Preparation of pH-adjusted ascorbic acid solution

Abstract

A method is provided for preparing an aqueous ascorbic acid solution having a pH between 2.0 and 4.0, the method comprising the steps of providing an initial aqueous solution of ascorbic acid and a base, the initial solution having a pH between 5.0 and 8.0, and combining the initial solution with a second acid to obtain an ascorbic acid solution having a pH between 2.0 and 4.0. Also provided is the use of an aqueous ascorbic acid solution having a pH between 2.0 and 4.0 prepared by the method described as a radiation stabilizer for radiolabeled compounds.

Description

[Technical field]

[0001] The present invention relates generally to methods for preparing pH-adjusted ascorbic acid solutions, the use of such solutions as stabilizers for radiolabeled compounds, and systems and methods for purifying reaction mixtures containing radiolabeled compounds. [Background technology]

[0002] Ascorbic acid has many industrial uses. However, it is known to be chemically unstable in solution. For example, aqueous ascorbic acid solutions (in the region of pH 2) turn yellow after a few hours. Pharmacopoeias recommend only short-term storage of ascorbic acid solutions, ensuring protection from light, metal ions, and high temperatures. This means that aqueous ascorbic acid solutions typically need to be prepared on the day of use.

[0003] One use of ascorbic acid is as a radiation stabilizer. Radiation stabilizers can be used in the manufacture of radiopharmaceuticals, which are pharmaceutical compounds that contain radioactive nuclides. Ascorbic acid in particular is a more efficient radiation stabilizer at low pH, i.e., in its protonated state. Radiation stabilizers are necessary because at relatively high concentrations, radiation can cause the degradation of the radiopharmaceutical by radiolysis. This is especially likely during purification, where the radioactivity can be concentrated in a column in a tight band. To minimize radiolysis and improve process yields and radiochemical purity (RCP), radiopharmaceuticals can be stabilized with ascorbic acid.

[0004] Automated synthesis systems are important for the production of radiopharmaceuticals. Prior art synthesis systems are described in WO 2007 / 042781 and WO 2011 / 097649.

[0005] Synthesis systems such as FASTlab® (GE Healthcare) provide for the production of radiopharmaceutical doses for clinical use. The FASTlab synthesiser operates a device-based method for producing radiopharmaceuticals.

[0006] Such synthesis systems / devices are used with cassettes customized for a particular radiopharmaceutical. Such cassettes typically include flow paths and valves oriented along said flow paths that are selectively fluidly connected to one of several components used to synthesize a particular radiopharmaceutical, such as the necessary reagent vials, reaction vessels, purification cartridges, syringes, tubing, connectors, etc. The device is configured to cooperatively engage the components of the cassette such that the device can drive a source fluid bearing a radioisotope to accomplish a chemical synthesis process by actuating pumps, syringes, valves, etc., as well as controlling the supply of motive gas (e.g., nitrogen) and application of vacuum.

[0007] A fully automated, single-use cassette-type synthesis product would incorporate all necessary synthesis and purification components. A system that could be provided to the end user that has all the necessary reagents for synthesis and purification and requires minimal input from the user to provide a ready-to-use radiopharmaceutical would be commercially attractive. Despite being an effective radiation stabilizer, there are challenges to using ascorbic acid in an automated, single-use cassette-type product, as it does not have a long enough shelf life to be commercially viable. It would be beneficial to provide a method that allows for the generation of acidic aqueous ascorbic acid solutions (in the region of pH 2-4) that overcomes the challenges posed by the short shelf life due to ascorbic acid degradation prior to use. Summary of the Invention

[0008] In a first aspect, the present invention provides a method of preparing an aqueous ascorbic acid solution having a pH between 2.0 and 4.0, the method comprising the steps of providing an initial aqueous solution of ascorbic acid and a base, the initial solution having a pH between 5.0 and 8.0, and combining the initial solution with a second acid to obtain an ascorbic acid solution having a pH between 2.0 and 4.0.

[0009] In a second aspect, the present invention provides the use of an aqueous ascorbic acid solution having a pH of 2.0 to 4.0 prepared by the method of the first aspect of the present invention as a radiation stabilizer for radiolabelled compounds.

[0010] In a third aspect, the present invention provides a method of stabilizing a radiolabeled compound, the method comprising preparing an aqueous ascorbic acid solution having a pH between 2.0 and 4.0 according to the method of the first aspect of the invention, and combining at least a portion of the aqueous ascorbic acid solution with the radiolabeled compound.

