤1.5 μg/GBq; or ≤1 μg/GBq.
Highly pure radiocopper compositions comprising 60Cu, 61Cu, 62Cu, 64Cu, or 67Cu are produced through the deuteron, proton, electron, or alpha particle bombardment of a coin prepared as described herein. In certain embodiments, the coin comprises a highly pure Nb backing, a target metal (e.g., a nickel isotope or a mixture thereof, or a zinc isotope, or mixture thereof) through a particle accelerator such as a cyclotron as described herein.
In certain embodiments, a high-purity copper radionuclide composition is obtained according to any one of the target metals, isotope enrichment levels, and incident beam energy described in in Table 1 below; wherein the irradiation occurs in a cyclotron (e.g., a medical cyclotron).
Radionuclidic solutions provided by the methods and materials described herein are characterized according to various properties and attributes. In some embodiments, for example, activity concentration can be determined by a dose calibrator; pH value can be determined by pH paper; radiochemical purity can be determined by radio thin-layer chromatography; radionuclidic purity and/or identity can be determined by gamma spectrometry; and chemical purity can be determined by inductively couple plasma mass spectrometry (ICP-MS). Among the non-limiting characterization profiles of radionuclidic and radiochemical compositions of the present disclosure, high-purity [61Cu]CuCl2 may be measured according to some of the properties below.
In certain embodiments, composition comprising a radioactive copper salt (e.g., [61Cu]CuCl2) as provided herein is characterized by a color or mixture of colors. In certain embodiments, a radioactive copper salt aqueous solution (e.g., [61Cu]CuCl2) is the color blue. In certain embodiments, a radioactive copper salt aqueous solution (e.g., [61Cu]CuCl2) is the color green. In certain embodiments, a radioactive copper salt aqueous solution (e.g., [61Cu]CuCl2) is the color turquoise. In certain embodiments, a radioactive copper salt aqueous solution (e.g., [61Cu]CuCl2) is colorless.
In certain embodiments, the radionuclide composition as described herein, is further characterized by one or more of: an activity concentration of 0.01-23.33 GBq/mL at calibration; a molar activity of 10-580 MBq/nmol at calibration; and an activity at end of synthesis of >500 MBq. An embodiment, as described above, further characterized by one or more of: an activity concentration of >25 MBq/mL at calibration, a molar activity of 10-580 MBq/nmol at calibration, and an activity at the end of synthesis of >150 MBq.
In certain embodiments, a radionuclide composition comprises a [61Cu]CuCl2 activity at end of synthesis of ≥500 MBq, ≥490 MBq, ≥480 MBq, ≥470 MBq, ≥460 MBq, ≥450 MBq, ≥440 MBq, ≥430 MBq, ≥420 MBq, ≥410 MBq, ≥400 MBq, ≥390 MBq, ≥380 MBq, ≥370 MBq, ≥360 MBq, ≥350 MBq, ≥340 MBq, ≥330 MBq, ≥320 MBq, ≥310 MBq, ≥300 MBq, ≥290 MBq, ≥280 MBq, ≥270 MBq, ≥260 MBq, ≥250 MBq, ≥240 MBq, ≥230 MBq, ≥220 MBq, ≥210 MBq, ≥200 MBq, ≥190 MBq, ≥180 MBq, ≥170 MBq, ≥160 MBq, ≥150 MBq, ≥140 MBq, ≥130 MBq, ≥120 MBq, ≥110 MBq, ≥100 MBq, ≥90 MBq, ≥80 MBq, ≥70 MBq, ≥60 MBq, ≥50 MBq, ≥40 MBq, ≥30 MBq, ≥20 MBq, or ≥10 MBq.
In certain embodiments, a radionuclide composition comprises a [61Cu]CuCl2 activity at end of synthesis of >500 MBq.
In certain embodiments, a radionuclide composition comprises a [61Cu]CuCl2 activity at end of synthesis of >150 MBq.
4.6.2.1 Activity Concentration
In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by an activity concentration of 50-400 MBq/mL, 55-395 MBq/mL, 60-390 MBq/mL, 65-385 MBq/mL, 70-380 MBq/mL, 75-375 MBq/mL, 80-370 MBq/mL, 85-365 MBq/mL, 90-360 MBq/mL, 95-355 MBq/mL, 100-350 MBq/mL, 105-345 MBq/mL, 110-340 MBq/mL, 115-335 MBq/mL, 120-330 MBq/mL, 125-325 MBq/mL, 130-320 MBq/mL, 135-315 MBq/mL, 140-310 MBq/mL, 145-305 MBq/mL, 150-300 MBq/mL, 155-295 MBq/mL, 160-290 MBq/mL, 165-285 MBq/mL, 170-280 MBq/mL, 175-275 MBq/mL, 180-270 MBq/mL, 185-265 MBq/mL, 190-260 MBq/mL, 195-255 MBq/mL, 200-250 MBq/mL, 205-245 MBq/mL, 210-240 MBq/mL, 215-235 MBq/mL, or 220-230 MBq/mL.
In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by an activity concentration of ≥400 MBq/mL, ≥395 MBq/mL, ≥390 MBq/mL, ≥385 MBq/mL, ≥380 MBq/mL, ≥375 MBq/mL, ≥370 MBq/mL, ≥365 MBq/mL, ≥360 MBq/mL, ≥355 MBq/mL, ≥350 MBq/mL, ≥345 MBq/mL, ≥340 MBq/mL, ≥335 MBq/mL, ≥330 MBq/mL, ≥325 MBq/mL, ≥320 MBq/mL, ≥315 MBq/mL, ≥310 MBq/mL, ≥305 MBq/mL, ≥300 MBq/mL, ≥295 MBq/mL, ≥290 MBq/mL, ≥285 MBq/mL, ≥280 MBq/mL, ≥275 MBq/mL, ≥270 MBq/mL, ≥265 MBq/mL, ≥260 MBq/mL, ≥255 MBq/mL, ≥250 MBq/mL, ≥245 MBq/mL, ≥240 MBq/mL, ≥235 MBq/mL, ≥230 MBq/mL, ≥225 MBq/mL, ≥220 MBq/mL, ≥215 MBq/mL, ≥210 MBq/mL, ≥205 MBq/mL, ≥200 MBq/mL, ≥195 MBq/mL, ≥190 MBq/mL, ≥185 MBq/mL, ≥180 MBq/mL, ≥175 MBq/mL, ≥170 MBq/mL, ≥165 MBq/mL, ≥160 MBq/mL, ≥155 MBq/mL, ≥150 MBq/mL, ≥145 MBq/mL, ≥140 MBq/mL, ≥135 MBq/mL, ≥130 MBq/mL, ≥125 MBq/mL, ≥120 MBq/mL, ≥115 MBq/mL, ≥110 MBq/mL, ≥105 MBq/mL, ≥100 MBq/mL, ≥95 MBq/mL, ≥90 MBq/mL, ≥85 MBq/mL, ≥80 MBq/mL, ≥75 MBq/mL, ≥70 MBq/mL, 65 MBq/mL, ≥60 MBq/mL, ≥55 MBq/mL, ≥50 MBq/mL, ≥45 MBq/mL, or ≥40 MBq/mL.
In certain embodiments, a radionuclide composition comprises a [61Cu]CuCl2 activity concentration at calibration of ≥30 MBq/mL, ≥29 MBq/mL, ≥28 MBq/mL, ≥27 MBq/mL, ≥26 MBq/mL, ≥25 MBq/mL, ≥24 MBq/mL, ≥23 MBq/mL, ≥22 MBq/mL, ≥21 MBq/mL, ≥20 MBq/mL, ≥19 MBq/mL, ≥18 MBq/mL, 17 MBq/mL, ≥16 MBq/mL, 15 MBq/mL, ≥14 MBq/mL, ≥13 MBq/mL, ≥12 MBq/mL, ≥11 MBq/mL, ≥10 MBq/mL, 9 MBq/mL, ≥8 MBq/mL, ≥7 MBq/mL, ≥6 MBq/mL, ≥5 MBq/mL, ≥4 MBq/mL, ≥3 MBq/mL, ≥2 MBq/mL, or ≥1 MBq/mL.
In certain embodiments, a radionuclide composition comprises a [61Cu]CuCl2 activity concentration at calibration of 0.01-25 GBq/mL.
In certain embodiments, a radionuclide composition comprises a [61Cu]CuCl2 activity concentration at calibration of 0.01-30 GBq/mL, 0.50-29.50 GBq/mL, 1-29 GBq/mL, 1.50-28.50 GBq/mL, 2-28 GBq/mL, 2.50-27.50 GBq/mL, 3-27 GBq/mL, 3.50-26.50 GBq/mL, 4-26 GBq/mL, 4.50-25.50 GBq/mL, 5-25 GBq/mL, 5.50-24.50 GBq/mL, 6-24 GBq/mL, 6.50-23.50 GBq/mL, 7-23 GBq/mL, 7.50-22.50 GBq/mL, 8-22 GBq/mL, 8.50-21.50 GBq/mL, 9-21 GBq/mL, 9.50-20.50 GBq/mL, 10-20 GBq/mL, 10.50-19.50 GBq/mL, 11-19 GBq/mL, 11.50-18.50 GBq/mL, 12-18 GBq/mL, 12.50-17.50 GBq/mL, 13-17 GBq/mL, 13.50-16.50 GBq/mL, 14-16 GBq/mL, or 14.50-15.50 GBq/mL.
In certain embodiments, a radionuclide composition comprises a [61Cu]CuCl2 activity concentration at calibration of 0.01-3 GBq/mL, 0.05-2.95 GBq/mL, 0.10-2.90 GBq/mL, 0.15-2.85 GBq/mL, 0.20-2.80 GBq/mL, 0.25-2.75 GBq/mL, 0.30-2.70 GBq/mL, 0.35-2.65 GBq/mL, 0.40-2.60 GBq/mL, 0.45-2.55 GBq/mL, 0.50-2.50 GBq/mL, 0.55-2.45 GBq/mL, 0.60-2.40 GBq/mL, 0.65-2.35 GBq/mL, 0.70-2.30 GBq/mL, 0.75-2.25 GBq/mL, 0.80-2.20 GBq/mL, 0.85-2.15 GBq/mL, 0.90-2.10 GBq/mL, 0.95-2.05 GBq/mL, 1-2 GBq/mL, 1.05-1.95 GBq/mL, 1.10-1.90 GBq/mL, 1.15-1.85 GBq/mL, 1.20-1.80 GBq/mL, 1.25-1.75 GBq/mL, 1.30-1.70 GBq/mL, 1.35-1.65 GBq/mL, 1.40-1.60 GBq/mL, or 1.45-1.55 GBq/mL.
