Methods of using alumina in molybdenum / technetium-99m generators

Abstract

A molybdenum / technetium 99-m generator contains a powder comprising a metal-molybdate salt and an alumina adsorbent. The preferred aluminum oxide adsorbent is gamma-phase aluminum oxide (gamma-Al2O3), chi-phase aluminum oxide (x-Al2O3), or a combination of the gamma-phase aluminum oxide and the chi-phase aluminum oxide.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 348613, filed in the U.S. Patent and Trademark Office on June 3, 2022, and U.S. Patent Application No. 18 / 204,049, filed on May 31, 2023. The disclosures of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention relates to a method of using alumina as a guard filter in a Mo / Tc-99m generator, and more particularly to a method of using alumina as a guard filter in a Mo / Tc-99m generator having a powder containing metal-molybdate. Background Art

[0004] Technetium-99m (Tc-99m) is the most commonly used radioisotope in nuclear medicine (e.g., medical diagnostic imaging). When used with some equipment, Tc-99m (m is metastable) is typically injected into a patient, which is used to image the patient's internal organs. However, Tc-99m has a half-life of only about six (6) hours. Therefore, in at least the field of nuclear medicine, readily available sources of Tc-99m are of particular interest and / or need.

[0005] Due to the short half-life of Tc-99m, Tc-99m is typically obtained via a Mo / Tc-99m generator at the location and / or time of need (e.g., pharmacies, hospitals, etc.). A Mo / Tc-99m generator is a device used to extract a metastable isotope of technetium (i.e., Tc-99m) from a decaying molybdenum source (typically Mo-99) by passing salt water through the Mo material. Mo-99 is unstable and decays into Tc-99m with a half-life of about 66 hours. Mo-99 is typically produced from the irradiation of a highly enriched uranium target (93% uranium-235) in a high flux nuclear reactor and transported to a Mo / Tc-99m generator manufacturing site. This is a conventional method of producing Mo-99, wherein the Mo breakthrough is typically only the Mo-99 produced by the fission of uranium. Mo breakthrough is an even significantly more important problem when the molybdenum is not just Mo-99, but all Mo, where the source is typically natural Mo.

[0006] Mo / Tc-99m generators are then distributed from these centralized locations to hospitals and pharmacies throughout the country. Due to the limited number of production locations, and coupled with the limited number of available high-throughput nuclear reactors, the supply of Mo-99 is prone to frequent interruptions and shortages, resulting in delayed nuclear medicine procedures.

[0007] Molybdenum (both in radioactive and chemical form) is considered a contaminant in the eluent. Mo / Tc-99m generators currently on the market use an alumina adsorbent (Brockmann I alumina adsorbent), which has a chemical structure of α-Al2O3. If Mo-99 is absorbed into the eluent along with sodium pertechnetate, the Mo-99 has already broken through the ion / anion separation process.

[0008] It is important to prevent Mo-99 from entering solutions of drugs labeled for injection into the human body. If left unmitigated, Mo-99 could expose patients to potentially high and unnecessary doses of radiation.

[0009] The conventional way to produce a Mo / Tc-99m generator involves using a column chemistry to function. Using a conventional generator, the molybdate species is doubly negatively charged (-2), and when it decays, the Tc-99m daughter is singly negatively charged and does not bind (or adsorb) to Al2O3, and can be eluted with a salt solution passed through an Al2O3 column. Figure 1 A conventional Mo / Tc-99m generator of the prior art is shown. Figure 1 As shown in step 1, molybdate (MoO4 2- ) Mo-99 in the liquid phase is adsorbed onto an acid-activated alumina (Al2O3) column. Mo-99 then decays to its daughter Tc-99m, which is less tightly bound to the alumina column. Figure 1 As shown in step 2 of FIG. 1 , elution with saline is effective, with the release of pertechnetate (TcO 4- ) ions while keeping Mo fixed.

[0010] When using conventional alumina adsorbents from Mo / Tc-99m generator technology, an alumina adsorbent having a chemical structure of α-Al 2 O 3 (Brockmann I alumina) would require an equal mass ratio of alumina to powder to sufficiently reduce the problem of Mo breakthrough. Figure 2 The morphology of Brockmann I alumina (α-Al2O3) is shown.

[0011] The use of Brockmann I alumina (α-Al 2 O 3 ) as adsorbent leads to disadvantageous problems for Mo / Tc-99m generators in terms of poor elution efficiency, alumina bed shielding, high quality requirements, and large size of the generator.