[0011] In a fourth aspect, the present invention provides a system for purification of a reaction mixture containing a radiolabeled compound, comprising: (i) a flow path; and (ii) a plurality of valves oriented along the flow path, each of the plurality of valves being selectively fluidly connected to one of several components; Including, The components are: a) a composition vial for receiving a reaction mixture; b) a vial of an initial aqueous solution of ascorbic acid and a base, the initial aqueous solution having a pH of 5.0 to 8.0; c) a vial of a second acid; d) one or more solid phase extraction (SPE) cartridges; and e) one or more solvent vials The present invention provides a system including:

[0012] In a fifth aspect, the present invention relates to a method for stabilizing a radiolabeled compound during its purification using a system as defined in the fourth aspect of the invention, comprising: (i) combining a second acid with the initial ascorbic acid solution to obtain an aqueous ascorbic acid solution having a pH of 2.0 to 4.0; (ii) transferring a reaction mixture containing the radiolabeled compound from the composition vial to at least one of the one or more SPE cartridges; (iii) eluting the purified compound from the SPE cartridge. Including, a) prior to step (ii), mixing at least a portion of an aqueous ascorbic acid solution having a pH between 2.0 and 4.0 with the reaction mixture; b) after step (ii) and before step (iii), washing the one or more SPE cartridges with at least a portion of an aqueous ascorbic acid solution having a pH of between 2.0 and 4.0; or c) prior to step (ii), mixing a portion of an aqueous ascorbic acid solution having a pH between 2.0 and 4.0 with the reaction mixture, and after step (ii) and prior to step (iii), washing the one or more SPE cartridges with at least a portion of the aqueous ascorbic acid solution having a pH between 2.0 and 4.0. The method further comprises:

[0013] The aqueous ascorbic acid solution having a pH of 2.0-4.0 may only be present prior to and / or during the process of purification of the radiolabeled compound. The aqueous ascorbic acid solution having a pH of 2.0-4.0 does not form part of the purified product containing the radiolabeled compound.

[0014] In a sixth aspect, the present invention provides a method for producing a composition comprising the steps of: a) (i) a flow path; and (ii) a plurality of valves oriented along the flow path, each of the plurality of valves selectively fluidly connected to one of several components; A cassette including b) one or more composition vials; c) a vial of an initial aqueous solution of ascorbic acid and a base, the initial aqueous solution having a pH between 5.0 and 8.0; d) a second vial of acid; e) one or more SPE cartridges; and f) one or more solvent vials A kit comprising: [Brief description of the drawings]

[0015] [Figure 1] FIG. 1 shows an example of a FASTlab cassette layout that may be used with the present invention. [Diagram 2] FIG. 1 shows chromatograms demonstrating the radiochemical purity of [18F]flurpiridaz prepared with (bottom) and without (top) the use of ascorbic acid in the purification process. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] The term "radiopharmaceutical" has its conventional meaning and refers to a radioactive compound suitable for in vivo mammalian administration for use in diagnosis or therapy. Radiopharmaceuticals as referred to herein can be PET tracers.

[0017] The term "radiation stabilizer" refers to a compound that inhibits decomposition reactions such as redox processes by scavenging highly reactive free radicals such as oxygen-containing free radicals resulting from the radiolysis of water. Radiation stabilizers protect radiolabeled compounds from radiolysis and thus reduce / prevent the loss of purity of the radiolabeled compounds over their shelf life. References herein to stabilizing radiolabeled compounds refer to protecting the radiolabeled compounds from radiolysis.

[0018] Radiochemical purity (RCP) can be determined using radio-thin layer chromatography (radio-TLC) or high performance liquid chromatography (HPLC) and defined as the ratio of the (radiolabeled) drug substance peak to the total (radiolabeled) peak in a chromatogram. When radiopharmaceuticals with a high radioactivity concentration (RAC) are produced, the decrease in RCP during storage is likely to be higher than with a lower RAC due to more radiolysis. High radioactivity leads to destruction of the drug substance itself (i.e., radiolysis).

[0019] The term "comprising" has its conventional meaning throughout this application and implies that a method, system, product, etc. must have the recited components, but that other unspecified components may also be present.