In certain embodiments, a radionuclide composition comprises a [61Cu]CuCl2 activity concentration at calibration of 0.25-0.50 GBq/mL, 0.50-0.75 GBq/mL, 0.75-1 GBq/mL, 1-1.25 GBq/mL, 1.25-1.50 GBq/mL, 1.50-1.75 GBq/mL, 1.75-2 GBq/mL, 2-2.25 GBq/mL, 2.25-2.50 GBq/mL, 2.50-2.75 GBq/mL, 2.75-3 GBq/mL, 3-3.25 GBq/mL, 3.25-3.50 GBq/mL, 3.50-3.75 GBq/mL, 3.75-4 GBq/mL, 4-4.25 GBq/mL, 4.25-4.50 GBq/mL, 4.50-4.75 GBq/mL, 4.75-5 GBq/mL, 5-5.25 GBq/mL, 5.25-5.50 GBq/mL, 5.50-5.75 GBq/mL, 5.75-6 GBq/mL, 6-6.25 GBq/mL, 6.25-6.50 GBq/mL, 6.50-6.75 GBq/mL, 6.75-7 GBq/mL, 7-7.25 GBq/mL, 7.25-7.50 GBq/mL, 7.50-7.75 GBq/mL, 7.75-8 GBq/mL, 8-8.25 GBq/mL, 8.25-8.50 GBq/mL, 8.50-8.75 GBq/mL, 8.75-9 GBq/mL, 9-9.25 GBq/mL, 9.25-9.50 GBq/mL, 9.50-9.75 GBq/mL, 9.75-10 GBq/mL, 10-10.25 GBq/mL, 10.25-10.50 GBq/mL, 10.50-10.75 GBq/mL, 10.75-11 GBq/mL, 11-11.25 GBq/mL, 11.25-11.50 GBq/mL, 11.50-11.75 GBq/mL, 11.75-12 GBq/mL, 12-12.25 GBq/mL, 12.25-12.50 GBq/mL, 12.50-12.75 GBq/mL, 12.75-13 GBq/mL, 13-13.25 GBq/mL, 13.25-13.50 GBq/mL, 13.50-13.75 GBq/mL, 13.75-14 GBq/mL, 14-14.25 GBq/mL, 14.25-14.50 GBq/mL, 14.50-14.75 GBq/mL, 14.75-15 GBq/mL, 15-15.25 GBq/mL, 15.25-15.50 GBq/mL, 15.50-15.75 GBq/mL, 15.75-16 GBq/mL, 16-16.25 GBq/mL, 16.25-16.50 GBq/mL, 16.50-16.75 GBq/mL, 16.75-17 GBq/mL, 17-17.25 GBq/mL, 17.25-17.50 GBq/mL, 17.50-17.75 GBq/mL, 17.75-18 GBq/mL, 18-18.25 GBq/mL, 18.25-18.50 GBq/mL, 18.50-18.75 GBq/mL, 18.75-19 GBq/mL, 19-19.25 GBq/mL, 19.25-19.50 GBq/mL, 19.50-19.75 GBq/mL, 19.75-20 GBq/mL, 20-20.25 GBq/mL, 20.25-20.50 GBq/mL, 20.50-20.75 GBq/mL, 20.75-21 GBq/mL, 21-21.25 GBq/mL, 21.25-21.50 GBq/mL, 21.50-21.75 GBq/mL, 21.75-22 GBq/mL, 22-22.25 GBq/mL, 22.25-22.50 GBq/mL, 22.50-22.75 GBq/mL, 22.75-23 GBq/mL, 23-23.25 GBq/mL, 23.25-23.50 GBq/mL, 23.50-23.75 GBq/mL, 23.75-24 GBq/mL, 24-24.25 GBq/mL, 24.25-24.50 GBq/mL, 24.50-24.75 GBq/mL, or 24.75-25 GBq/mL.
4.6.2.2 Molar Activity
In certain embodiments, a composition according to the present disclosure is characterized by a [61Cu]CuCl2 molar activity concentration at calibration of 10-600 MBq/nmol, 25-600 GBq/nmol, 50-600 GBq/nmol, 75-600 GBq/nmol, 100-600 GBq/nmol, 125-600 GBq/nmol, 150-600 GBq/nmol, 175-600 GBq/nmol, 200-600 GBq/nmol, 225-600 GBq/nmol, 250-600 GBq/nmol, 275-600 GBq/nmol, 300-600 GBq/nmol, 325-600 GBq/nmol, 350-600 GBq/nmol, 375-600 GBq/nmol, 400-600 GBq/nmol, 425-600 GBq/nmol, 450-600 GBq/nmol, 475-600 GBq/nmol, 500-600 GBq/nmol, 525-600 GBq/nmol, 550-600 GBq/nmol, or 575-600 GBq/nmol.
In certain embodiments, a composition according to the present disclosure is characterized by a [61Cu]CuCl2 molar activity concentration at calibration of 10-25 GBq/nmol, 10-50 GBq/nmol, 10-75 GBq/nmol, 10-100 GBq/nmol, 10-125 GBq/nmol, 10-150 GBq/nmol, 10-175 GBq/nmol, 10-200 GBq/nmol, 10-225 GBq/nmol, 10-250 GBq/nmol, 10-275 GBq/nmol, 10-300 GBq/nmol, 10-325 GBq/nmol, 10-350 GBq/nmol, 10-375 GBq/nmol, 10-400 GBq/nmol, 10-425 GBq/nmol, 10-450 GBq/nmol, 10-475 GBq/nmol, 10-500 GBq/nmol, 10-525 GBq/nmol, 10-550 GBq/nmol, 10-575 GBq/nmol, 25-600 GBq/nmol, 50-575 GBq/nmol, 75-550 GBq/nmol, 100-525 GBq/nmol, 125-500 GBq/nmol, 150-475 GBq/nmol, 175-450 GBq/nmol, 200-425 GBq/nmol, 225-400 GBq/nmol, 250-375 GBq/nmol, 275-350 GBq/nmol, or 300-325 GBq/nmol.
In certain embodiments, a composition according to the present disclosure is characterized by a [61Cu]CuCl2 molar activity concentration at calibration of 10-150 MBq/nmol, 20-150 MBq/nmol, 30-150 MBq/nmol, 40-150 MBq/nmol, 50-150 MBq/nmol, 60-150 MBq/nmol, 70-150 MBq/nmol, 80-150 MBq/nmol, 90-150 MBq/nmol, 100-150 MBq/nmol, 110-150 MBq/nmol, 120-150 MBq/nmol, 130-150 MBq/nmol, 140-150 MBq/nmol, 10-140 MBq/nmol, 10-130 MBq/nmol, 10-120 MBq/nmol, 10-110 MBq/nmol, 10-100 MBq/nmol, 10-90 MBq/nmol, 10-80 MBq/nmol, 10-70 MBq/nmol, 10-60 MBq/nmol, 10-50 MBq/nmol, 10-40 MBq/nmol, 10-30 MBq/nmol, 10-20 MBq/nmol, 10-80 MBq/nmol, 20-90 MBq/nmol, 30-100 MBq/nmol, 40-110 MBq/nmol, 50-120 MBq/nmol, 60-130 MBq/nmol, or 70-140 MBq/nmol.
In certain embodiments, a radionuclide composition comprises a [61Cu]CuCl2 molar activity concentration at calibration of 10-150 MBq/nmol.
In certain embodiments, composition comprising [61Cu]CuCl2 as provided herein is characterized by a pH of 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.5, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68, 1.69, or 1.7.
In certain embodiments, the pH of a [61Cu]CuCl2 solution is 1-1.6. In certain embodiments, the pH is 1.05-1.55, 1.10-1.45, 1.15-1.35, 1.20-1.25.
In certain embodiments, the pH of a [61Cu]CuCl2 solution is from 0.11 to 1.7, 0.12 to 1.69, 0.13 to 1.68, 0.14 to 1.67, 0.15 to 1.66, 0.16 to 1.65, 0.17 to 1.64, 0.18 to 1.63, 0.19 to 1.62, 0.2 to 1.61, 0.21 to 1.6, 0.22 to 1.59, 0.23 to 1.58, 0.24 to 1.57, 0.25 to 1.56, 0.26 to 1.55, 0.27 to 1.54, 0.28 to 1.53, 0.29 to 1.52, 0.3 to 1.51, 0.31 to 1.5, 0.32 to 1.49, 0.33 to 1.48, 0.34 to 1.47, 0.35 to 1.46, 0.36 to 1.45, 0.37 to 1.44, 0.38 to 1.43, 0.39 to 1.42, 0.4 to 1.41, 0.41 to 1.4, 0.42 to 1.39, 0.43 to 1.38, 0.44 to 1.37, 0.45 to 1.36, 0.46 to 1.35, 0.47 to 1.34, 0.48 to 1.33, 0.49 to 1.32, 0.5 to 1.31, 0.51 to 1.3, 0.52 to 1.29, 0.53 to 1.28, 0.54 to 1.27, 0.55 to 1.26, 0.56 to 1.25, 0.57 to 1.24, 0.58 to 1.23, 0.59 to 1.22, 0.6 to 1.21, 0.61 to 1.2, 0.62 to 1.19, 0.63 to 1.18, 0.64 to 1.17, 0.65 to 1.16, 0.66 to 1.15, 0.67 to 1.14, 0.68 to 1.13, 0.69 to 1.12, 0.7 to 1.11, 0.71 to 1.1, 0.72 to 1.09, 0.73 to 1.08, 0.74 to 1.07, 0.75 to 1.06, 0.76 to 1.05, 0.77 to 1.04, 0.78 to 1.03, 0.79 to 1.02, 0.8 to 1.01, 0.81 to 1, 0.82 to 0.99, 0.83 to 0.98, or 0.84 to 0.97.
