Method and kit for purifying radioactive gallium

Description

[0001] University of Ulm

[0002] P148463PC00

[0003] Method and kit for the purification of radioactive gallium

[0004] A method and kit for purifying radioactive gallium are provided. The method provides an aqueous solution containing nitric acid and / or hydrochloric acid, radioactive gallium, and a zinc isotope, and a container containing a cation exchange material. The aqueous solution is passed through the container, binding the radioactive gallium to the cation exchange material. Subsequently, an aqueous rinsing solution containing or consisting of nitric acid and water is passed through the container, removing the zinc isotope from the gallium.

[0005] Cation exchange material is eluted, and then an aqueous elution solution suitable for eluting radioactive gallium from the cation exchange material is passed through the vessel and into a collection vessel, providing an aqueous solution containing radioactive gallium in the collection vessel. Radioactive gallium isotopes (such as...) 68 (Ga) are used as radioactive probes for the production of radioactive "contrast agents." Together with a homing precursor compound, these radioactive isotopes enable molecular imaging using positron emission tomography (PET) (see, e.g., Engle, JW et al., Appl. Radiat. Isot., 70(8):1892-1796). In PET or single-photon emission computed tomography (SPECT), peptides (e.g., edotreotide, DOTATOC), or citrate, are known to be combined with radionuclides (e.g., 68 Gallium or 67Gallium) and use it as a radiopharmaceutical, also called a tracer. The radiopharmaceutical distributes throughout the human body and accumulates in tumor cells or other target tissues. Imaging techniques can detect and localize this accumulation and thus a higher decay rate of the corresponding gallium radionuclides.

[0006] It is known that the isotope 68Gallium, with a half-life of 67.629 minutes, decays 89% of the time by emitting a positron with a maximum energy of 1.9 MeV and 11% by electron capture. In nuclear medicine applications, the emitted positron encounters an electron after traveling a few millimeters and annihilates with it, producing two photons, each with an energy of 511 keV. These two photons are emitted from the point of annihilation at an angle of almost 180° to each other. Due to the penetrating power of the emitted photons, they can be detected outside of a patient using appropriate detectors. By reconstructing the detection events, the location of the annihilation can be determined quite precisely.

[0007] Due to the short half-lives of the radioactive gallium isotopes, the radiopharmaceutical cannot be stored for a longer period of time, but must be produced relatively shortly before the intended use.

[0008] 68Gallium can be produced, among other things, using so-called germanium-68 / gallium-68 generators, also 68 Ge / 68 Ga-generators, as they are called, from 68 Germanium is produced. The amount of radioactivity available for radiopharmaceutical production is... 68 Ga for the production of 68 Ga radiopharmaceuticals are distinguished by the generator size (amount of activity). 68 The production of gallium isotopes is limited. Such a generator can only produce a few patient doses per day. Another way to provide larger quantities of the relatively short-lived, radioactive gallium isotopes is cyclotron-based production, starting from the corresponding stable zinc isotopes (Hemalatha, M. et al., Excitation functions of the Zn(p,xn)Ga reactions, Applied Radiation and Isotopes, 156:108968). Various radioisotopes of gallium can be produced using smaller cyclotrons with a power output of < 100 MeV via nuclear reactions of the general form 64,66,67,68,702. n( p^ n j64,66,67,68,70Q a u n c | 64,66,67,68,702 n ( p 2n) 63 - 65 - 66 - 67 - 69 To produce gallium (Ga), protons (p) accelerated by a cyclotron are fired at a target containing the corresponding stable zinc isotope. The target can be a solid or a solution of the zinc isotope. Depending on the energy of the protons used for irradiation, the nuclear reaction is initiated, emitting one or two neutrons from the nucleus. After irradiation of the zinc isotopes, a mixture of the stable zinc precursor is present, along with the resulting radioisotope of gallium. Depending on the target design, the target material is then processed.

[0009] A solid target could, for example, be a solid 68A zinc target is used (which is arranged, for example, on a disk, on a transport shuttle, a carrier strip, or a revolver system) and irradiated, whereby the solid, irradiated 68 Zn target then dissolved and the 68 Ga is purified from the aforementioned aqueous solution (Svedjehed, J. et al., Nuclear Medicine and Biology, 104-105:1-10). Dissolution is usually achieved using an acid or a salt solution at concentrations of 5 mol / L or higher.

[0010] The liquid target is usually a nitric acid solution that is sufficiently concentrated and aqueous. 68 Zn(NO3)2 solution irradiated and the 68 Ga was separated and purified from the aforementioned aqueous solution (Pandey, MK et al., Am. J. Nucl. Med. Mol. Imaging, 4(4):303-310). In liquid target systems, transfer for processing can be carried out via appropriate capillary lines.

[0011] The gallium isotope produced via the respective manufacturing process must be separated from the starting material after its production. This requires separating a relatively large mass-related amount of zinc starting material from a very small mass-related amount of the corresponding gallium isotope. For further radiopharmaceutical processing of the resulting gallium isotope, an almost quantitative separation of the zinc is necessary, as it interferes with the subsequent radiochemical labeling reaction to produce the radioactive drug.