[0020] A "vial" as referred to herein is a container that can be used to contain liquids. A vial can be sealed using a cap, a stopper, or both. A vial can be made of glass or plastic and can be sealed with a plastic or rubber stopper, a metal cap, or a combination of both. A liquid contained in a vial can be removed, for example, by withdrawing it from a sealed vial with a syringe (e.g., through a stopper). A vial can be formed of clear or non-clear (colored) glass or plastic. A clear vial, which is transparent and non-colored, allows the contents of the vial to be viewed, for example, to examine the color of a solution. A non-clear (or colored) vial can be used in situations where this is necessary to shield the contents of the vial from light, for example, to prevent degradation by light. An "ampule" as referred to herein is a glass container that is sealed by melting the top of the container to form a sealed neck, such that it is necessary to snap the neck to release the contents of the ampoule. A vial as referred to herein is preferably not an ampule.

[0021] "Inert gas" as referred to herein may be, for example, nitrogen, argon, or a mixture thereof. The inert gas may be of European Pharmacopoeia quality.

[0022] In a first aspect, the present invention provides a method of preparing an aqueous ascorbic acid solution having a pH between 2.0 and 4.0, the method comprising the steps of providing an initial aqueous solution of ascorbic acid and a base, the initial solution having a pH between 5.0 and 8.0, and combining the initial solution with a second acid to obtain an ascorbic acid solution having a pH between 2.0 and 4.0.

[0023] Aqueous solutions of ascorbic acid pH adjusted to a pH of 5.0-8.0 by the addition of base have been determined to exhibit good stability. The decomposition seen in low pH ascorbic acid solutions is not observed in solutions having a pH of 5.0-8.0. Thus, this process allows low pH ascorbic acid solutions (e.g., pH 2.0-4.0, preferably 2.0-3.0) to be prepared prior to use while mitigating the problem of short shelf life by allowing the ascorbic acid solution to be stored in a stable pH adjusted form. Such methods may be used, for example, in automated systems utilizing premixed pH adjusted ascorbic acid solutions that may be used to prepare low pH ascorbic acid solutions (e.g., pH 2.0-4.0, preferably 2.0-3.0) prior to use.

[0024] The pH of the initial solution may be 5.5 to 7.5, preferably 5.8 to 6.7, more preferably 5.8 to 6.5, more preferably 6.0 to 6.5.

[0025] The concentration of ascorbic acid in the initial solution may be 1 mg / mL to 100 mg / mL. The concentration may be 10 mg / mL to 100 mg / mL. The concentration may be 10 mg / mL to 30 mg / mL.

[0026] The initial aqueous solution may be prepared by dissolving ascorbic acid in water and adjusting the pH with a base.

[0027] The base may be a metal hydroxide, a metal carbonate, or a mixture thereof. The base may be selected from sodium hydroxide, sodium carbonate, and a mixture thereof. The base may be sodium hydroxide.

[0028] The initial aqueous ascorbic acid solution may be purged with an inert gas, such as nitrogen or argon.

[0029] It will be understood by those skilled in the art that the second acid is preferably not ascorbic acid. The second acid may be a mineral acid. The mineral acid may be selected from phosphoric acid, nitric acid, sulfuric acid, hydrochloric acid, and mixtures thereof. The mineral acid may be a mineral acid other than hydrochloric acid. The mineral acid may be phosphoric acid. The second acid may be provided in an aqueous solution, for example, at an acid concentration of 200-250 mg / mL.

[0030] The initial solution may be stored for a period of at least 12 hours before combining the initial solution with the second acid to obtain an ascorbic acid solution having a pH of 2.0 to 4.0. The initial solution may be stored for a period of at least 24 hours, at least 7 days, at least 6 months, or at least 1 year, preferably at least 2 years, before combining with the second acid.

[0031] The initial solution may be provided in a vial containing the solution and an inert gas. The inert gas may fill the headspace of the vial. The vial may be a clear glass vial. The vial may be sealed with a stopper and / or cap. The initial solution may be combined with the second acid using a syringe, for example, by syringe-injecting the second acid into the vial.

[0032] The initial solution is combined with the second acid to obtain an ascorbic acid solution having a pH of 2.0 to 4.0. It will be understood that a suitable amount of the second acid may be used to provide an ascorbic acid solution having a pH of 2.0 to 4.0. The method of the first aspect of the present invention may be for preparing an ascorbic acid solution having a pH of 2.0 to 3.2, preferably 2.0 to 3.0, more preferably 2.1 to 2.6, for example 2.5. Thus, the initial ascorbic acid solution may be combined with the second acid to obtain an ascorbic acid solution having a pH of 2.0 to 3.2, preferably 2.0 to 3.0, more preferably 2.1 to 2.6, for example 2.5.