In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by a radionuclidic purity of ≥99.99%, ≥99.98%, ≥99.97%, ≥99.96%, ≥99.95%, ≥99.94%, ≥99.93%, ≥99.92%, ≥99.91%, ≥99.90%, ≥99.89%, ≥99.88%, ≥99.87%, ≥99.86%, ≥99.85%, ≥99.84%, ≥99.83%, ≥99.82%, ≥99.81%, ≥99.80%, ≥99.79%, ≥99.78%, ≥99.77%, ≥99.76%, ≥99.75%, ≥99.74%, ≥99.73%, ≥99.72%, ≥99.71%, ≥99.70%, ≥99.69%, ≥99.68%, ≥99.67%, ≥99.66%, ≥99.65%, ≥99.64%, ≥99.63%, ≥99.62%, ≥99.61%, ≥99.60%, ≥99.59%, ≥99.58%, ≥99.57%, ≥99.56%, ≥99.55%, ≥99.54%, ≥99.53%, ≥99.52%, ≥99.51%, ≥99.50%, ≥99.49%, ≥99.48%, ≥99.47%, ≥99.46%, ≥99.45%, ≥99.44%, ≥99.43%, ≥99.42%, ≥99.41%, ≥99.40%, ≥99.39%, ≥99.38%, ≥99.37%, ≥99.36%, ≥99.35%, ≥99.34%, ≥99.33%, ≥99.32%, ≥99.31%, ≥99.30%, ≥99.29%, ≥99.28%, ≥99.27%, ≥99.26%, ≥99.25%, ≥99.24%, ≥99.23%, ≥99.22%, ≥99.21%, ≥99.20%, ≥99.19%, ≥99.18%, ≥99.17%, ≥99.16%, ≥99.15%, ≥99.14%, ≥99.13%, ≥99.12%, ≥99.11%, ≥99.10%, ≥99.09%, ≥99.08%, ≥99.07%, ≥99.06%, ≥99.05%, ≥99.04%, ≥99.03%, ≥99.02%, ≥99.01%, ≥99.00%, ≥98.99%, ≥98.98%, ≥98.97%, ≥98.96%, ≥98.95%, ≥98.94%, ≥98.93%, ≥98.92%, ≥98.91%, ≥98.90%, ≥98.89%, ≥98.88%, ≥98.87%, ≥98.86%, ≥98.85%, ≥98.84%, ≥98.83%, ≥98.82%, ≥98.81%, ≥98.80%, ≥98.79%, ≥98.78%, ≥98.77%, ≥98.76%, ≥98.75%, ≥98.74%, ≥98.73%, ≥98.72%, ≥98.71%, ≥98.70%, ≥98.69%, ≥98.68%, ≥98.67%, ≥98.66%, ≥98.65%, ≥98.64%, ≥98.63%, ≥98.62%, ≥98.61%, ≥98.60%, ≥98.59%, ≥98.58%, ≥98.57%, ≥98.56%, ≥98.55%, ≥98.54%, ≥98.53%, ≥98.52%, ≥98.51%, ≥98.50%, ≥98.49%, ≥98.48%, ≥98.47%, ≥98.46%, ≥98.45%, ≥98.44%, ≥98.43%, ≥98.42%, ≥98.41%, ≥98.40%, ≥98.39%, ≥98.38%, ≥98.37%, ≥98.36%, ≥98.35%, ≥98.34%, ≥98.33%, ≥98.32%, ≥98.31%, ≥98.30%, ≥98.29%, ≥98.28%, ≥98.27%, ≥98.26%, ≥98.25%, ≥98.24%, ≥98.23%, ≥98.22%, ≥98.21%, ≥98.20%, ≥98.19%, ≥98.18%, ≥98.17%, ≥98.16%, ≥98.15%, ≥98.14%, ≥98.13%, ≥98.12%, ≥98.11%, ≥98.10%, ≥98.09%, ≥98.08%, ≥98.07%, ≥98.06%, ≥98.05%, ≥98.04%, ≥98.03%, ≥98.02%, ≥98.01%, ≥98.00%, ≥97.99%, ≥97.98%, ≥97.97%, ≥97.96%, ≥97.95%, ≥97.94%, ≥97.93%, ≥97.92%, ≥97.91%, ≥97.90%, ≥97.89%, ≥97.88%, ≥97.87%, ≥97.86%, ≥97.85%, ≥97.84%, ≥97.83%, ≥97.82%, ≥97.81%, ≥97.80%, ≥97.79%, ≥97.78%, ≥97.77%, ≥97.76%, ≥97.75%, ≥97.74%, ≥97.73%, ≥97.72%, ≥97.71%, ≥97.70%, ≥97.69%, ≥97.68%, ≥97.67%, ≥97.66%, ≥97.65%, ≥97.64%, ≥97.63%, ≥97.62%, ≥97.61%, ≥97.60%, ≥97.59%, ≥97.58%, ≥97.57%, ≥97.56%, ≥97.55%, ≥97.54%, ≥97.53%, ≥97.52%, ≥97.51%, ≥97.50%, ≥97.49%, ≥97.48%, ≥97.47%, ≥97.46%, ≥97.45%, ≥97.44%, ≥97.43%, ≥97.42%, ≥97.41%, ≥97.40%, ≥97.39%, ≥97.38%, ≥97.37%, ≥97.36%, ≥97.35%, ≥97.34%, ≥97.33%, ≥97.32%, ≥97.31%, ≥97.30%, ≥97.29%, ≥97.28%, ≥97.27%, ≥97.26%, ≥97.25%, ≥97.24%, ≥97.23%, ≥97.22%, ≥97.21%, ≥97.20%, ≥97.19%, ≥97.18%, ≥97.17%, ≥97.16%, ≥97.15%, ≥97.14%, ≥97.13%, ≥97.12%, ≥97.11%, ≥97.10%, ≥97.09%, ≥97.08%, ≥97.07%, ≥97.06%, ≥97.05%, ≥97.04%, ≥97.03%, ≥97.02%, ≥97.01%, or ≥97%.
In certain embodiments of a method of producing high-purity radionuclides as provided herein, comprising the step of isolating a desired radionuclide the method further comprises the step of purifying a radionuclide salt solution to decrease amounts of chemical impurities. In certain of these embodiments, purifying includes anion/cation exchange chromatography. In certain embodiments, purifying comprises alkyl phosphate resin chromatography. In certain embodiments, purifying comprises weak cation exchange chromatography. In certain embodiments, purifying comprises decreasing the specific activity (e.g., in Bq/g) of certain radionuclides below a certain threshold.
4.6.5.1 Cobalt Isotopes—56Co, 57Co, 58Co, and 60Co
In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by aa 56Co specific activity of ≤1500 Bq/g, ≤1450 Bq/g, ≤1400 Bq/g, ≤1350 Bq/g, ≤1300 Bq/g, ≤1250 Bq/g, ≤1200 Bq/g, ≤1150 Bq/g, ≤1100 Bq/g, ≤1050 Bq/g, ≤1000 Bq/g, ≤950 Bq/g, ≤900 Bq/g, ≤850 Bq/g, ≤800 Bq/g, ≤750 Bq/g, ≤700 Bq/g, ≤650 Bq/g, ≤600 Bq/g, ≤550 Bq/g, ≤500 Bq/g, ≤450 Bq/g, ≤400 Bq/g, ≤350 Bq/g, ≤300 Bq/g, ≤250 Bq/g, ≤200 Bq/g, ≤150 Bq/g, ≤100 Bq/g, or ≤50 Bq/g.
In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by a 57Co specific activity of ≤100 Bq/g, ≤95 Bq/g, ≤90 Bq/g, ≤85 Bq/g, ≤80 Bq/g, ≤75 Bq/g, ≤70 Bq/g, ≤65 Bq/g, ≤60 Bq/g, ≤55 Bq/g, ≤50 Bq/g, ≤45 Bq/g, ≤40 Bq/g, ≤35 Bq/g, ≤30 Bq/g, ≤25 Bq/g, ≤20 Bq/g, ≤15 Bq/g, ≤10 Bq/g, ≤5 Bq/g, ≤4.6 Bq/g, ≤4.5 Bq/g, ≤4.4 Bq/g, ≤4.3 Bq/g, ≤4.2 Bq/g, ≤4.1 Bq/g, ≤4 Bq/g, ≤3.9 Bq/g, ≤3.8 Bq/g, ≤3.7 Bq/g, ≤3.6 Bq/g, ≤3.5 Bq/g, ≤3.4 Bq/g, ≤3.3 Bq/g, ≤3.2 Bq/g, ≤3.1 Bq/g, ≤3 Bq/g, ≤2.9 Bq/g, ≤2.8 Bq/g, ≤2.7 Bq/g, ≤2.6 Bq/g, ≤2.5 Bq/g, ≤2.4 Bq/g, ≤2.3 Bq/g, ≤2.2 Bq/g, ≤2.1 Bq/g, ≤2 Bq/g, ≤1.9 Bq/g, ≤1.8 Bq/g, ≤1.7 Bq/g, ≤1.6 Bq/g, ≤1.5 Bq/g, ≤1.4 Bq/g, ≤1.3 Bq/g, ≤1.2 Bq/g, ≤1.1 Bq/g, ≤1 Bq/g, ≤0.9 Bq/g, ≤0.8 Bq/g, ≤0.7 Bq/g, ≤0.6 Bq/g, ≤0.5 Bq/g, ≤0.4 Bq/g, ≤0.3 Bq/g, ≤0.2 Bq/g, or ≤0.1 Bq/g.
In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by a 58Co specific activity of ≤1500 Bq/g, ≤1450 Bq/g, ≤1400 Bq/g, ≤1350 Bq/g, ≤1300 Bq/g, ≤1250 Bq/g, ≤1200 Bq/g, ≤1150 Bq/g, ≤1100 Bq/g, ≤1050 Bq/g, ≤1000 Bq/g, ≤950 Bq/g, ≤900 Bq/g, ≤850 Bq/g, ≤800 Bq/g, ≤750 Bq/g, ≤700 Bq/g, ≤650 Bq/g, ≤600 Bq/g, ≤575 Bq/g, ≤550 Bq/g, ≤525 Bq/g, ≤500 Bq/g, ≤475 Bq/g, ≤450 Bq/g, ≤425 Bq/g, ≤400 Bq/g, ≤375 Bq/g, ≤350 Bq/g, ≤325 Bq/g, ≤300 Bq/g, ≤275 Bq/g, ≤250 Bq/g, ≤225 Bq/g, ≤200 Bq/g, ≤175 Bq/g, ≤150 Bq/g, ≤125 Bq/g, ≤100 Bq/g, ≤75 Bq/g, ≤50 Bq/g, or ≤25 Bq/g.