[0012] For the separation and purification of radioactive gallium isotopes from aqueous solutions containing said radioactive gallium isotopes and their parent substances (e.g. 68 Various methods are known in the prior art for Zn-containing products.

[0013] For example, it is known to pass the aqueous solutions over a column containing a cation exchange material in order to first 68 Ga and 68 to bind Zn to the cation exchange material, and then to pass a rinsing solution through the column to remove the 68To dissolve zinc from the cation exchange material, the rinsing solution contains 80 vol% acetone in water and 0.5 mol / l hydrobromic acid (Pandey, MK et al., Am. J. Nucl. Med. Mol. Imaging, 4(4):303-310). The disadvantage of this approach is the use of organic solvents such as acetone, which results in higher process costs, a risk to the operator's health (e.g., fire hazard and other health risks), and residual solvents in the radiopharmaceutical. Furthermore, the use of hydrobromic acid is a disadvantage, as it tends to outgas from solutions and can therefore pose a health risk to the operator (e.g., risk of chemical burns from inhaling gaseous HBr).Furthermore, HBr is highly corrosive, so containers used in the process have to be replaced regularly, which makes it difficult to carry out the process uninterrupted over long periods and causes high costs due to resulting downtime and material costs.

[0014] Furthermore, it is known to pass the aqueous solution through several different columns, each containing a different material, for example, a first affinity column (e.g., with hydroxamate or octanol as the bonding group), an anion exchange column, a second affinity column (e.g., with triphenylphosphine oxide as the bonding group), and a hydrophobic column (e.g., with cis-alkyl resin) (Svedjehed, J. et al., Nuclear Medicine and Biology, 104-105:1-10). Organic solvents (e.g., ethanol) are also used in such procedures. This method has the disadvantage of being at least material-intensive, time-consuming, and costly.

[0015] Based on this, the object of the present invention was to provide a method and a kit for purifying radioactive gallium that overcomes at least one disadvantage of the prior art. In particular, the method and kit should make it possible to purify radioactive gallium in a simpler, faster and / or more cost-effective manner, especially with minimal risk to the health of the operator of the method, a reduced risk to the environment and / or a low risk of interruptions due to material damage.

[0016] The problem is solved by the method with the features of claim 1 and the kit with the features of claim 12. The dependent claims describe advantageous further developments.

[0017] According to the invention, a method for purifying radioactive gallium is provided, comprising or consisting of the following steps: a) providing an aqueous solution containing or consisting of nitric acid and / or hydrochloric acid in a concentration in the range of 0.01 mol / l to 1 mol / l, water, radioactive gallium, and a zinc isotope; b) providing a container containing a cation exchange material; c) passing the aqueous solution through the container, whereby radioactive gallium binds to the cation exchange material; d) passing an aqueous rinsing solution containing or consisting of nitric acid in a concentration in the range of 0.01 mol / l to 1 mol / l and water through the container, whereby the zinc isotope elutes from the cation exchange material;and e) Passing an aqueous elution solution suitable for elution of radioactive gallium from the cation exchange material through the container into a collection container, wherein an aqueous solution containing radioactive gallium is provided in the collection container.

[0018] The process according to the invention makes it possible to purify radioactive gallium in a simpler, faster, and more cost-effective manner than with known methods, minimizing the risk to the health of the operator, reducing the risk to the environment, and minimizing the risk of interruptions due to material damage. The aqueous solution containing radioactive gallium can be used, for example, for medical and pharmaceutical applications (e.g., radiopharmaceuticals). The process according to the invention does not require organic solvents (such as acetone). Therefore, no determination of residual solvents in the purified aqueous elution solution (gallium solution) is necessary. In this way, compared to methods known from the prior art, it is also unnecessary to demonstrate that the organic solvent used (e.g., acetone) is free of harmful substances.Acetone) has been completely removed, so that no intensive quality control, for example using a gas chromatograph, is required. This reduces the technical effort for routine use in hospitals or radiopharmaceutical manufacturers.

[0019] The preparation of the aqueous solution in step a) may, for example, comprise or consist of dissolving a solid target containing or consisting of radioactive gallium and a zinc isotope in (preferably concentrated) nitric acid and / or (preferably concentrated) hydrochloric acid, in particular (preferably concentrated) nitric acid. Furthermore, the preparation may comprise diluting the solution (with water) so that the acid concentration is in the range of 0.01 to 1 mol / l.

[0020] In step a) of the process, an aqueous solution can also be provided containing nitric acid in a concentration in the range of 0.02 mol / l to 0.8 mol / l, preferably in the range of 0.04 mol / l to 0.6 mol / l, particularly preferably in the range of 0.06 mol / l to 0.4 mol / l, especially in the range of 0.08 mol / l to 0.2 mol / l, optionally in the range of 0.09 mol / l to 0.11 mol / l. Furthermore, in step a) of the process, an aqueous solution can be provided containing hydrochloric acid in a concentration in the range of 0.02 mol / l to 0.8 mol / l, preferably in the range of 0.04 mol / l to 0.6 mol / l, particularly preferably in the range of 0.06 mol / l to 0.4 mol / l, especially in the range of 0.08 mol / l to 0.2 mol / l, optionally in the range of 0.09 mol / l to 0.11 mol / l.