[0012] Therefore, there is a need to find suitable alternatives to solve Mo breakthrough and alleviate the above-mentioned problems when using a molybdenum / technetium-99m (Tc-99m) generator with a metal-molybdate containing powder material. Summary of the invention

[0013] The present invention relates to systems and methods for using alumina (e.g., gamma-phase alumina (γ-Al2O3), chi-phase alumina (χ-Al2O3), or combinations thereof) as a preventive or protective filter in a molybdenum (Mo) / technetium-99m (Tc-99m) generator, preferably in a Mo / Tc-99m generator having a powder containing a metal-molybdate. The gamma-phase alumina (γ-Al2O3) and / or chi-phase alumina (χ-Al2O3) may be acidic, basic, or neutral. As used herein, the term "protective filter" generally refers to alumina that acts as a physical / mechanical barrier rather than an adsorbent.

[0014] The present invention uses alumina as a guard filter to control the amount of impurities (including soluble Mo species) reporting to the eluent. Mo breakthrough is an inherent challenge for molybdenum / technetium-99m (Tc-99m) generators, but more particularly for molybdenum (non-uranium) production of molybdenum-99. The method of the present invention addresses molybdenum breakthrough. The method of the present invention also addresses the chemical and radiological purity of the powder to identify radioisotope impurities that need to be mitigated to produce a cleaner powder for use in the final medical product. The method of the present invention not only uses alumina as a guard filter to prevent or mitigate breakthrough of Mo, but also prevents or mitigates breakthrough of other radioisotopes and other chemical impurities such as one or more of the following: Be, Li, Ti, V, Cr, Mn, Co, Ni, Cu, Zn, Ru, Rh, Pd, Ag, Cd, Sn, Ba, W, Ir, Pt, Au, Tl, Pb. The guard filter preferably has a pH in the range of 3.5 to 7.5, preferably 3.5 to 5.

[0015] In an embodiment of the invention, the method comprises passing the eluent through a molybdenum / technetium-99m generator, preferably a molybdenum / technetium-99m generator with a powder containing metal-molybdate, and selectively filtering molybdate and / or other radioisotope impurities using a preventive filter of aluminum oxide, preferably γ-Al2O3 and / or χ-Al2O3. γ-Al2O3 and χ-Al2O3 may, for example, have a microcrystalline or nanocrystalline grain size. Alpha-phase aluminum oxide may be used in combination with γ-Al2O3 and / or χ-Al2O3.

[0016] Among other features of the aluminum oxide that may be used, the aluminum oxide has a moisture content of less than 3.5 weight percent (based on the weight of the aluminum oxide). The aluminum oxide has a relative humidity of greater than or equal to 140 m 2 / g of surface area. Alumina can vary in its particle size distribution.

[0017] In embodiments of the invention, a mass ratio of chi-phase alumina to metal-molybdate powder (Al:P) in the range of 0.025:1 (Al:P) to 5:1 (Al:P) may be used to filter Mo from the metal-molybdate containing powder in the generator.

[0018] In embodiments of the invention, a mass ratio of gamma-phase alumina to metal-molybdate powder (Al:P) in the range of 0.025:1 (Al:P) to 5:1 (Al:P) may be used to effectively filter Mo from the metal-molybdate containing powder in the generator.

[0019] Further application areas of the present invention will become clear from the detailed description provided below.It should be understood that the detailed description and specific examples, although indicating preferred embodiments of the present invention, are only intended for illustrative purposes and are not intended to limit the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The present invention will be more fully understood from the detailed description and accompanying drawings (which are not necessarily drawn to scale), in which:

[0021] Figure 1 A conventional Mo / Tc-99m generator of the prior art is shown.

[0022] Figure 2 The morphology of Brockmann I alumina (α-Al2O3) is shown.

[0023] Figure 3 A Mo / Tc-99m generator according to one aspect of the present invention is shown.

[0024] Figure 4 The morphology of gamma alumina (γ-Al 2 O 3 ) which can be used according to the invention is shown.

[0025] Figure 5 The morphology of chi-phase alumina (χ-Al2O3) which can be used according to the invention is shown. DETAILED DESCRIPTION

[0026] The invention will now be described more fully below with reference to the accompanying drawings, in which some, but not all, embodiments of the invention are shown. In fact, the invention can be implemented in many different forms and should not be construed as limited to the embodiments set forth herein; on the contrary, these embodiments are provided so that the disclosure will satisfy applicable legal requirements. As used in the specification and the appended claims, the singular forms "a (kind) (indefinite articles a and an)", "the" include plural referents unless the context clearly dictates otherwise.

[0027] As used herein, the term "metal-molybdate" (also referred to herein as Metal-Mo) generally refers to metal-molybdate, metal-molybdenum, molybdenum-metallate, or any form of Mo-metal or metal-Mo species.