In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by a 60Co specific activity of ≤15 Bq/g, ≤14 Bq/g, ≤13 Bq/g, ≤12 Bq/g, ≤11 Bq/g, ≤10 Bq/g, ≤9 Bq/g, ≤8 Bq/g, ≤7 Bq/g, ≤6 Bq/g, ≤5 Bq/g, ≤4 Bq/g, ≤3 Bq/g, ≤2.9 Bq/g, ≤2.8 Bq/g, ≤2.7 Bq/g, ≤2.6 Bq/g, ≤2.5 Bq/g, ≤2.4 Bq/g, ≤2.3 Bq/g, ≤2.2 Bq/g, ≤2.1 Bq/g, ≤2 Bq/g, ≤1.9 Bq/g, ≤1.8 Bq/g, ≤1.7 Bq/g, ≤1.6 Bq/g, ≤1.5 Bq/g, ≤1.4 Bq/g, ≤1.3 Bq/g, ≤1.2 Bq/g, ≤1.1 Bq/g, ≤1 Bq/g, ≤0.9 Bq/g, ≤0.8 Bq/g, ≤0.7 Bq/g, ≤0.6 Bq/g, ≤0.5 Bq/g, ≤0.4 Bq/g, ≤0.3 Bq/g, ≤0.2 Bq/g, or ≤0.1 Bq/g.
In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by a 108mAg specific activity of ≤2 Bq/g, ≤1.9 Bq/g, ≤1.8 Bq/g, ≤1.7 Bq/g, ≤1.6 Bq/g, ≤1.5 Bq/g, ≤1.4 Bq/g, ≤1.3 Bq/g, ≤1.2 Bq/g, ≤1.1 Bq/g, ≤1 Bq/g, ≤0.9 Bq/g, ≤0.8 Bq/g, ≤0.7 Bq/g, ≤0.6 Bq/g, ≤0.5 Bq/g, ≤0.4 Bq/g, ≤0.3 Bq/g, ≤0.2 Bq/g, ≤0.1 Bq/g.
In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by a 110mAg specific activity of ≤5 Bq/g, ≤4.9 Bq/g, ≤4.8 Bq/g, ≤4.7 Bq/g, ≤4.6 Bq/g, ≤4.5 Bq/g, ≤4.4 Bq/g, ≤4.3 Bq/g, ≤4.2 Bq/g, ≤4.1 Bq/g, ≤4 Bq/g, ≤3.9 Bq/g, ≤3.8 Bq/g, ≤3.7 Bq/g, ≤3.6 Bq/g, ≤3.5 Bq/g, ≤3.4 Bq/g, ≤3.3 Bq/g, ≤3.2 Bq/g, ≤3.1 Bq/g, ≤3 Bq/g, ≤2.9 Bq/g, ≤2.8 Bq/g, ≤2.7 Bq/g, ≤2.6 Bq/g, ≤2.5 Bq/g, ≤2.4 Bq/g, ≤2.3 Bq/g, ≤2.2 Bq/g, ≤2.1 Bq/g, ≤2 Bq/g, ≤1.9 Bq/g, ≤1.8 Bq/g, ≤1.7 Bq/g, ≤1.6 Bq/g, ≤1.5 Bq/g, ≤1.4 Bq/g, ≤1.3 Bq/g, ≤1.2 Bq/g, ≤1.1 Bq/g, ≤1 Bq/g, ≤0.9 Bq/g, ≤0.8 Bq/g, ≤0.7 Bq/g, ≤0.6 Bq/g, ≤0.5 Bq/g, ≤0.4 Bq/g, ≤0.3 Bq/g, ≤0.2 Bq/g, or ≤0.1 Bq/g.
In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by a 109Cd specific activity of ≤15 Bq/g, ≤14 Bq/g, ≤13 Bq/g, ≤12 Bq/g, ≤11 Bq/g, ≤10 Bq/g, ≤9 Bq/g, ≤8 Bq/g, ≤7 Bq/g, ≤6 Bq/g, ≤5 Bq/g, ≤4 Bq/g, ≤3 Bq/g, ≤2 Bq/g, or ≤1 Bq/g.
In certain embodiments, the presence and/or quantity of 61Cu is characterized by γ-photons. In certain embodiments, 61CU is characterized by γ-photons with energy peak at: 511±20 keV. In certain embodiments, 61CU is characterized by γ-photons with energy peak at: 511±20 keV and 283 keV 20 keV. In certain embodiments, 61Cu is characterized by 7-photons with energy peak at: 511±20 keV, 283 keV±20 keV, and 656 keV±20 keV. In certain embodiments, 61Cu is characterized by γ-photons with energy peak at: 511±20 keV (eventually sum peak at 1022 keV±20 keV), 283 keV±20 keV and 656 keV±20 keV.
In certain embodiments, 61Cu can be characterized by other chemical impurities. In certain embodiments, non-radioactive (cold) elements are present in a [61Cu]CuCl2 solution. In certain embodiments, cold elements are present and quantified by ICP-MS (inductively coupled plasma mass spectrometry). In some embodiments, 61Cu is a transmutation product provided by methods described in the present disclosure. In some embodiments, transmutation of a target metal (e.g., natNi, 60Ni, or 61Ni) provides 61Cu in varying levels of radiochemical purity.
4.6.7.1 Aluminum
In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by comprising aluminum (e.g., non-radioactive) in an amount ≤2 ng/MBq, ≤1.9 ng/MBq, ≤1.8 ng/MBq, ≤1.7 ng/MBq, ≤1.6 ng/MBq, ≤1.5 ng/MBq, ≤1.4 ng/MBq, ≤1.3 ng/MBq, ≤1.2 ng/MBq, ≤1.1 ng/MBq, ≤1 ng/MBq, ≤0.9 ng/MBq, ≤0.8 ng/MBq, ≤0.7 ng/MBq, ≤0.6 ng/MBq, ≤0.5 ng/MBq, ≤0.4 ng/MBq, ≤0.3 ng/MBq, ≤0.2 ng/MBq, or ≤0.1 ng/MBq.
4.6.7.2 Cobalt
In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by comprising cobalt (e.g., non-radioactive) in an amount ≤2 ng/MBq, ≤1.9 ng/MBq, ≤1.8 ng/MBq, ≤1.7 ng/MBq, ≤1.6 ng/MBq, ≤1.5 ng/MBq, ≤1.4 ng/MBq, ≤1.3 ng/MBq, ≤1.2 ng/MBq, ≤1.1 ng/MBq, ≤1 ng/MBq, ≤0.9 ng/MBq, ≤0.8 ng/MBq, ≤0.7 ng/MBq, ≤0.6 ng/MBq, ≤0.5 ng/MBq, ≤0.4 ng/MBq, ≤0.3 ng/MBq, ≤0.2 ng/MBq, or ≤0.1 ng/MBq.
4.6.7.3 Copper
In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by comprising copper (e.g., non-radioactive) in an amount ≤2 ng/MBq, ≤1.9 ng/MBq, ≤1.8 ng/MBq, ≤1.7 ng/MBq, ≤1.6 ng/MBq, ≤1.5 ng/MBq, ≤1.4 ng/MBq, ≤1.3 ng/MBq, ≤1.2 ng/MBq, ≤1.1 ng/MBq, ≤1 ng/MBq, ≤0.9 ng/MBq, ≤0.8 ng/MBq, ≤0.7 ng/MBq, ≤0.6 ng/MBq, ≤0.5 ng/MBq, ≤0.4 ng/MBq, ≤0.3 ng/MBq, ≤0.2 ng/MBq, or ≤0.1 ng/MBq.
4.6.7.4 Iron
In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by comprising iron (e.g., non-radioactive) in an amount ≤3 ng/MBq, ≤2.9 ng/MBq, ≤2.8 ng/MBq, ≤2.7 ng/MBq, ≤2.6 ng/MBq, ≤2.5 ng/MBq, ≤2.4 ng/MBq, ≤2.3 ng/MBq, ≤2.2 ng/MBq, ≤2.1 ng/MBq, ≤2 ng/MBq, ≤1.9 ng/MBq, ≤1.8 ng/MBq, ≤1.7 ng/MBq, ≤1.6 ng/MBq, ≤1.5 ng/MBq, ≤1.4 ng/MBq, ≤1.3 ng/MBq, ≤1.2 ng/MBq, ≤1.1 ng/MBq, ≤1 ng/MBq, ≤0.9 ng/MBq, ≤0.8 ng/MBq, ≤0.7 ng/MBq, ≤0.6 ng/MBq, ≤0.5 ng/MBq, ≤0.4 ng/MBq, ≤0.3 ng/MBq, ≤0.2 ng/MBq, or ≤0.1 ng/MBq.
4.6.7.5 Lead
In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by comprising lead (e.g., non-radioactive) in an amount ≤2 ng/MBq, ≤1.9 ng/MBq, ≤1.8 ng/MBq, ≤1.7 ng/MBq, ≤1.6 ng/MBq, ≤1.5 ng/MBq, ≤1.4 ng/MBq, ≤1.3 ng/MBq, ≤1.2 ng/MBq, ≤1.1 ng/MBq, ≤1 ng/MBq, ≤0.9 ng/MBq, ≤0.8 ng/MBq, ≤0.7 ng/MBq, ≤0.6 ng/MBq, ≤0.5 ng/MBq, ≤0.4 ng/MBq, ≤0.3 ng/MBq, ≤0.2 ng/MBq, or ≤0.1 ng/MBq.