[0021] Furthermore, in step a) of the procedure, an aqueous solution containing radioactive gallium selected from the group consisting of 66 Ga, 67Ga, 68 Ga and combinations thereof.

[0022] Apart from that, in step a) of the procedure an aqueous solution can be provided containing a zinc isotope selected from the group consisting of 66 Zn, 67 Zn, 68 Zn and combinations thereof.

[0023] The provision of the aqueous solution in step a) may include or consist of the following steps: i) Irradiation of a solid target containing or consisting of a zinc isotope with protons of an energy in the range of 7 to 30 MeV, wherein the zinc isotope is selected from the group consisting of 66 Zn, 67 Zn and 68Zn, wherein the irradiation preferably takes place in a cyclotron; ii) dissolving the irradiated solid target in an aqueous solution containing an acid, wherein the acid is preferably selected from the group consisting of hydrochloric acid and nitric acid; and iii) adjusting a concentration of nitric acid in the aqueous solution to a concentration in the range of 0.01 mol / l to 1 mol / l, preferably 0.02 mol / l to 0.8 mol / l, particularly preferably in the range of 0.04 mol / l to 0.6 mol / l, most preferably in the range of 0.06 mol / l to 0.4 mol / l, particularly in the range of 0.08 mol / l to 0.2 mol / l, optionally in the range of 0.09 mol / l to 0.11 mol / l.

[0024] Alternatively, the provision of the aqueous solution in step a) may comprise or consist of the following steps: i) Irradiation of an aqueous solution containing or consisting of water, nitric acid and a zinc isotope, with protons of an energy in the range of 7 to 30 MeV, wherein the zinc isotope is selected from the group consisting of Zn 66 , Zn 67 and Zn 68 , wherein the irradiation preferably takes place in a cyclotron; and ii) adjusting the concentration of nitric acid in the irradiated aqueous solution to a concentration in the range of 0.01 mol / l to 1 mol / l, preferably 0.02 mol / l to 0.8 mol / l, particularly preferably in the range of 0.04 mol / l to 0.6 mol / l, most preferably in the range of 0.06 mol / l to 0.4 mol / l, in particular in the range of 0.08 mol / l to 0.2 mol / l, optionally in the range of 0.09 mol / l to 0.11 mol / l.

[0025] The cation exchange material of the container provided in step b) may contain or consist of particles of a material to which an anionic group is chemically covalently bonded.

[0026] The material of the particles can be selected from the group consisting of organic polymer, inorganic polymer and combinations thereof, wherein the material of the particles preferably contains or consists of silica gel.

[0027] Furthermore, the anionic group of the particles can be a strongly anionic group, wherein the strongly anionic group preferably contains a compound or cider consisting thereof, which is selected from the group consisting of alkylsulfonic acid, arylsulfonic acid and combinations thereof.

[0028] Furthermore, the particles can have a particle size in the range of 10 pm to 80 pm, preferably in the range of 20 pm to 75 pm, particularly preferably in the range of 30 pm to 70 pm, and most preferably in the range of 40 pm to 65 pm.

[0029] Furthermore, the particles can have pores with a pore size in the range of 30 Å to 120 Å, preferably in the range of 40 Å to 100 Å, particularly preferably in the range of 45 Å to 80 Å, especially in the range of 50 Å to 70 Å.

[0030] In step d) of the process, an aqueous rinsing solution containing nitric acid in a concentration in the range of 0.01 mol / l to 1 mol / l, preferably 0.02 mol / l to 0.8 mol / l, particularly preferably in the range of 0.04 mol / l to 0.6 mol / l, most preferably in the range of 0.06 mol / l to 0.4 mol / l, particularly in the range of 0.08 mol / l to 0.2 mol / l, optionally in the range of 0.09 mol / l to 0.11 mol / l, can be passed through the container.

[0031] Furthermore, in step d) of the procedure, an aqueous rinsing solution can be passed through the container which does not contain a zinc isotope selected from the group consisting of 66 Zn, 67 Zn, 68 Zn and combinations thereof, preferably containing no zinc at all.

[0032] Furthermore, in step d) of the procedure, an aqueous rinsing solution containing no acetone, and optionally no organic solvent, can be passed through the vessel. The advantage is that the procedure can be carried out more cost-effectively and in a more environmentally friendly manner than a procedure in which the rinsing solution contains an organic solvent (such as acetone). An additional advantage is that it eliminates the possibility of an aqueous solution containing radioactive gallium, eluted from the cation exchange material, being contaminated by acetone, an organic solvent, or their reaction products.