[0033] The initial aqueous ascorbic acid solution may exhibit good stability from degradation without the need to include any additional stabilizers or preservatives. The initial solution may be free of metal complexing (chelating) agents. For example, the solution may be free of ethylenediaminetetraacetic acid (EDTA), sodium diethyldithiocarbamate, propyl gallate, dimercaptopropanol, 8-hydroxyquinoline and aminopolycarboxylic acids (such as diethylenetriaminepentaacetic acid (DTPA), N-hydroxyethylethylenediaminetriacetic acid (HEDTA) and salts thereof). The initial solution may be free of any radiolabeled compounds. The solution may consist essentially of ascorbic acid and a base dissolved in water. It will be understood that within the solution, the ascorbic acid may be present as an ascorbate salt, for example, as sodium ascorbate when the base is sodium hydroxide or sodium carbonate.

[0034] In a second aspect, the present invention provides the use of an aqueous ascorbic acid solution having a pH of 2.0-4.0 prepared by the method of the first aspect of the invention as a radiation stabilizer for a radiolabeled compound. The use may comprise combining the aqueous ascorbic acid solution having a pH of 2.0-4.0 prepared according to the method of the first aspect of the invention with the radiolabeled compound prior to or during the process of purification of the radiolabeled compound. The purification may be an SPE or HPLC purification. The use may comprise combining the aqueous ascorbic acid solution having a pH of 2.0-4.0 prepared according to the method of the first aspect of the invention with the radiolabeled compound to obtain a radiopharmaceutical composition comprising the radiolabeled compound and ascorbic acid. The aqueous ascorbic acid solution having a pH of 2.0-4.0 may be present only prior to and / or during the purification of the radiolabeled compound.

[0035] In a third aspect, the present invention provides a method of stabilizing a radiolabeled compound, the method comprising preparing an aqueous ascorbic acid solution having a pH between 2.0 and 4.0 according to the method of the first aspect of the invention, and combining at least a portion of the aqueous ascorbic acid solution with the radiolabeled compound.

[0036] The method of stabilizing a radiolabeled compound can be a method of stabilizing a radiolabeled compound during purification of the radiolabeled compound. The purification can be purification of the radiolabeled compound by solid phase extraction (SPE) or high performance liquid chromatography (HPLC). Preferably, the purification can be purification by SPE. The purification can be performed on a reaction mixture that includes the radiolabeled compound in a mixture with one or more impurities. The step of combining the aqueous ascorbic acid solution having a pH of 2.0-4.0 with the radiolabeled compound may be performed by: a) mixing at least a portion of the aqueous ascorbic acid solution having a pH of 2.0-4.0 with the radiolabeled compound prior to loading the radiolabeled compound onto an SPE cartridge or HPLC column; b) loading the radiolabeled compound onto an SPE cartridge or HPLC column and washing the SPE cartridge or HPLC column with at least a portion of the aqueous ascorbic acid solution having a pH of 2.0-4.0; or c) mixing a portion of the aqueous ascorbic acid solution having a pH of 2.0-4.0 with the radiolabeled compound prior to loading the radiolabeled compound onto an SPE cartridge or HPLC column, loading the radiolabeled compound onto an SPE cartridge or HPLC column and washing the SPE cartridge or HPLC column with a portion of the aqueous ascorbic acid solution having a pH of 2.0-4.0. Purification of the radiolabeled compound may be performed in an automated purification system.

[0037] In a fourth aspect, the present invention provides a system for purification of a reaction mixture containing a radiolabeled compound, comprising: (i) a flow path; and (ii) a plurality of valves oriented along the flow path, each of the plurality of valves being selectively fluidly connected to one of several components; Including, The components are: a) a composition vial for receiving a reaction mixture; b) a vial of an initial aqueous solution of ascorbic acid and a base, the initial aqueous solution having a pH of 5.0 to 8.0; c) a vial of a second acid; d) one or more SPE cartridges; and e) one or more solvent vials The present invention provides a system including:

[0038] The system of the present invention has a flow path. The flow path is a channel suitable for transporting materials, particularly fluids, such as solvents and reaction mixtures. The flow path may be configured to allow the initial solution to be combined with a second acid to obtain an ascorbic acid solution having a pH of 2.0 to 4.0. The "reaction mixture" may include the radiolabeled compound in mixture with one or more impurities.

[0039] An aqueous ascorbic acid solution having a pH between 2.0 and 4.0 may only be present prior to and / or during the purification of the radiolabeled compound.