4.6.7.6 Nickel
In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by comprising nickel (e.g., non-radioactive) in an amount ≤4.5 ng/MBq, ≤4.4 ng/MBq, ≤4.3 ng/MBq, ≤4.2 ng/MBq, ≤4.1 ng/MBq, ≤4 ng/MBq, ≤3.9 ng/MBq, ≤3.8 ng/MBq, ≤3.7 ng/MBq, ≤3.6 ng/MBq, ≤3.5 ng/MBq, ≤3.4 ng/MBq, ≤3.3 ng/MBq, ≤3.2 ng/MBq, ≤3.1 ng/MBq, ≤3 ng/MBq, ≤2.9 ng/MBq, ≤2.8 ng/MBq, ≤2.7 ng/MBq, ≤2.6 ng/MBq, ≤2.5 ng/MBq, ≤2.4 ng/MBq, ≤2.3 ng/MBq, ≤2.2 ng/MBq, ≤2.1 ng/MBq, ≤2 ng/MBq, ≤1.9 ng/MBq, ≤1.8 ng/MBq, ≤1.7 ng/MBq, ≤1.6 ng/MBq, ≤1.5 ng/MBq, ≤1.4 ng/MBq, ≤1.3 ng/MBq, ≤1.2 ng/MBq, ≤1.1 ng/MBq, ≤1 ng/MBq, ≤0.9 ng/MBq, ≤0.8 ng/MBq, ≤0.7 ng/MBq, ≤0.6 ng/MBq, ≤0.5 ng/MBq, ≤0.4 ng/MBq, ≤0.3 ng/MBq, ≤0.2 ng/MBq, or ≤0.1 ng/MBq.
4.6.7.7 Zinc
In certain embodiments, a composition comprising [61Cu]CuCl2 as provided herein is characterized by comprising zinc (e.g., non-radioactive) in an amount ≤2 ng/MBq, ≤1.9 ng/MBq, ≤1.8 ng/MBq, ≤1.7 ng/MBq, ≤1.6 ng/MBq, ≤1.5 ng/MBq, ≤1.4 ng/MBq, ≤1.3 ng/MBq, ≤1.2 ng/MBq, ≤1.1 ng/MBq, ≤1 ng/MBq, ≤0.9 ng/MBq, ≤0.8 ng/MBq, ≤0.7 ng/MBq, ≤0.6 ng/MBq, ≤0.5 ng/MBq, ≤0.4 ng/MBq, ≤0.3 ng/MBq, ≤0.2 ng/MBq, or ≤0.1 ng/MBq.
Aspects of the present disclosure are directed to a rapid electroplating method in a basic medium for producing coins to be used in particle accelerator-based radionuclide production. Examples of raw material to be irradiated using the provided method typically pertain to the isotopes of nickel and zinc electroplated on niobium, a relatively inert backing material.
Aspects of the present disclosure provide technology that enables the production of highly pure radionuclides in an aqueous chloride form (e.g., [61Cu]CuCl2) to be used as a precursor in radiopharmaceuticals. The production of the highly pure radionuclide composition starts with irradiating a target coating comprising a target metal (e.g., natural or enriched nickel or zinc isotopes) through a particle accelerator, e.g., a medical cyclotron, to produce an irradiated target coating, i.e., a radionuclide. The purity of the target metal and coin backing is one aspect that allows the production of a high-quality radionuclide composition in terms of radionuclidic and chemical purity. The present disclosure provides a process using superior quality target metal and backing available at relatively low cost and large quantities for industrial radionuclide production and enables the production of coin manufacturing in much less time than methods in present use.
Aspects of the coin preparation method of the present disclosure provide significant improvements to the current coin plating methods currently found in the literature. For example, embodiments of the presently disclosed method rely on nitric acid to dissolve a target metal source material for electroplating, which stands in contrast to known electroplating methods employed in literature, which require hydrochloric and sulfuric acids. In the current literature, additional chemical constituents are used during plating solution preparation, such as cyanide or bromide, that act as buffers which pose health hazards for the operator during the chemical process and are not suitable for use with radiopharmaceuticals. Provided are methods of production that do not rely on such constituents and, thus, allow the negation of these risk factors.
In addition, aspects of the present disclosure introduce the concept of an electrolytic bath or plating solution with a significantly higher pH (e.g., 9.9-10.8) (e.g., prepared by dissolving the target metal in nitric acid, and then using a buffer based on ammonium chloride/hydroxide solution) that unexpectedly overcomes challenges in producing high quality, highly adhesive, electroplated target metal and enables coin production in a much shorter period of time. Reliance on the disclosed basic plating solution significantly differs from typical protocols, which rely on acidic or mildly basic solutions to plate target coatings for coin production. Below is a table obtained from IAEA RADIOISOTOPES AND RADIOPHARMACEUTICALS, REPORTS, No. 1, (INTERNATIONAL ATOMIC ENERGY AGENCY, Cyclotron produced radionuclides: Emerging positron emitters for medical applications: 64Cu and 124I, Radioisotopes and Radiopharmaceuticals Reports 1, IAEA, Vienna (2016) 63—“IAEA report”) indicating the electroplating conditions for nickel electroplating procedures.
The higher pH of the presently disclosed methods is achieved through the addition of NH4OH which shifts the anode-cathode to a higher potential, reduces the rate of H2 evolution on the cathode, and reduces the cycle time required for a plating procedure from 24 hours to less than 3 hours for a complete plating of, e.g., 100 mg of target metal, while producing a high-quality coating having a more homogenous and uniform porous structure. See
In contrast, mildly basic solutions are predominantly found in the literature, as illustrated in the Table 2, above. Reliance on H2SO4 is also consistentl
y given, as evidenced by the presence of the sulfate counter ion in all basic examples shown in the IAEA Table 3. As an initial matter, a mildly basic solution is used throughout all experiments compared to the more strongly alkaline pH used in the technology described herein. This indicates that current market suppliers are unaware or unable to produce the benefits of increased ammonium content in the plating solution. The present disclosure is the first to report the advantages of increasing ammonia concentration in the plating solution and using a highly basic pH. These advantages appear to be related to the observation that the more homogeneous porosity of the crystal structure of nickel plated onto a backing material suggests that the amount of hydrogen evolution is significantly reduced. Without being bound by theory, this may be attributed to the chemical characteristic state of NH3 and its tendency to bond with protons to form NH4+.
Additionally, the mildly basic pH levels utilized in the prior art methods referenced in Table 2, above restrict the optimal voltage that can be reached during the electroplating process due to a lower NH3 content that influences the possible anode-cathode potential. In comparison, the present method describes a more alkaline plating solution that tolerates a higher anode-cathode potential that allows for a relatively increased optimal voltage. As a result, the electroplating durations can be shortened from an average of 24 hours to <3 hours while yielding similar plated masses.
Prior to the present disclosure, the advantages associated with a Nb were not contemplated in part because it was thought that Nb resulted in poor adhesion. In fact, the implementation of a niobium backing has been expressly disfavored (see, e.g., Table 3 below, reproduced from the IAEA report). The prior art methods require a weaker acid when dissolving the target metal for plating since these methods relied on producing coins for irradiation based on silver, gold, or platinum as their target backing materials. However, these materials cannot withstand the acidic properties of a strong acid such as HNO3 as they will begin to dissolve upon contact. Niobium, on the other hand, is highly resistant to acids at room temperature and allows the utilization of a more aggressive acid such as HNO3. Embodiments of the presently disclosed method allows the use of HNO3 (nitric acid) to produce Ni(NO3)2 in place of the more commonly utilized H2SO4 (sulfuric acid) that produces NiSO4. In contrast to the prevailing wisdom, the present disclosure reveals that good adhesion between Ni target coating and Nb backing is possible, and many unexpected advantages are achieved. For example, the strongly acidic properties of nitric acid allow the raw material to dissolve faster and to a higher concentration than the use of sulfuric acid. With this, the losses of highly expensive isotopically enriched materials can be avoided, thus making the use of enriched targets more economically viable.
Moreover, the dominance of NiSO4 in the IAEA report (and inspection of the related reports) suggests that the nickel-plating solution used was bought as nickel sulfate from a supplier. This factor introduces the possibility of contamination or impurities in the plating solution as it depends on the parameters from sources and suppliers of said chemicals. This difference between 99.9% purity and 99.99% purity plays a major role in the resulting radionuclidic, radiochemical and chemical purity of a radiopharmaceutical that incorporates a radionuclide, where the presence of cold copper, zinc, iron or cadmium is an issue. Furthermore, the possibility of a raw material pre-purification is considered not feasible. All procurement of chemicals and processes pertaining to the electroplating procedures in embodiments of the presently disclosed method are conducted using pure reagent and inert non-metal materials under controlled conditions. This significantly reduces the possibility of contamination from trace metals or other unwanted chemicals detected during the purification process. During the whole process, the use of metal tools and accessories in contact with solutions and raw materials was eliminated. Even in less-than-ideal temperatures and air quality conditions, a procedure of the present disclosure ensures the production of high-quality coins.
The above Table 3 from page 8 of the IAEA report identifies possible backing materials used in cyclotron-produced radioisotopes for medical purposes. It indicates the lack of understood advantages from Nb. This is accompanied by documented data yielding insufficient electroplating qualities due to its poor adhesion. On the contrary, the previously observed poor adhesion when using Nb-backing was not observed upon applying the electroplating methods provided herein. The electrochemical plating process is distinct from plasma coating procedures. Plasma coating alters the grain structure of the backing material through thermal processes, leading to changes in grain structure and high bonding of the plated material to the backing material. However, these changes hinder the effective dissolution in an acidic solution. In certain embodiments, by modifying the surface structure, e.g., by abrasion of the backing material, as disclosed herein, the inert nature and ability of niobium to resist acids at room temperature can be utilized for radioisotope production.