[0033] Furthermore, in step d) of the procedure, an aqueous rinsing solution containing no hydrobromic acid and / or acetone can be passed through the container. The advantage is that the procedure does not require organic solvents such as acetone, which significantly simplifies radiopharmaceutical production and quality control.

[0034] Apart from that, in step d) of the procedure, an aqueous rinsing solution consisting of water and nitric acid can be passed through the container.

[0035] In step d) of the process, the aqueous rinsing solution can be passed through the container in an amount of at least 0.05 ml of rinsing solution, preferably at least 0.075 ml of rinsing solution, optionally at least 0.1 ml of rinsing solution, per mg of cation exchange material contained in the container. The more rinsing solution is passed through the container, the purer the aqueous solution eluted from the cation exchange material can be compared to other components other than radioactive gallium.

[0036] In step e) of the process, an aqueous elution solution containing an acid at a concentration in the range of 0.2 to 6 mol / l, preferably in the range of 0.3 mol / l to 5.5 mol / l, particularly preferably in the range of 0.4 mol / l to 5.0 mol / l, most preferably in the range of 0.6 mol / l to 4.5 mol / l, particularly in the range of 0.8 to 4.2 mol / l, and optionally in the range of 1.0 mol / l to 4.0 mol / l, can be passed through the vessel. The aqueous elution solution most preferably consists of water and at least one acid. The acid is particularly selected from the group consisting of hydrochloric acid, nitric acid, phosphoric acid, citric acid, formic acid, and combinations thereof.

[0037] Alternatively, in step e) of the process, an aqueous elution solution containing an alkali metal salt and / or alkaline earth metal salt in a concentration in the range of 1 to 6 mol / l, preferably in the range of 2 mol / l to 5.8 mol / l, particularly preferably in the range of 3 mol / l to 5.6 mol / l, most preferably in the range of 4 mol / l to 5.4 mol / l, particularly in the range of 4.5 mol / l to 5.2 mol / l, and optionally in the range of 4.9 mol / l to 5.1 mol / l, can be passed through the vessel. The aqueous elution solution particularly preferably consists of water and at least one alkali metal salt and / or at least one alkaline earth metal salt. The alkali metal salt is particularly a sodium salt.Optionally, the aqueous elution solution can contain an acid at a concentration in the range of 0.01 to 6 mol / l, preferably in the range of 0.02 mol / l to 5.5 mol / l, particularly preferably in the range of 0.04 mol / l to 5.0 mol / l, most preferably in the range of 0.06 mol / l to 4.5 mol / l, particularly in the range of 0.08 to 4.2 mol / l, and optionally in the range of 0.09 mol / l to 4.0 mol / l. In this case, the aqueous elution solution optionally consists of water, at least one acid, and at least one alkali metal salt and / or at least one alkaline earth metal salt. The acid is particularly selected from the group consisting of hydrochloric acid, nitric acid, phosphoric acid, citric acid, formic acid, and combinations thereof.The aqueous elution solution in step e) of the process can be passed through the container in an amount of up to 500 µl of elution solution, preferably up to 300 µl of elution solution, particularly preferably up to 100 µl of elution solution, most preferably up to 50 µl of elution solution, particularly preferably up to 10 µl of elution solution, optionally up to 1.25 pl of elution solution, per mg of cation exchange material located in the container. The smaller the amount of elution solution, the more concentrated the aqueous solution is with respect to its radioactive gallium content, and the faster and more cost-effective the process can be carried out.

[0038] In a preferred embodiment, the elution solution after step e) is not passed through any further container containing an ion exchange material, and preferably, the elution solution after step e) does not come into contact with any ion exchange material. The advantage is that the process can be carried out faster and more cost-effectively.

[0039] According to the invention, a kit for purifying radioactive gallium is further provided, comprising or consisting of: a) a container containing a cation exchange material; b) an aqueous rinsing solution containing or consisting of nitric acid in a concentration in the range of 0.01 mol / l to 1 mol / l and water; and c) an aqueous elution solution suitable for elution of radioactive gallium from the cation exchange material.

[0040] The kit according to the invention makes it possible to purify radioactive gallium in a simpler, faster, and more cost-effective manner than with known methods, minimizing the risk to the health of the operator, reducing the risk to the environment, and minimizing the risk of interruptions due to material damage. The kit according to the invention can be used routinely in clinical practice in 68 The Ga-labeling method is used. The cleaning process with the kit requires only one cleaning cartridge with the corresponding ion exchanger; that is, no additional cleaning cartridge is necessary. The achievable amount (radioactivity) of the corresponding gallium isotope is up to approximately 80% to 90% of the available amount of gallium, which was produced, for example, by irradiation of the target in a cyclotron.

[0041] The container of the kit can contain 0.3 g to 3 g, preferably 0.5 g to 2 g, particularly preferably 0.8 g to 1.2 g, especially 1 g, of the cation exchange material.

[0042] The cation exchange material of the kit's container may contain or consist of particles made of a material to which an anionic group is chemically covalently bonded.

[0043] The material of the particles can be selected from the group consisting of organic polymer, inorganic polymer and combinations thereof, wherein the material of the particles preferably contains or consists of a silica gel.