[0028] Figure 3 FIG. 1 shows a Mo / Tc-99m generator 100 according to an embodiment of the present invention. Figure 3 As shown in FIG. 1 , the Mo / Tc-99m generator 100 has one or more columns 110 having a length to diameter (L Mo / D Mo ) ratio, an optional boundary layer 130 to prevent particle migration, and a bed of protective filter material (γ-Al2O3 or χ-Al2O3 as shown) 140 having a length to diameter (L / D) ratio of . Using the Mo / Tc-99m generator 100, for example, 0.9% NaCl brine is used to elute TcO 4- The boundary layer 130 is a separator for controlling the fine powder from migrating from one layer to the next layer. The boundary layer 130 may include alumina, PVDF (polyvinylidene fluoride), PES (polyethersulfone), MCE (mixed cellulose esters), or glass microfiber.

[0029] In an embodiment of the invention, the Mo / Tc-99m generator has a column having a height (length) of a bed containing a protective filter material and a column inner diameter (D). Preferably, the ratio of length to diameter (L / D) is in the range of 0.25 to 10 to exhibit desired filtration performance in terms of molybdenum (Mo) breakthrough. Filtration is important because it prevents Mo from entering a solution of a drug labeled for injection into the human body. If not mitigated, Mo-99 can expose patients to potentially high and unnecessary doses of radiation.

[0030] In an embodiment of the present invention, the Mo / Tc-99m generator includes metal-molybdate powder and alumina as a protective filter. The eluent passes through the bed of metal-molybdate powder and elutes both Mo and Tc. Mo is selectively purified using alumina as a protective or preventive filter to reduce Mo breakthrough.

[0031] The protective filter is alumina, preferably γ-phase alumina (γ-Al2O3), chi-phase alumina (χ-Al2O3), or a combination thereof. Alpha-phase alumina (α-Al2O3) can be used in combination with γ-Al2O3 and / or χ-Al2O3. Alternatively, other protective filter materials (which do not significantly adsorb the desired TcO 4-, but adsorbs unwanted Mo species and other undesirable impurities) can be used in combination with γ-Al2O3 and / or χ-Al2O3, and is selected from MSU-X mesoporous alumina, polymeric titanium dioxide compounds (PTC), polymer embedded nanocrystalline titanium dioxide, polymeric zirconium oxide compounds (PZC), tetragonal nanozirconia, chitosan-based products, iron, and activated carbon.

[0032] The advantage of using γ-Al2O3 or χ-Al2O3 is that the main impurities are reduced. Although the elution time using γ-Al2O3 or χ-Al2O3 can vary, the elution time should be as low as reasonably achievable. It is expected that the elution time is less than 10 minutes, preferably less than 5 minutes. Figure 4 The morphology of the gamma-phase alumina (γ-Al 2 O 3 ) which can be used according to the invention is shown. Figure 5 The morphology of chi-phase alumina (χ-Al2O3) which can be used according to the invention is shown.

[0033] In embodiments of the invention, a mass ratio of gamma-phase alumina to metal-molybdate powder (Al:P) in the range of 0.025:1 (Al:P) to 5:1 (Al:P) may be used to effectively filter Mo from the metal-molybdate containing powder in the generator.

[0034] In embodiments of the invention, a mass ratio of chi-phase alumina to metal-molybdate powder (Al:P) in the range of 0.025:1 (Al:P) to 5:1 (Al:P) may be used to filter Mo from the metal-molybdate containing powder in the generator.

[0035] In an embodiment of the invention, the release of Tc-99m meets the United States Pharmacopeia (USP) monograph standards for "Sodium Pertechnetate Tc-99m Injection". In an embodiment of the invention, there is effective release of Tc-99m and thereby meets the USP specification for radiopurity, wherein the ratio of Mo to Tc-99m must be less than (<) 0.15 μCi / mCi.

[0036] Comparative Example

[0037] Table 1

[0038]

[0039]

[0040] The data in Table 1 show that the Brockmann I adsorbent is too inefficient, with the highest Tc-99m yield being only 35%. However, γ-Al2O3 and χ-Al2O3 yield 89% Tc-99m. Furthermore, at a 0.1:1 ratio of Al2O3 to powder, γ-Al2O3 and χ-Al2O3 achieve the highest yields. γ-Al2O3 and χ-Al2O3 perform better using far less material than the Brockmann I adsorbent. Therefore, it can be concluded that conventional aluminas will have poor elution efficiency when using a powder bed.

[0041] Example

[0042] The following test was performed. The chromatographic columns with the guard filters listed in Table 2 were eluted, and the L / D of each guard filter was measured. The measurement results are shown in Table 2.