By applying this consensus to the production of radionuclides and the manufacturing of plating solutions under controlled environments (as stated in the section above), a difference in results is obtained from a purification and dissolution standpoint. The data of
As seen, irradiation of Nb backed coins prepared according to the present disclosure demonstrate a 89.3% reduction of radionuclidic impurities when compared with Ni on conventional silver to niobium backings, a 94% reduction of radionuclidic impurities when comparing natNi on conventional silver backings to 61Ni on niobium backings, and a 45.9% reduction of radionuclidic impurities when comparing Ni on niobium backings to 61Ni on niobium backings, when accounting for the sum of total impurities
The described factors affect the radionuclidic and chemical purity of a radionuclide, which impacts the purity of a radiopharmaceutical prepared from the radionuclide described in more detail below:
Trace metals and cold copper compete with 61Cu to bind a chelator (for example, NODAGA) in this order: cold Cu(II) (i.e., stable isotopes)>Zn(II)>Fe(III)>Sn(IV)>Ti(IV)>Al(III.). The competition from these trace metals and cold copper decreases the tracer's radiolabeling yield and radiochemical purity significantly, see Innovative Complexation Strategies for the Introduction of Short-lived PET Isotopes into Radiopharmaceuticals (p. 105). Frequent sources of trace metals are the raw nickel metal powder itself, especially isotopically enriched nickel, reagents, and any metals in instruments used, such as iron. The purification process (ion-exchange columns) removes much of the trace metals except for cold (of particular relevance are stable isotopes 69Cu and 65Cu), which passes through into the product fraction by being the same element as the desired 61Cu. One way of preventing cold copper contamination and the associated reduction in chemical purity is to pass the dissolved nickel raw material (stable isotopes) through the process and separate the cold copper from the nickel before plating (see
Radionuclidic purity is important in radiopharmacy since any radionuclidic impurities introduce uncertainty in the radiation dose received by the patient and may also degrade the quality of any imaging procedure performed. For example, if significant levels of other radionuclides are present, then biological distribution may be altered. Radionuclide samples contain some contaminants arising from the production process or the decay of the primary radioisotope. Radionuclide impurities can occur as a result of the manufacturing process, for example, for nuclides produced by cyclotron there can be contaminants due to impurities in the target or by the energy of the reaction. Impurities in the target coating may be transmuted into many minor elements, multiplying the impurity profile after bombardment. In order to control the effects of these contaminants on the radiation dose received by the patient, limits are set on the maximum levels of contamination allowed. These limits are defined by governmental agencies, e.g., in pharmacopoeia monographs, and vary depending upon the radionuclide concerned and the physical decay characteristics of the likely contaminants. Measurement of radionuclidic purity may be performed high resolution using gamma-ray spectroscopy on samples well after bombardment. The activity of the long-lived isotopes is then extrapolated back to EoB or EoS or even at expiration. High activity emitted from long lived radionuclidic impurities greatly increases the cost and complexity of managing the disposal of all consumables that come into contact with the nuclide composition.
Through the deuteron irradiation of natural nickel and 60Ni, and proton irradiation of 61Ni, long-lived isotopes of cobalt are produced: 56Co, 57Co, 58Co and 60Co. Other long-lived radionuclides such as 110mAg, 108mAg and 109Cd are produced through the irradiation of commonly used silver backing material, which are dissolved along with starting material during the purification process. Due to their long half-lives, the proportion of these radionuclides increases with time compared to the 61Cu, decreasing the radionuclidic purity of the product, especially at later time points when using natNi as a starting material. Though most cobalt isotopes can be separated in the purification process, the 110mAg, 108mAg and 109Cd end up in the 61Cu fraction and nickel solution that is further used in recycling of irradiated target coating. The long-lived radionuclides become problematic when considering the radiation burden to the patient and the accumulation of radioactive waste. Third-party coin manufacturers did not publish the contamination from the non-niobium coin backings (e.g., silver). As provided by the present disclosure, the method of making and using coins comprising niobium represents an advantage, e.g., in view of the radionuclidic and chemical purity of samples produced following subatomic particle bombardment, isolation, and purification. A detailed comparison of the known 61Cu products to 61Cu as provided by the present disclosure is provided below.
With these factors in mind, a niobium backing material was chosen due to its inert nature to acids at room temperature and at elevated temperatures. This characteristic allows the niobium backing material to resist the acid medium used during the dissolution and purification process. By doing so, higher radionuclidic and chemical purity can be achieved in the radiometal aqueous solution, eventually resulting in higher purity for the radiopharmaceutical prepared from the desired 61Cu isotope. Although plating methods of niobium exist, the element has not yet been used for radionuclide production due to the poor adhesion of the plated Ni material (as discussed above). The Ni (or 68Zn for the production of 68Ga) requires sufficient adhesion for the coin to survive thermal loads (1200 W) during irradiation and pneumatic shuttle acceleration at 5 bar to 7 bar of pressure and abrupt stop at the head. On the other hand, however, the plated Ni (or Zn) must dissolve sufficiently during the dissolution and purification process. Attempts were made to plasma-coat niobium backings for plating nickel (Ni). However, this process resulted in losses and incomplete dissolution of Ni from the niobium backing. The thermal processes involved in plasma coating altered the grain structure of the niobium backing material, leading to a strong bond between the plated nickel and niobium. This strong bond made it difficult for the nickel to fully dissolve, causing losses. The plasma coating process itself resulted in very high losses in target coating, rendering the process not viable for use, especially with very expensive highly enriched target metals. The main reference to this summary is the IAEA documentation regarding cyclotron radionuclide production, IAEA RADIOISOTOPES AND RADIOPHARMACEUTICALS, REPORTS, No. 1. (INTERNATIONAL ATOMIC ENERGY AGENCY VIENNA, 2016) Additionally, a monetary evaluation regarding the procurement costs of niobium utilized as a backing material displays a 40% lower cost in comparison to commonly used backing materials such as gold, silver, and platinum where costs range from €80 to €120 per backing material (single coin).
Parallel to this, elements pertaining to the radiochemical purity of the labelling process can be controlled by manufacturing the plating solution under controlled conditions described herein. By procuring the plating solution from a raw base material of, e.g., nickel, the possibility of contamination is now independent from outside sources and suppliers. Such material and equipment used in these cases are inert glass beakers and falcon tubes (ensured to not contain any undesirable substances), TraceSelect pure water, pure reagents (trace-metal grade), inert coin adapter and electrolytic cell (on the electroplating unit), etc. Through this, the contaminants of trace metals can be minimized reduced or avoided all together. This difference between 99.9% purity and 99.99% purity plays a role in the resulting chemical purity of a radionuclide and therefore in the radiochemical purity of a radiopharmaceutical prepared from the radionuclide, where the presence of cold Cu, Zn, Fe, Sn, Ti, or Al or any salt thereof are an issue as they will compete for binding to the chelator in the tracer along with the desired radionuclide (61Cu).
Robustness of plating is tested through a drop and scratch test. This assessment ensures that the electrodeposited substrate on the backing will survive mechanical impacts of the shuttling system and establishes an increased probability of survivability under the cyclotron beam.
In certain embodiments, coins are irradiated with 8.4 MeV deuterons for an average duration of 120 mins at a range of 40 μA to 45 μA or with 13.2 MeV deuterons at 40 μA to 45 μA using an ARTMS or GE shuttling system on a GE PET Trace cyclotron.
In certain embodiments, the coins are irradiated with 8.4 MeV deuterons for an average duration of 120 mins at a range of 40 μA to 45 μA or with 10 μA to 100 μA 13 MeV protons using an ARTMS or GE shuttling system on a GE PET Trace cyclotron.
Dissolution of Ni from the niobium backing is undergone via the utilization of a dissolution system in 10 M HCl. The subsequent 61Cu is then purified with two subsequent ion exchange resins in a FASTlab synthesis unit. The processing time for these purifications can reach up to 60 minutes.
The resulting [61Cu]CuCl2 solution of the plated material has an average activity of 1.7-4.5 GBq. This activity is measured using a dose calibrator and its radionuclidic purity by a calibrated gamma spectrometer e.g., at PSI in Switzerland.
Gamma spectrometry measurements were performed to identify any radionuclidic impurities, particularly long-lived radionuclides. These results indicate an 89.3% and 94% reduction in impurities for nat Ni and 61Ni on niobium backing materials with respect to silver backing materials when utilizing the methods disclosed herein. ICP-MS measurements are performed on the product of cold dissolutions by Labor Veritas in Switzerland to monitor elemental impurities present in the product according to ICH-Q3D. All detected impurities are within regulated ICH-Q3D concentrations (see ICH-Q3D Guidelines, pg 25).
The plating of highly enriched 61Ni is also enabled with the same plating parameters as described above, for a higher yield and industrial production using proton irradiation (typically at 10 μA to 100 μA, 13 MeV protons for 20 minutes to 2 hours and up to one half-life of 61Cu).
Following automated transportation of the irradiated coin from the cyclotron to the hot cell docking station, the capsule was transferred to a QIS dissolution unit with tongs. The transmuted target metal was dissolved from the niobium backing material using 1:1 7M HCl: 30% H2O2 (ultratrace analysis, Merck) (4 mL). The acid-peroxide mixture is circulated, immersing the coin and target metal surface to dissolve all irradiated elements at 2 mL/min for about 23 minutes at about 60° C. When the target metal was fully dissolved, acidic solution containing the dissolved metal was withdrawn and the QIS system was flushed with 10M HCl (3 mL). The combined acidic solutions were then fed forward to the FASTlab purification unit.
5.2.1.1 Preparation of Buffer Solution
Ammonium Chloride (4.6 g, Aldrich: 326372, Trace Select) was weighed into a clean (no metal) Falcon Tube (50 mL), and the previously cleaned magnetic stirring bar was added. 6 mL of Trace Select water (Honeywell 95305) was added in one aliquot to flush walls of the Falcon in case any salt sticks to the Falcon tube walls. 1 mL of ammonium hydroxide 28% (Sigma 338818) was added with a 1000 μL pipette with a respective pipette tip, 8× times. The lid of the Falcon was closed, and the Falcon is, in turns, vortexed (1-2 minutes) (immersion in an ultra-sonic bath was a possible alternative for 1-2 minutes) and shaken, until all salt was dissolved. The Falcon tube can also be warmed (e.g., by rolling between hands) to improve solubility, temperature (e.g., around 23° C., preferably between 23-25° C.). After complete dissolution of the salt, the pH acceptance criteria, pH range 9.28-9.62, needs to be verified by pH measurement of the solution at RT, e.g., with and electronic pH meter. The Falcon tube was closed with parafilm and stored at room temperature. Prior to use, any solid salt formation was redissolved. 5.2.1.2 Preparation of Nickel Nitrate Plating Solution
A 50 mL glass beaker was washed with nitric acid (Trace Select) followed by water (Trace Select). In a fume hood, the beaker was dried by placing it on a heating plate set to 150° C. To the beaker was added 210 mg of natural (isotopic distribution) nickel (powder, Sigma-Aldrich<50 μm, 99.7% trace metals basis, essentially free from any impurities, except iron. The copper impurity amounts to <0.3 ppm.) were weighed into the beaker and 4 mL of 65% nitric acid were added using a pipette. The beaker was placed back on the active heating plate and the stirring was set to 300 rpm. Ensure the ventilation of the fume hood was functioning properly (evolution of NO2). During the dissolution, the solution turns green. The solution was reduced by evaporation to a volume of ≈600 μL and taken from the heating plate to cool down to room temperature. The remaining solution was transferred to a 50 mL metal-free Falcon tube. The glass beaker was rinsed with a total of 2.8 mL of Trace Select water, in steps of 0.8 mL, 1 mL, and 1 mL, where each step was transferred to the Falcon tube before the adding the next washing fraction. Buffer solution (4 mL), 11 mL of Trace Select water, and 3 mL of ammonium hydroxide 28% (Sigma 338818) were added to the Falcon tube. The pH of the solution was measured and adjusted to the required pH by adding ammonium hydroxide 28% (Aldrich 338818) using sterile B-Braun syringes.