[0044] Furthermore, the anionic group of the particles can be a strongly anionic group, wherein the strongly anionic group preferably contains a compound or cider consisting thereof, which is selected from the group consisting of alkylsulfonic acid, arylsulfonic acid and combinations thereof.

[0045] Furthermore, the particles can have a particle size in the range of 10 pm to 80 pm, preferably in the range of 20 pm to 75 pm, particularly preferably in the range of 30 pm to 70 pm, and most preferably in the range of 40 pm to 65 pm.

[0046] Apart from that, the particles can have pores with a pore size in the range of 30 Å to 120 Å, preferably in the range of 40 Å to 100 Å, particularly preferably in the range of 45 Å to 80 Å, especially in the range of 50 Å to 70 Å.

[0047] The aqueous rinsing solution of the kit may contain nitric acid in a concentration in the range of 0.02 mol / l to 1.0 mol / l, particularly preferably in the range of 0.03 mol / l to 0.8 mol / l, most preferably in the range of 0.04 mol / l to 0.6 mol / l, particularly in the range of 0.06 mol / l to 0.4 mol / l, optionally in the range of 0.08 to 0.2 mol / l or in the range of 0.09 mol / l to 0.11 mol / l.

[0048] The kit can contain 10 to 400 ml, preferably 20 to 300 ml, particularly preferably 50 to 200 ml, most preferably 80 to 120 ml, particularly 100 ml, of the aqueous rinsing solution (in a container).

[0049] Furthermore, the aqueous rinsing solution of the kit cannot contain a zinc isotope selected from the group consisting of 66 Zn, 67 Zn, 68 Zn and combinations thereof, preferably containing no zinc at all.

[0050] Furthermore, the aqueous rinsing solution of the kit must not contain acetone, and optionally, it must not contain any organic solvent.

[0051] Apart from that, the aqueous rinsing solution of the kit cannot contain hydrobromic acid.

[0052] Furthermore, the aqueous rinsing solution of the kit can consist of water and nitric acid.

[0053] The aqueous elution solution of the kit can contain an alkali metal salt and / or alkaline earth metal salt in a concentration in the range of 1 to 6 mol / l, preferably in the range of 2 mol / l to 5.8 mol / l, particularly preferably in the range of 3 mol / l to 5.6 mol / l, most preferably in the range of 4 mol / l to 5.4 mol / l, particularly in the range of 4.5 mol / l to 5.2 mol / l, optionally in the range of 4.9 mol / l to 5.1 mol / l. The alkali metal salt is in particular a sodium salt.

[0054] The kit can contain 0.2 ml to 4 ml, preferably 0.3 ml to 3 ml, particularly preferably 0.4 ml to 2.5 ml, most preferably 0.5 ml to 2 ml, particularly 0.6 ml to 1.5 ml, optionally 0.8 ml to 1.2 ml, of the aqueous elution solution (in a container).

[0055] The aqueous elution solution can consist of 3-6 mol / l, preferably 5 mol / l, sodium chloride and 0.01 mol / l to 1 mol / l, preferably 0.1 mol / l, hydrochloric acid in water. Furthermore, the aqueous elution solution of the kit can consist of water and at least one alkali metal salt and / or at least one alkaline earth metal salt.

[0056] The following figures and example are intended to explain the subject matter of the invention in more detail, without limiting it to the specific embodiments shown here.

[0057] Figure 1 schematically shows a kit 1 according to the invention for the purification of radioactive gallium, consisting of a cation exchange cartridge 2, a container 3 with a rinsing solution and a container 4 with an elution solution.

[0058] Figure 2 schematically shows a method according to the invention for purifying radioactive gallium using a kit according to the invention. An irradiated target 5, which here contains or consists of a solid target with radioactive gallium and a zinc isotope, yields the corresponding gallium isotope. After dissolving the irradiated target 5 in (preferably concentrated) nitric acid and / or hydrochloric acid, the solution is adjusted to an acid concentration in the range of 0.01 mol / l to 1 mol / l (preferably by dilution with water), resulting in an acidic, dilute target solution 6. For irradiated targets 5 that are liquid targets containing or consisting of radioactive gallium and a zinc isotope, the liquid target 5 is also adjusted to an acid concentration in the range of 0.01 mol / l to 1 mol / l (preferably by dilution with water or, if necessary, dilute nitric acid), resulting analogously in an acidic, dilute target solution 6.This acidic, dilute target solution 6 is passed through a cation exchange cartridge 2, which retains the gallium isotope. The fluid from this cartridge, which mainly contains the unreacted zinc, is collected separately in a waste collection container 7 and can be disposed of or reprocessed in accordance with legal regulations. The cation exchange cartridge 2 is then rinsed with an aqueous rinsing solution from a container 3, which contains said aqueous rinsing solution, thereby eluting any remaining traces of zinc. The rinsing solution that has passed through the cation exchange cartridge 2 can also be transferred to the waste collection container 7 and disposed of and / or reprocessed.Subsequently, the gallium isotope bound to the cation exchange material of the cation exchange cartridge 2 can be eluted from a container 4, which contains said aqueous elution solution, into a reaction vessel 8 using an aqueous elution solution. There, it is reacted with a suitable buffer solution and a corresponding labeling precursor. In this process, a labeling precursor in the reaction vessel 8 is labeled with the gallium isotope, forming a radioactive tracer 9. At the end of the reaction, a suitable buffer can be added, and the mixture can then be filtered under sterile conditions. The radiopharmaceutical 10 produced in this way can then be used medically, in compliance with applicable pharmaceutical regulations.