[0040] "Fluidly connected" means that fluid can enter the vial, exit the vial, and (optionally) pass through the valve to other parts of the system. A suitable valve may be a three-way valve having three ports and a means for fluidly connecting any two of the three associated ports to one another while fluidly isolating the third port. A suitable valve may also be a stopcock valve including a rotatable stopcock.

[0041] The system may include a cassette. The cassette houses one or more of the components of the system. The cassette may be configured to interface with any components of the system not housed therein.

[0042] The system can be connected to or adapted to a system or device for the synthesis of radiolabeled compounds, such as the FASTlab system.The system or device for the synthesis of radiolabeled compounds can provide the synthesis of radiolabeled compounds from radiolabeled compound precursors, such as those described in WO2011 / 097649.Thus, the system can be integrated with a system or device for the synthesis of radiolabeled compounds, so as to provide an integrated system for the synthesis and purification of radiolabeled compounds.The integrated system can be fully automated.

[0043] The system may also include one or more of a product vial for receiving the eluted radiolabeled compound, a waste vial for receiving the eluted impurities, and a transfer line.

[0044] The vials containing the initial solution may be prepared by providing an initial aqueous solution of ascorbic acid and base having a pH between 5.0 and 8.0, degassing the solution with an inert gas, dispensing the solution into vials, and degassing the vial headspace with an inert gas. The vials may then be sealed, for example, using stoppers and / or caps.

[0045] The step of degassing the solution with an inert gas includes bubbling the solution with an inert gas. Bubbling the inert gas through the solution can be performed while stirring the solution. This process is useful for removing unwanted dissolved reactive gases, such as oxygen and carbon dioxide, from the solution. The inert gas can be nitrogen, argon, or a mixture thereof. The inert gas can be nitrogen.

[0046] The step of degassing the vial headspace is useful for removing undesired reactive gases, such as oxygen and carbon dioxide, from the vial headspace. The vial headspace refers to any space in the vial that is not occupied by the aqueous solution of ascorbic acid and base. Degassing involves dispensing an inert gas into the vial headspace to replace any other gases present therein. The inert gas can be nitrogen, argon, or a mixture thereof. The inert gas can be nitrogen.

[0047] The initial solution may be prepared by dissolving ascorbic acid in water and adjusting the pH with a base.

[0048] The pH of the initial solution may be 5.5 to 7.5, preferably 5.8 to 6.7, more preferably 5.8 to 6.5, more preferably 6.0 to 6.5.

[0049] The concentration of ascorbic acid in the initial solution may be 1 mg / mL to 100 mg / mL. The concentration may be 10 mg / mL to 100 mg / mL. The concentration may be 10 mg / mL to 30 mg / mL.

[0050] The base in the initial aqueous ascorbic acid solution may be a metal hydroxide, a metal carbonate, or a mixture thereof. The base may be selected from sodium hydroxide, sodium carbonate, and a mixture thereof. The base may be sodium hydroxide.

[0051] The initial aqueous ascorbic acid solution may exhibit good stability from degradation without the need to include any additional stabilizers or preservatives. The initial solution may be free of metal complexing (chelating) agents. For example, the solution may be free of ethylenediaminetetraacetic acid (EDTA), sodium diethyldithiocarbamate, propyl gallate, dimercaptopropanol, 8-hydroxyquinoline and aminopolycarboxylic acids (such as diethylenetriaminepentaacetic acid (DTPA), N-hydroxyethylethylenediaminetriacetic acid (HEDTA) and the like), and their salts. The initial solution may be free of any radiolabeled compounds. The solution may consist essentially of ascorbic acid and a base dissolved in water. It will be understood that within the solution, the ascorbic acid may be present as an ascorbate salt, for example, as sodium ascorbate when the base is sodium hydroxide or sodium carbonate.

[0052] The second acid is preferably not ascorbic acid. The second acid may be a mineral acid. The mineral acid may be selected from phosphoric acid, nitric acid, sulfuric acid, hydrochloric acid, and mixtures thereof. The mineral acid may be a mineral acid that is not hydrochloric acid. The mineral acid may be phosphoric acid.

[0053] The solvent vial or vials may be solvent vials containing an eluent, for example, acetonitrile in water (eg, 40% acetonitrile), ethanol in water (eg, a 45% ethanol solution), or another solvent system suitable for SPE elution.