5.2.1.3 Examples of Suitable Starting Material to Prepare 60Ni and 61Ni Electroplating Solutions
The following are example lots of 60Ni and 61Ni (certificate as provided by Isoflex, USA, March 2018):
61Ni
61Ni
60Ni
The samples of natural nickel from Sigma-Aldrich were essentially free from any impurities, except iron. The copper impurity amounts to <0.3 ppm. Please see certificate of analysis as described in Example 2. Additional suitable sources of natural Ni include:
5.2.1.4 Preparation of Zinc Nitrate Plating Solution
A 50 mL glass beaker was washed with nitric acid (Trace Select) followed by water (Trace Select). In a fume hood, the beaker was dried by placing it on a heating plate set to 150° C. 210 mg of natural (isotopic distribution) zinc (zinc powder, Sigma-Aldrich<10 μm, >98%) were weighed into the beaker and 4 mL of 65% nitric acid were added using a pipette. The beaker was placed back on the active heating plate and the stirring was set to 300 rpm. Ensure the ventilation of the fume hood was functioning properly (evolution of NO2). During the dissolution, the solution turns green. The solution was reduced by evaporation to a volume of ˜600 μL and taken from the heating plate to cool down to room temperature. The remaining solution was transferred to a 50 mL metal-free Falcon tube. The glass beaker was rinsed with a total of 2.8 mL of Trace Select water, in steps of 0.8 mL, 1 mL, and 1 mL, where each step was transferred to the Falcon tube before the adding the next washing fraction. 4 mL of the buffer solution (prepared in Section 5.2.1.1), 11 mL of Trace Select water, and 3 mL of ammonium hydroxide 28% (Sigma 338818) were added to the Falcon tube. The pH of the solution was measured and adjusted to the required pH by adding ammonium hydroxide 28% (Aldrich 338818) using sterile B-Braun syringes.
Optional Abrasion of the Backing Surface
In certain embodiments, if the target coating was not sufficiently adhered to the backing surface, the Nb backing surface may be surface-treated prior to the process of electroplating to improve adhesion of the target coating. It was found that adhesion results were close to ideal when the backing surface was treated with abrasion prior to electroplating. While not to be bound by theory, one consideration was that oxides were formed on the surface of the Niobium backing, e.g., either through a process during manufacturing, storage or prior use and that the presence of oxides hinders the adhesion of a target metal, e.g., Ni or Zn, to the Nb backing. Another consideration was that the process of removing oxides may impart nucleation sites onto the Nb backing surface that enables adhesion of the target metal deposition.
Implementing particular surface pre-treatments, e.g., those that remove the oxide layer on received backing, sufficient adhesion of the target coating was reliably achieved.
In certain embodiments, niobium backing may be surface treated with the use of a Bosch Impact 12 hand grinder, grinding handgun was used at 50 rpm for a duration of roughly 45 to 60 seconds (pink corundum abrasive grit size 60) washed with ethanol.
Electroplating the Backing Surface
A disc shaped niobium backing was obtained from high purity Nb as described herein and (28 mm×1 mm) was cleaned with ethanol (high-purity) and inserted in a Comecer Electroplating Unit V21204. A platinum wire anode was positioned so that the distance relative to the coin surface was between about 1 and 3 mm, adjusted by a polymer spacer. The coin mass was determined to be 5.25 grams. Niobium backing (22 mm×1 mm weighs 3.3 g). The plating solution was charged to the electrolyte container and attached to the apparatus. The voltage was set to 4.5V. The current reading after 5 min stabilization was 180 PA. The duty cycle for pump was set to 45%. The plating liquid turned from blue to transparent, slow decrease of current to 160 μA was observed over the period of 120 minutes. The plating process was stopped. The coin was taken out of the electrolytic cell and its weight was measured. The coin also underwent microscopic evaluation,
5.2.1.5 Results of the Electroplating
Upon completion of electroplating, the coin underwent a microscopic evaluation using a DINOLite digital microscope to observe the crystal structure and homogeneity of the surface. As can be seen in
The purpose of this example was to enable the bulk production of copper-61 (61Cu) from the deuteron irradiation of natural nickel and/or enriched 60Ni. This effort was a proof of concept, and, therefore, there were no benchmarked specifications for 61Cu. However, we optimize target performance, target geometry/material use, irradiation parameters, and chemical processing methods to produce [61Cu]CuCl2 following enriched 60Ni irradiation, or, scaled accordingly for natNi irradiation. There were no pharmacopoeia specifications for radio-copper explicitly, however, test QC methods include assessment of radionuclidic purity and apparent molar activity (to demonstrate usability of the extracted [61Cu]CuCl2). The final yield parameters were determined mutually to confirm a commercially viable production of [61Cu]CuCl2) (USZ, GE, SN) after the first irradiations and yield measurements.
This example considers use of two different types of targets, natural nickel (natmNi) targets and highly enriched Nickel-60 (60Ni) targets both of which were suitable for deuteron bombardment. However, natNi was cheap and available in high-purity while 60Ni was still costly and requires efficiency measures. If even higher yields were desired, target coating preparation efforts may be directly translated into the proton-based 61Ni(p,n)61Cu route, however, given the cost of enriched 61Ni (c.a. $25 USD/mg), such an approach imposes the need for target metal recycling.
The set of guidelines below enable all types of targets in the production of 61Cu, including the production of high-purity [61Cu]CuCl2 from the Nb coins with a Zn or Ni (any isotopic enrichment) coating electroplated thereon as provided herein. Specific details are also provided for deuteron, and proton irradiations, respectively. This protocol was followed to generate all the [61Cu]Cl compositions evaluated in the following examples.
61Ni Scenario #1 (11→9 MeV)
61Ni Scenario #1 (12→8 MeV)
61Ni Scenario #1 (13→7 MeV)
61Ni Scenario #1 (13→4 MeV)
61Cu (t 1/2 = 3.339 h) include:
58Cu (t ½ = 3.204 s)
60Cu (t ½ = 23.7 m)
64Cu (t ½ = 12.701 h)
The irradiated target coating was dissolved in a total volume of 7 mL of 6 M HCl with the addition of 30% hydrogen peroxide via a dissolution chamber. Separation and purification was accomplished using a cassette-based FASTlab platform using a TBP (tributylphosphate-based) resin (1 mL) (particle size 50-100 μm; pre-packed, Triskem) then a weakly basic (tertiary amine; TK201) resin (2 mL) (particle size 50-100 μm; pre-packed, Triskem) each of which were pre-conditioned with H2O (7 mL) and HCl (OM, 7 mL). The cassette reagent vials were prepared using concentrated HCl (Optima Grade, Fischer Scientific), NaCl (ACS, Fischer Scientific) and milli-Q water (Millipore system, 18 MΩ-cm resistivity). 6M HCl (2×4.2 mL), 5M NaCl in 0.05 M HCl (4.2 mL). The subsequent 61Cu was then purified with two subsequent ion exchange resins in a FASTlab synthesis unit as follows.
The resulting [61Cu]CuCl2 solution of the plated material has an average activity of 1-4.5 GBq. This activity was measured using a dose calibrator from Comecer and its radionuclidic purity by a gamma spectrometer at PSI in Switzerland.
Gamma spectrometry measurements were performed to identify any radionuclidic impurities, particularly long-lived radionuclides. These results indicate a 89.3% and 94% reduction in impurities for natNi and 61Ni on niobium backing materials with respect to silver backing materials when utilizing the methods disclosed herein. ICP-MS measurements were performed on the product of cold dissolutions by Labor Veritas in Switzerland to monitor elemental impurities present in product according to ICH-Q3D. All detected impurities were within regulated ICH-Q3D concentrations (see ICH-Q3D Guidelines, pg 25).
The plating of highly enriched 61Ni was also enabled with the same plating parameters as described above, for a higher yield and industrial production using proton irradiation (typically at 80 μA to 100 μA, 13 MeV protons for 1 hour to 2 hours and up to one half-life of 61Cu).
This example presents information on the activity of the produced 61Cu generated using the Nb backing, Ni electrodeposited coins of the present disclosure; alongside cobalt radioisotopes, that were produced with deuteron irradiation using the coin comprising a natural nickel target coating and the coin comprising enriched 60Ni as target metal, i.e., natNi(d,n)61Cu and 60Ni(d,n)61Cu, respectively. The irradiated materials were dissolved and purified as described in Example 3.
The obtained and purified [61Cu]Cu product and waste generated during purification from the products of deuteron irradiation of natural nickel/Nb coin and 60Ni/Nb coin, respectively, was processed and analysed by gamma-spectrometry and presented below.
TENDL-2019 based thick target coating yield calculations using isotopic abundancy of natural nickel/Nb coin and enriched 60Ni/Nb coin, respectively.
Table 8 contains activities of cobalt radioisotopes in the different fractions post FASTlab purification as a mean of three measurements (n=3 irradiations) using natNi/Nb coin. The activities were extrapolated to a 3 h and 50 μA beam at EoB (end of bombardment)+2 h. The activity of [61Cu]CuCl2 in these irradiations was determined experimentally and confirmed to be ˜80% of TENDL-2019 based estimates.
Activity of produced 61Cu for irradiation with deuteron at 8.4 MeV, 3 h at 50 μA at 80% efficiency (EoB+2 h): 3052 MBq. Also see
56Co
57Co
58Co
60Co
Table 9 contains calculated activities of cobalt radioisotopes that would be obtained by using 99% enriched 60Ni as target metal. The activities were extrapolated to a 3 h and 50 μA beam at EoB (end of bombardment)+2 h. The activity of 61Cu was calculated accordingly.