[0043] Table 2

[0044] column Bed height inner diameter L / D (mm) (mm) <![CDATA[γ-Al2O3 (Literature)]]> 53.36 19.9 2.68 <![CDATA[γ-Al2O3]]> 45.28 19.9 2.27 <![CDATA[χ-Al2O3]]> 36.07 19.9 1.81

[0045] Therefore, it will be readily understood by those skilled in the art that the present invention has wide practicality and application. In addition to what is described herein, many embodiments and adaptations of the present invention, as well as many variations, modifications and equivalent arrangements, will be clearly or reasonably implied by the present invention and the foregoing description thereof, without departing from the spirit or scope of the present invention. Therefore, although the present invention has been described in detail herein with respect to its preferred embodiments, it should be understood that this disclosure is only illustrative and exemplary of the present invention, and is only for the purpose of providing a complete and feasible disclosure of the present invention. The foregoing disclosure is not intended to or should be interpreted as limiting the present invention or otherwise excluding any such other embodiments, adaptations, variations, modifications and equivalent arrangements.

Claims

1. Molybdenum / Technetium 99-m generator, including: A powder containing metal-molybdate (Mo); and Contains protective filter made of aluminum oxide.

2. The molybdenum / technetium 99-m generator according to claim 1, wherein the alumina is selected from γ-phase alumina (γ-Al2O3), chi-phase alumina (χ-Al2O3), and combinations thereof.

3. The molybdenum / technetium 99-m generator according to claim 1, wherein the protection filter further comprises a material selected from the following: MSU-X mesoporous alumina, polymeric titanium dioxide compounds (PTC), polymer embedded nanocrystalline titanium dioxide, polymeric zirconium oxide compounds (PZC), tetragonal nanozirconia, chitosan-based products, iron, activated carbon, and combinations thereof.

4. Molybdenum / Technetium 99-m generator, including: A powder comprising a metal-molybdate; and Gamma phase alumina (γ-Al2O3).

5. The molybdenum / technetium 99-m generator of claim 4, wherein the molybdenum / technetium 99-m generator comprises a column.

6. The Mo / Technetium 99-m generator of claim 5, wherein the column comprises a Mo powder bed containing the metal-molybdate containing powder.

7. The Mo / Technetium 99-m generator of claim 5, wherein the column comprises a guard filter bed containing gamma-phase alumina (γ-Al2O3).

8. The molybdenum / technetium 99-m generator of claim 7, wherein the guard filter bed further comprises a material selected from the group consisting of: MSU-X mesoporous alumina, polymeric titanium dioxide compounds (PTC), polymer embedded nanocrystalline titanium dioxide, polymeric zirconium oxide compounds (PZC), tetragonal nanozirconia, chitosan-based products, iron, activated carbon, and combinations thereof.

9. The Mo / Technetium 99-m generator of claim 7, wherein the guard filter bed has a bed height (length) to column inner diameter (D) L / D ratio in the range of 0.25 to 10.

10. The molybdenum / technetium-99-m generator of claim 4, wherein the mass ratio of gamma-phase alumina to metal-molybdate powder (Al:P) is in the range of 0.025:1 to 5:

1.

11. Molybdenum / Technetium 99-m generator, including: A powder comprising a metal-molybdate; and Chi-phase alumina (χ-Al2O3).

12. The molybdenum / technetium 99-m generator of claim 11, wherein the molybdenum / technetium 99-m generator comprises a column.

13. The Mo / Technetium 99-m generator of claim 12, wherein the column comprises a Mo powder bed containing the metal-molybdate containing powder.

14. The molybdenum / technetium 99-m generator of claim 12, wherein the column comprises a guard filter bed containing chi-phase alumina (χ-Al2O3).

15. The molybdenum / technetium 99-m generator of claim 14, wherein the guard filter bed further comprises a material selected from the group consisting of: MSU-X mesoporous alumina, polymeric titanium dioxide compounds (PTC), polymer embedded nanocrystalline titanium dioxide, polymeric zirconium oxide compounds (PZC), tetragonal nanozirconia, chitosan-based products, iron, activated carbon, and combinations thereof.

16. The Mo / Technetium 99-m generator of claim 14, wherein the guard filter bed has a L / D ratio of bed height (length) to column inner diameter (D) in the range of 0.25 to 10.

17. The Mo / Technetium-99-m generator of claim 11, wherein the mass ratio of the Chi-phase alumina to the metal-molybdate powder (Al:P) is in the range of 0.025:1 to 5:

1.

18. A method of use, comprising: A protection filter comprising aluminum oxide selected from the group consisting of γ-Al2O3, χ-Al2O3, and combinations thereof is introduced into a Mo / Technetium 99-m generator comprising a powder containing metal-molybdate (Mo).

19. The method of use according to claim 18, wherein the protection filter further comprises a material selected from the group consisting of: MSU-X mesoporous alumina, polymeric titania compounds (PTC), polymer embedded nanocrystalline titania, polymeric zirconia compounds (PZC), tetragonal nanozirconia, chitosan-based products, iron, activated carbon, and combinations thereof.

20. The method of use according to claim 18, wherein the protection filter has a pH in the range of 3.5 to 7.5.

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