[0054] In a fifth aspect, the present invention relates to a method for stabilizing a radiolabeled compound during its purification using a system as defined in the fourth aspect of the invention, comprising: (i) combining a second acid with the initial ascorbic acid solution to obtain an aqueous ascorbic acid solution having a pH of 2.0 to 4.0; (ii) transferring a reaction mixture containing the radiolabeled compound from the composition vial to at least one of the one or more SPE cartridges; (iii) eluting the purified compound from the SPE cartridge. Including, a) prior to step (ii), mixing at least a portion of an aqueous ascorbic acid solution having a pH between 2.0 and 4.0 with the reaction mixture; b) after step (ii) and before step (iii), washing the one or more SPE cartridges with at least a portion of an aqueous ascorbic acid solution having a pH of between 2.0 and 4.0; or c) prior to step (ii), mixing a portion of an aqueous ascorbic acid solution having a pH between 2.0 and 4.0 with the reaction mixture, and after step (ii) and prior to step (iii), washing the one or more SPE cartridges with at least a portion of the aqueous ascorbic acid solution having a pH between 2.0 and 4.0. The method further comprises:

[0055] An aqueous ascorbic acid solution having a pH between 2.0 and 4.0 is optionally absent from the purified radiolabeled compound.

[0056] The term "eluting" refers to passing a solution through the SPE cartridge in order to release one or more compounds of interest bound to the solid phase. Elution can be performed by passing an organic solvent through the SPE cartridge. The eluting step can further include passing the organic solvent through a transfer line for collection. The organic solvent can be a mixture of organic solvent and water.

[0057] The above method may further comprise a step of conditioning the one or more SPE cartridges, i.e., rinsing the SPE sorbent before transferring the reaction mixture to the one or more SPE cartridges. The conditioning step may be carried out after step (i) and before step (ii) with an aqueous ascorbic acid solution having a pH of 2.0-4.0.

[0058] The above method may further comprise a step of eluting impurities. Elution of impurities may be carried out before and / or after the above step (iii) of eluting the desired product. Preferably, elution of impurities may be carried out before and after the above step (iii) of eluting the desired product.

[0059] If the SPE cartridge or cartridges are washed with at least a portion of an aqueous ascorbic acid solution having a pH between 2.0 and 4.0 after step (ii) and before step (iii), this washing may act to elute one or more impurities (e.g., hydrophilic chemical and radiochemical impurities) and / or to wash away the original solvent used in the reaction mixture. One or more elution steps may be performed with a different solvent system, such as acetonitrile in water (e.g., 40% acetonitrile), to elute additional impurities and / or transfer the desired radiolabeled compound from one SPE cartridge to another. One or more elution steps may be performed after the SPE cartridge or cartridges are washed with at least a portion of an aqueous ascorbic acid solution having a pH between 2.0 and 4.0. Any of the one or more elution steps may be followed by a solvent exchange step in which the SPE cartridge or cartridges are washed with at least a portion of an aqueous ascorbic acid solution having a pH between 2.0 and 4.0.

[0060] The elution step (iii) may be carried out with a suitable eluent, such as a solution of ethanol in water (eg a 45% ethanol solution).

[0061] Purification of the radiolabeled compound may provide the radiolabeled compound with an RCP of at least 95%, preferably at least 97%.

[0062] All the configurations of the fourth aspect of the invention apply mutatis mutandis to the fifth aspect of the invention.The invention also provides a compound as purified according to the fifth aspect of the invention.

[0063] Various embodiments of the present invention refer to an aqueous ascorbic acid solution having a pH of 2.0 to 4.0. In any of these embodiments, the aqueous ascorbic acid solution may have a pH of 2.0 to 3.2, preferably 2.0 to 3.0, and more preferably 2.1 to 2.6.

[0064] The radiolabeled compound as referred to in any embodiment of the present invention may be a radiopharmaceutical. The radiolabeled compound may be a PET tracer.