[0059] Example - Specific method according to the invention

[0060] In the case of a solid, the irradiated target material is dissolved in a suitable volume, preferably nitric acid of a suitable concentration.

[0061] A container is provided that holds a cation exchange material, in this case an SCX cartridge. The SCX cartridge can be pre-conditioned before use to remove residual foreign ions, such as iron. This can be done, for example, by rinsing the cartridge with either hydrochloric acid at a concentration of 5.5 mol / L HCl, or with a 0.1 molar solution of hydrochloric acid with a sodium chloride concentration of 5 mol / L, or with an acidified organic solvent, and in all cases, followed by a final rinse of the cartridge with water.

[0062] The solution containing the dissolved target material is diluted with water, if necessary, to a nitric acid concentration of preferably 0.1 mol / L and then passed through the SCX cartridge. In the case of a liquid, irradiated target material, preferably based on an aqueous zinc nitrate nitric acid solution, the solution can be passed through said SCX cartridge after suitable dilution with water or nitric acid, the target nitric acid concentration preferably being 0.1 mol / L.

[0063] When the solution passes through the SCX cartridge, primarily the corresponding gallium isotope is retained. Unreacted zinc migrates through the cartridge.

[0064] Any remaining zinc is removed by rinsing this cartridge with diluted nitric acid.

[0065] The elution of the gallium isotope remaining on the cartridge can then be carried out using hydrochloric acid with a concentration of 0.1 mol / L and / or a concentrated salt solution. If a 0.1 molar hydrochloric acid solution with a sodium chloride concentration of, for example, 5 mol / L is used to elute the purified gallium isotope, a small elution volume, e.g., 0.5 mL, can be used to directly elute the solution into a reaction solution. If a pharmaceutically safe buffer, e.g., based on sodium acetate, and a precursor, e.g., PSMA-HBED, are used for the reaction solution, the resulting gallium-labeled PSMA-HBED can be used for radiopharmaceutical production without further separation procedures.

[0066] The radiopharmaceutical can be applied, for example, following sterile filtration with subsequent quality control.

[0067] However, the gallium isotope remaining on the SCX and purified can also be eluted with citrate-containing solutions, whereby in the case of the radioisotope 67 Ga, which can be used as a radiopharmaceutical 67 Ga-citrate is eluted.

[0068] Typically, the residual concentration of zinc is reduced by a factor of 2000 - 4000.

[0069] Reference symbol list

[0070] 1: Kit for cleaning radioactive gallium 2: Cation exchange cartridge;

[0071] 3: Container with aqueous rinsing solution;

[0072] 4: Container with aqueous elution solution;

[0073] 5: Target containing or consisting of radioactive gallium and a zinc isotope;

[0074] 6: acidic, diluted target solution

[0075] 7: Waste collection containers;

[0076] 8: Reaction vessel;

[0077] 9: Radioactive tracer; and

[0078] 10: Radiopharmaceutical.

Claims

University of Ulm P148463PC00 Patent claims 1. A method for purifying radioactive gallium, comprising or consisting of the following steps: a) providing an aqueous solution containing nitric acid and / or hydrochloric acid at a concentration in the range of 0.01 mol / l to 1 mol / l, water, radioactive gallium, and a zinc isotope or cider thereof; b) providing a container containing a cation exchange material; c) passing the aqueous solution through the container, whereby radioactive gallium binds to the cation exchange material; d) passing an aqueous rinsing solution containing or consisting of nitric acid at a concentration in the range of 0.01 mol / l to 1 mol / l and water through the container, whereby the zinc isotope elutes from the cation exchange material;and e) Passing an aqueous elution solution suitable for elution of radioactive gallium from the cation exchange material through the container into a collection container, wherein an aqueous solution containing radioactive gallium is provided in the collection container.

2. A method according to the preceding claim, characterized in that in step a) an aqueous solution is provided which contains i) nitric acid in a concentration in the range of 0.02 mol / l to 0.8 mol / l, preferably in the range of 0.04 mol / l to 0.6 mol / l, particularly preferably in the range of 0.06 mol / l to 0.4 mol / l, especially in the range of 0.08 mol / l to 0.2 mol / l, optionally in the range of 0.09 mol / l to 0.11 mol / l; and / or ii) hydrochloric acid in a concentration in the range of 0.02 mol / l to 0.8 mol / l, preferably in the range of 0.04 mol / l to 0.6 mol / l, particularly preferably in the range of 0.06 mol / l to 0.4 mol / l, especially in the range of 0.08 mol / l to 0.2 mol / l, optionally in the range of 0.09 mol / l to 0.11 mol / l; and / or iii) radioactive gallium selected from the group consisting of 66 Ga, 67 Ga, 68 Ga and combinations thereof; and / or iv) contains a zinc isotope selected from the group consisting of 66 Zn, 67 Zn, 68 Zn and combinations thereof.