Activity of produced 61Cu with deuteron irradiation at 8.4 MeV, 3 h at 50 μA at 80% efficiency (EoB+2 h): 11.552 MBq. Also see
61Cu fraction
56Co
57Co
58Co
60Co
Based on a combination of theoretical calculations and experimental results, the purity of [61Cu]CuCl2 produced from deuteron irradiation of natNi/Nb target coin was compared with [61Cu]CuCl2 from deuteron irradiation of enriched 60Ni/Nb coin.
In Table 10, the extrapolated radiocobalt activity content and 61Cu purity of [61Cu]CuCl2 solution produced by natNi as target metal for a 50 μA, 3 h deuteron irradiation after FASTlab purification were presented.
61Cu
64Cu
61Cu +
61Cu
64 Cu
Less than 0.03% non-Cu radioisotopes (56Co and 58Co) will be left in the copper fraction, assuming a product expiry time of 8 h post EoB. This value was lower than the limit allowed for 68Ga cyclotron-produced as found in the Pharmacopeia (*0.1% at expiry for non-Ga radioisotopes):
The 64Cu originating from natNi irradiation (content˜5% at expiry) will be the main impurity, reducing the radioisotopic purity of 61Cu product at longer timescales post-irradiation times or shelf-life (illustrated as the grey curve in
In Table 11: 60Ni/Nb coin-Analysis of 61Cu activity and purity and after FASTlab purification.
60Ni/Nb coin - Analysis of 61Cu activity and
61Cu
64Cu
61Cu +
61Cu
64Cu
Less than 0.01% non-Cu radioisotopes (56Co and 58Co) were left in the Cu fraction, assuming a product expiry time of 8 h post EoB. This value was ten times lower than the allowed limit for 68Ga cyclotron-produced as found in the Pharmacopeia (0.1% at expiry for non-Ga radioisotopes*).
Less than 0.02% 64Cu was left in the copper fraction at an expiry time of 8 h post EoB, one hundred times lower than the specification required for 68Ga (2% Ga radioisotopes were allowed for 68Ga).
In Table 12, a comparison of the regulatory specifications on the purity of commercially available radionuclides were given along with the characteristics of the high purity [61Cu]CuCl2 produced from deuteron irradiation of natNi/Nb and enriched 60Ni/Nb coin (50 μA, 3 h) and after FASTlab purification were presented.
111In1
65Zn, 114mIn
18F2
56Co
18F 3
56Co
68Ga
68Ga
68Ge
177Lu6
61Cu from
56Co, 58Co
natNi
61Cu from
56Co, 58Co
60Ni
1https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/in111mal021902LB.pdf
2a. Pharmacopeia
3 ULg, USZ communication
4http://www.radiofarmacia.org/wp-content/uploads/2018/10/MONOGRAF%D6A-GA68Cl.pdf
5a. https://www.ire.eu/medias/164/Brochure-galli-Eo.pdf
6a. https://www.diagimaging.com/literature/ITG/ITG%20Lu-177%20n.c.a.pdf
As the first notable comparison, cyclotron production of 68Ga from proton irradiation also produces long lived radionuclides, (see, e.g., Applied Radiation and Isotopes, 65(10), 1101-1107, IAEA-TECDOC-1863 Gallium-68 Cyclotron Production) notably 65Zn (half-life=244 days) from the 66Zn(p,pn)65Zn decay. With a roughly 0.365% of 66Zn in an enriched 68Zn starting target metal, about 770 Bq of 65Zn will be produced from a 50 μA, 3 h beam with an energy of 13 MeV in a thick target coating (TENDL-2019 based calculations). Using natural Zn with 27.7% abundancy in 66Zn, 58 kBq of 65Zn will be produced in one run of 50 μA for 3 h beam. The isotopic purity of Zn in the target metal is, thus, very important.
Similar with [61Cu]CuCl2 production, cyclotron production of [64Cu]CuCl2 from proton irradiation also produces long-lived cobalt radionuclides, namely, 55Co, 57Co, 58Co, and 60Co. (See, e.g., Nuclear Medicine & Biology, Vol. 24, pp. 35-43, 1997; Applied Radiation and Isotopes 68 (2010) 5-13) By operating with a degraded beam of below 13 MeV, 60Co (from 64Ni(p,na)60Co) was reduced to 1 Bq per run of 50 μA, 3 h. With beam energies below 13 MeV, 55Co, formed from the 58Ni(p,a)55Co reaction, will remain the main impurity (half-life=17.53 hours). The 170 Bq of the long-lived 57Co was formed in about 170 Bq in these conditions mostly from 60Ni(p,a)57Co.
Note: These estimates were computed from thick target coating yields using TENDL-2019 cross section data and isotopic abundancy of enriched 64Ni as follows: 0.00376% 58Ni, 0.00298% 60Ni, 0.0058% 61Ni, 0.135% 62Ni, 99.858% 64Ni).
61Cu was produced through the proton bombardment of 61Ni electroplated Nb backed coin via cyclotron equipped with a solid target system irradiating a highly pure Niobium coin plated with highly pure 61Ni (purity 99.42%). The proton beam currents used were up to 100 μA, and beam energy of 13 MeV. An aluminum beam degrader was used.
The solid target irradiated material was dissolved in a total volume of 7 mL of 6M HCl with the addition of 30% H2O2 in a heated dissolution chamber. The 61Cu was purified from metal and radiometal impurities via a GE Healthcare FASTlab 2 module through a tributyl phosphate resin cartridge and a tertiary-amine-based weak ionic exchange resin containing long-chained alcohols. The product was finally eluted in an ISO class 5 environment in 3 mL 0.05 M HCl through a sterile filter Millex 4 mm Durapore PVDF 0.22 μm into a sterile evacuated vial. The vial was handled with care using the appropriate shielding and can be stored at room temperature until use using appropriate shielding for transport and handling.
#measured periodically
As shown in Table 14, and
The presence of long-lived impurities causes complications in the handling and waste management of contaminated materials. These data show that the provided compositions have a significantly reduced radiation burden to patients and also significantly reduce the cost and complexity of waste management. All materials/consumables that come into contact with the [61Cu]CuCl2 solution must be disposed of according to local governmental regulations. Costs of waste disposal rise proportionately with the activity and half-life of the radionuclidic impurities present.
61Cu compared to high-purity [61Cu]Cl2 of the present
61Ni on Nb
61Ni on Nb
The bacterial endotoxins were determined by LAL test using the Charles River Endosafe™-PTS system.
During dispensing of the [61Cu]CuCl2 solution, an aliquot of 1 mL was dispensed for quality control tests. The tests were carried out in a non-classified quality control laboratory. The solution was composed of [61Cu]CuCl2, 0.05 M HCl(aq).
The [61Cu]CuCl2 solution (pH 1.3) was diluted before the analysis using LAL reagent water and a buffer in order to reach a pH value in the range 6-7.6. To adjust the pH, TRIS buffer was added to the [61Cu]CuCl2 solution.
A dilution was prepared of the [61Cu]CuCl2 to be tested mixing the reagents in the endotoxin-free dilution tubes as follows: dilution factor (1:75); [61Cu]CuCl2 sample (10 μL); TRIS buffer (40 μL); water (700 μL). Mix for about 30 seconds.
The experimental activities of [61Cu]CuCl2 produced after deuteron irradiation were about 80% of the theoretical yield as calculated from TENDL-2019 cross section data.
The main long-lived nuclides in the radioactive waste fraction from cyclotron production of [61Cu]CuCl2 are radiocobalt species of 56Co, 57Co, 58Co and 60Co. After four years, 56Co, 57Co, and 58Co were calculated to have decayed below Swiss clearance limits, LL, leaving only 60Co. *Clearance limit (LL) means the value corresponding to the specific activity level of a material below which handling of this material was no longer subject to mandatory licensing or, accordingly, supervision).
To improve the yield and purity of the [61Cu]CuCl2 product, coins with 99% enriched 60Ni or 61Ni can be used. Using these targets, the extrapolated purity of 61Cu will be higher as 64Cu will not be formed as a radioisotopic impurity. Additionally, the 56Co and 60Co contents will be reduced by a factor of 100. On the other hand, 57Co amounts will quadruple, and 58Co amounts will be doubled but the former one was in low activity (which will decay below LL before 56Co/58Co) and the later has an increased LL of 1 Bq/g (vs 0.1 Bq/g for 56Co and 60Co). Overall the Co-waste handling will remain similar (dispatch to long term storage after four years) but the amount of 60Co can be reduced one hundred times with 60Ni instead of natural Ni.
The planned process pertaining to irradiation and purification for 68Ga production was listed below.
Zinc electroplating example procedure: The plating of highly enriched (e.g, ≥99%) 68Zn was conducted with the same plating parameters as described above for a higher yield and industrial production using proton irradiation (typically at 80-100 μA, 13.5 MeV protons for 1-2 h).
The 68Zn target metal on Nb coins were irradiated with 13.5 MeV protons for an average of 120 mins at a range of 10 to 100 μA on a cyclotron.
The dissolution of the 68Zn from the niobium backing will be made via an ARTMS system in 10 M HCl. The subsequent [68Ga]GaCl3 was then purified with 2 subsequent ion exchange resins in a FASTlab synthesis unit. The average processing time for these purifications was around 30-60 mins.
With 100% dissolution of the plated material, the average activity of the resulting [68Ga]GaCl3 will be measured and the decay-corrected yield was calculated. The measurement tools used were a dose calibrator from COMECER and its radionuclidic purity by a gamma spectrometer at PSI in Switzerland.
Gamma spectrometry measurements were performed to record any radionuclidic impurities, especially long-lived radionuclides. At the same time, ICP-MS measurements were performed on the product of cold dissolutions by Labor Veritas in Switzerland to monitor elemental impurities present in the product according to ICH-Q3D regulations.
While aspects of the present disclosure have been particularly shown and described with reference to certain embodiments and various alternate embodiments, it will be understood by persons skilled in the relevant art that various changes in form and details can be made therein without departing from the spirit and scope of the present disclosure.
All references, issued patents, and patent applications cited within the body of the instant specification are hereby incorporated by reference in their entirety, for all purposes. In particular, U.S. Provisional Patent Application No. 63/409,684, filed Sep. 23, 2022, is hereby incorporated by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 63409684 | Sep 2022 | US |