[0065] The radiolabeled compound may include various radioisotopes. For example, the radiolabeled compound may be (i) an F-18 labeled radiopharmaceutical or a pharmaceutical acceptable salt thereof, (ii) a C-11 labeled radiopharmaceutical or a pharmaceutical acceptable salt thereof, (iii) a C-14 labeled radiopharmaceutical or a pharmaceutical acceptable salt thereof, (iv) an I-123 labeled radiopharmaceutical or a pharmaceutical acceptable salt thereof, (v) an I-124 labeled radiopharmaceutical or a pharmaceutical acceptable salt thereof, (vi) an I-125 labeled radiopharmaceutical or a pharmaceutical acceptable salt thereof, (v (ii) I-131 labeled radiopharmaceuticals or pharmaceutical acceptable salts thereof, (viii) Br-75 labeled radiopharmaceuticals or pharmaceutical acceptable salts thereof, (ix) Br-76 labeled radiopharmaceuticals or pharmaceutical acceptable salts thereof, (x) Br-77 labeled radiopharmaceuticals or pharmaceutical acceptable salts thereof, (xi) Br-78 labeled radiopharmaceuticals or pharmaceutical acceptable salts thereof, (xii) O-15 labeled radiopharmaceuticals or pharmaceutical acceptable salts thereof, (xiii) N-13 labeled (xiv) a P-32 labeled radiopharmaceutical or a pharmaceutical acceptable salt thereof, (xv) a Cu-62 labeled radiopharmaceutical or a pharmaceutical acceptable salt thereof, (xvi) a Ga-67 labeled radiopharmaceutical or a pharmaceutical acceptable salt thereof, (xvii) a Ga-68 labeled radiopharmaceutical or a pharmaceutical acceptable salt thereof, (xviii) a Rb-82 labeled radiopharmaceutical or a pharmaceutical acceptable salt thereof, (xix) a Sr-89 labeled radiopharmaceutical. (xx) a Tc-99m labeled radiopharmaceutical or a pharmaceutical acceptable salt thereof, (xxxi) an In-111 labeled radiopharmaceutical or a pharmaceutical acceptable salt thereof, (xxii) an Sm-153 labeled radiopharmaceutical or a pharmaceutical acceptable salt thereof, (xxiii) a Re-186 labeled radiopharmaceutical or a pharmaceutical acceptable salt thereof, (xxiv) a Tl-201 labeled radiopharmaceutical or a pharmaceutical acceptable salt thereof, or a combination thereof.

[0066] The radiolabeled compound is: (i) an F-18 labeled radiopharmaceutical or a pharmaceutical acceptable salt thereof; (ii) a C-11 labeled radiopharmaceutical or a pharmaceutical acceptable salt thereof; (iii) a C-14 labeled radiopharmaceutical or a pharmaceutical acceptable salt thereof; (iv) an I-123 labeled radiopharmaceutical or a pharmaceutical acceptable salt thereof; (v) an I-124 labeled radiopharmaceutical or a pharmaceutical acceptable salt thereof; (vi) an I-125 labeled radiopharmaceutical or a pharmaceutical acceptable salt thereof; (vii) an I-131 labeled radiopharmaceutical or a pharmaceutical acceptable salt thereof; (viii) a Br-75 labeled radiopharmaceutical or a pharmaceutical acceptable salt thereof; (ix) a Br-76 labeled radiopharmaceutical or a pharmaceutical acceptable salt thereof; (x) a phenyl-2-amino-1,3-diphenyl-2-propanediol (PA) or a pharma-ceutical acceptable salt thereof, (x) a Br-77 labeled radiopharmaceutical or a pharma-ceutical acceptable salt thereof, (xi) a Br-78 labeled radiopharmaceutical or a pharma-ceutical acceptable salt thereof, (xii) an O-15 labeled radiopharmaceutical or a pharma-ceutical acceptable salt thereof, (xiii) an N-13 labeled radiopharmaceutical or a pharma-ceutical acceptable salt thereof, (xiv) a P-32 labeled radiopharmaceutical or a pharma-ceutical acceptable salt thereof, (xv) a Cu-62 labeled radiopharmaceutical or a pharma-ceutical acceptable salt thereof, (xvi) a Ga-67 labeled radiopharmaceutical or a pharma-ceutical acceptable salt thereof, (xvii) a Ga-68 labeled radiopharmaceutical or a pharma-ceutical acceptable salt thereof, or a combination thereof.

[0067] The radiolabeled compound may be an F18-labeled radiopharmaceutical or a pharma- ceutical acceptable salt thereof. Examples of such F18-labeled radiopharmaceuticals include [F-18]FDG (2-deoxy-2-[18F]fluoro-D-glucose), [F-18]FMAU (2'-deoxy-2'-[18F]fluoro-5-methyl-1-beta-D-arabinofuranosyluracil), [F-18]FMISO ([18F]fluoromisonidazole), [F-18]FHBG (9-(4-[18F]-fluoro-3-[hydroxymethyl]butyl)guanine), [18F]FES (16a-[18F]-fluoro-17b-estrogen), [18F]FES (18 ... [F-18]tradiol), [F-18]AV-45, [F-18]AV-19, [F-18]AV-1, [F-18]flutemetamol, [F-18]flurpiridaz, [F-18]K5, [F-18]HX4, [F-18]W372, [F-18]VM4-037, [F-18]CP18, [F-18]ML-10, [F-18]T808, [F-18]T807, 2-[F-18]fluoromethyl-L-phenylalanine, [F-18]fluciclatide, GE-212, GE-226, or combinations thereof.