3. A method according to any of the preceding claims, characterized in that the provision of the aqueous solution in step a) comprises or consists of the following steps: i) irradiation of a solid target containing or consisting of a zinc isotope with protons of an energy in the range of 7 to 30 MeV, wherein the zinc isotope is selected from the group consisting of 66 Zn, 67 Zn and 68Zn, wherein the irradiation preferably takes place in a cyclotron; ii) dissolving the irradiated solid target in an aqueous solution containing an acid, wherein the acid is preferably selected from the group consisting of hydrochloric acid and nitric acid; and iii) adjusting a concentration of nitric acid in the aqueous solution to a concentration in the range of 0.01 mol / l to 1 mol / l, preferably 0.02 mol / l to 0.8 mol / l, particularly preferably in the range of 0.04 mol / l to 0.6 mol / l, most preferably in the range of 0.06 mol / l to 0.4 mol / l, particularly in the range of 0.08 mol / l to 0.2 mol / l, optionally in the range of 0.09 mol / l to 0.11 mol / l.

4. Method according to one of claims 1 or 2, characterized in that the provision of the aqueous solution in step a) comprises or consists of the following steps: i) Irradiation of an aqueous solution containing or consisting of water, nitric acid and a zinc isotope, with protons of an energy in the range of 7 to 30 MeV, wherein the zinc isotope is selected from the group consisting of Zn 66 , Zn 67 and Zn 68 , wherein the irradiation preferably takes place in a cyclotron; and ii) adjusting the concentration of nitric acid in the irradiated aqueous solution to a concentration in the range of 0.01 mol / l to 1 mol / l, preferably 0.02 mol / l to 0.8 mol / l, particularly preferably in the range of 0.04 mol / l to 0.6 mol / l, most preferably in the range of 0.06 mol / l to 0.4 mol / l, in particular in the range of 0.08 mol / l to 0.2 mol / l, optionally in the range of 0.09 mol / l to 0.11 mol / l.

5. A method according to any one of the preceding claims, characterized in that the cation exchange material of the container provided in step b) contains or consists of particles made of a material to which an anionic group is chemically covalently bonded, wherein i) the material of the particles is selected from the group consisting of organic polymer, inorganic polymer and combinations thereof, wherein the material of the particles preferably contains or consists of silica gel; and / or ii) the anionic group of the particles is a strongly anionic group, wherein the strongly anionic group preferably contains or consists of a compound selected from the group consisting of alkylsulfonic acid, arylsulfonic acid and combinations thereof;and / or iii) the particles have a particle size in the range of 10 pm to 80 pm, preferably in the range of 20 pm to 75 pm, particularly preferably in the range of 30 pm to 70 pm, and most preferably in the range of 40 pm to 65 pm; and / or; iv) the particles have pores with a pore size in the range of 30 Å to 120 Å, preferably in the range of 40 Å to 100 Å, particularly preferably in the range of 45 Å to 80 Å, especially in the range of 50 Å to 70 Å.

6. A method according to any one of the preceding claims, characterized in that in step d) an aqueous rinsing solution is passed through the container, which i) contains nitric acid in a concentration in the range of 0.01 mol / l to 1 mol / l, preferably 0.02 mol / l to 0.8 mol / l, particularly preferably in the range of 0.04 mol / l to 0.6 mol / l, most preferably in the range of 0.06 mol / l to 0.4 mol / l, particularly in the range of 0.08 mol / l to 0.2 mol / l, optionally in the range of 0.09 mol / l to 0.11 mol / l; and / or ii) does not contain a zinc isotope selected from the group consisting of 66 Zn, 67 Zn, 68 Zn and combinations thereof, preferably containing no zinc at all; and / or iii) containing no acetone, optionally no organic solvent; and / or iv) containing no hydrobromic acid; and / or v) consisting of water and nitric acid.

7. Method according to one of the preceding claims, characterized in that the aqueous rinsing solution in step d) is passed through the container in an amount in the range of at least 0.05 ml rinsing solution, preferably at least 0.075 ml rinsing solution, optionally at least 0.1 ml rinsing solution, per mg of cation exchange material located in the container.

8. Method according to one of the preceding claims, characterized in that in step e) an aqueous elution solution is passed through the container, which contains an acid in a concentration in the range of 0.2 to 6 mol / l, preferably in the range of 0.3 mol / l to 5.5 mol / l, particularly preferably in the range of 0.4 mol / l to 5.0 mol / l, most preferably in the range of 0.6 mol / l to 4.5 mol / l, particularly in the range of 0.8 to 4.2 mol / l, optionally in the range of 1.0 mol / l to 4.0 mol / l, wherein the aqueous elution solution particularly preferably consists of water and at least one acid, wherein the acid is particularly selected from the group consisting of hydrochloric acid, nitric acid, phosphoric acid, citric acid, formic acid and combinations thereof.

9. A method according to any one of claims 1 to 7, characterized in that in step e) an aqueous elution solution is passed through the container, which i) contains an alkali metal salt and / or alkaline earth metal salt in a concentration in the range of 1 to 6 mol / l, preferably in the range of 2 mol / l to 5.8 mol / l, particularly preferably in the range of 3 mol / l to 5.6 mol / l, most preferably in the range of 4 mol / l to 5.4 mol / l, particularly in the range of 4.5 mol / l to 5.2 mol / l, optionally in the range of 4.9 mol / l to 5.1 mol / l, wherein the aqueous elution solution particularly preferably consists of water and at least one alkali metal salt and / or at least one alkaline earth metal salt, wherein the alkali metal salt is in particular a sodium salt;and ii) optionally an acid in a concentration in the range of 0.01 to 6 mol / l, preferably in the range of 0.02 mol / l to 5.5 mol / l, particularly preferably in the range of 0.04 mol / l to 5.0 mol / l, most preferably in the range of 0.06 mol / l to 4.5 mol / l, in particular in the range of 0.08 to 4.2 mol / l, optionally in the range of 0.09 mol / l to 4.0 mol / l, wherein the acid is in particular selected from the group consisting of hydrochloric acid, nitric acid, phosphoric acid, citric acid, formic acid and combinations thereof; 10. Method according to one of the preceding claims, characterized in that the aqueous elution solution in step e) is in a Amount in the range of a maximum of 500 µl of elution solution, preferably a maximum of 300 µl of elution solution, particularly preferably a maximum of 100 µl of elution solution, most preferably a maximum of 50 µl of elution solution, in particular a maximum of 10 µl of elution solution, optionally a maximum of 1.25 µl of elution solution, per mg of cation exchange material that is in the container and passed through the container.

11. Method according to one of the preceding claims, characterized in that the aqueous elution solution after step e) is not passed through any further container containing an ion exchange material, preferably is not in contact with any ion exchange material.

12. Kit for the purification of radioactive gallium, containing or consisting of: a) a container containing a cation exchange material; b) an aqueous rinsing solution containing or consisting of nitric acid in a concentration in the range of 0.01 mol / l to 1 mol / l and water; and c) an aqueous elution solution suitable for elution of radioactive gallium from the cation exchange material.

13. Kit according to claim 12, characterized in that the cation exchange material of the container contains or consists of particles made of a material to which an anionic group is chemically covalently bonded, wherein i) the material of the particles is selected from the group consisting of organic polymer, inorganic polymer and combinations thereof, wherein the material of the particles preferably contains or consists of silica gel; and / or ii) the anionic group of the particles is a strongly anionic group, wherein the strongly anionic group preferably contains or consists of a compound selected from the group consisting of alkylsulfonic acid, arylsulfonic acid and combinations thereof; and / or iii) the particles have a particle size in the range of 10 µm to 80 µm, preferably in the range of 20 µm to 75 µm, particularly preferably in the range of 30 to 70 µm, and most preferably in the range of 40 µm to 65 µm; and / or iv) the particles have pores with a pore size in the range of 30 µm to 120 µm, preferably in the range of 40 µm to 100 µm, particularly preferably in the range of 45 µm to 80 µm, and especially in the range of 50 µm to 70 µm.

14. Kit according to one of claims 12 or 13, characterized in that the aqueous rinsing solution contains i) nitric acid in a concentration in the range of 0.02 mol / l to 0.8 mol / l, particularly preferably in the range of 0.04 mol / l to 0.6 mol / l, most preferably in the range of 0.06 mol / l to 0.4 mol / l, particularly in the range of 0.08 mol / l to 0.2 mol / l, optionally in the range of 0.09 mol / l to 0.11 mol / l; and / or ii) does not contain a zinc isotope selected from the group consisting of 66 Zn, 67 Zn, 68 Zn and combinations thereof, preferably containing no zinc at all; and / or iii) containing no acetone, optionally no organic solvent; and / or iv) containing no hydrobromic acid; and / or v) consisting of water and nitric acid.

15. Kit according to any one of claims 12 to 14, characterized in that the aqueous elution solution i) contains an alkali metal salt and / or alkaline earth metal salt in a concentration in the range of 1 to 6 mol / l, preferably in the range of 2 mol / l to 5.8 mol / l, particularly preferably in the range of 3 mol / l to 5.6 mol / l, most preferably in the range of 4 mol / l to 5.4 mol / l, in particular in the range of 4.5 mol / l to 5.2 mol / l, optionally in the range of 4.9 mol / l to 5.1 mol / l, wherein the alkali metal salt is in particular a sodium salt; and / or ii) consists of water and at least one alkali metal salt and / or at least one alkaline earth metal salt.

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