[0068] The radiolabeled compound has the formula (I):

[0069] [ka] (Wherein, A is N(R 7 ), S, O, C(=O), C(=O)O, NHCH2CH2O, a bond, or C(=O)N(R 7 ), When present, B is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C1-C6 alkyl optionally substituted with an imaging moiety, heteroaryl, and an imaging moiety; When present, C is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C1-C6 alkyl optionally substituted with an imaging moiety, heteroaryl, and an imaging moiety; D is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C1-C6 alkyl optionally substituted with imaging moieties, heteroaryl, and imaging moieties; or C and D together with the atoms to which they are attached form a 3- or 4-membered carbocyclic ring; G is halo or haloalkyl; n is 0, 1, 2, or 3; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 is independently selected from hydrogen, C1-C6 alkyl optionally substituted with an imaging moiety, and an imaging moiety; R 8 is a C1-C6 alkyl optionally substituted with an imaging moiety; E is selected from a bond, carbon, and oxygen, with the proviso that when E is a bond, then B and C are absent and D is selected from aryl and heteroaryl, with the proviso that when E is oxygen, then B and C are absent and D is selected from hydrogen, alkoxyalkyl, aryl, C1-C6 alkyl optionally substituted with an imaging moiety, and heteroaryl; provided that at least one imaging moiety is present in formula (I).

[0070] The substituent A in formula (I) can be O. 8 can be tert-butyl. G can be chloro. The imaging moiety can be any radioisotope as referred to herein, for example, F-18.

[0071] The radiolabeled compound has the following structure:

[0072] [ka] [F-18]flurpiridaz may be of the formula:

[0073] In a sixth aspect, the present invention provides a method for producing a composition comprising the steps of: a) (i) a flow path; and (ii) a plurality of valves oriented along the flow path, each of the plurality of valves selectively fluidly connected to one of several components; A cassette including b) one or more composition vials; c) a vial of an initial aqueous solution of ascorbic acid and a base, the initial aqueous solution having a pH between 5.0 and 8.0; d) a second vial of acid; e) one or more SPE cartridges; and f) one or more solvent vials A kit comprising:

[0074] The initial solution and / or the second acid may be as defined with respect to any of the preceding aspects of the invention. The flow path may be configured to allow the initial solution to be combined with the second acid to obtain an ascorbic acid solution having a pH of 2.0-4.0. The kit may also include one or more of a product vial for receiving the eluted radiolabeled compound, a waste vial for receiving the eluted impurities, and a transfer line.

[0075] The methods, systems and kits of the present invention provide stable ascorbic acid solutions, for example as an effective radiation stabilizer, that can be stored until ready for use and then pH adjusted on-site at the time of use.

[0076] The invention will now be further described with reference to the following non-limiting examples. EXAMPLES

[0077] [Example 1] Ascorbic acid-based SPE purification 18 Radiosynthesis of [F]flurpiridaz This process was carried out using a FASTlab™ cassette setup as shown in Figure 1. The components of the setup include a vial 1 of an initial aqueous solution of ascorbic acid and base, a vial 2 of a second acid, in this example phosphoric acid, and two SPE cartridges 3, 4.

[0078] The preparation step of the FASTlab™ process ([ 18 A solution of phosphoric acid (225 mg / mL, 3.7 mL) was added to a solution of ascorbic acid (20 mg / mL, pH 6.5, 61.5 mL) prior to the addition of [F] fluoride. The combined solution had a pH of 2.5 and an ascorbic acid concentration of 18.9 mg / mL and was used in the automated FASTlab™ synthesis.

[0079] Using a GE Medical Systems PETtrace cyclotron with a silver target, 18 O](p,n)[ 18 F] nuclear reaction, 18 A total target volume of 3.2–4.8 mL was used. Radioactive fluoride was captured on a Waters QMA cartridge (preconditioned with carbonate) and fluoride was eluted with a solution of tetrabutylammonium bicarbonate (22 mg) in water (100 μL) and acetonitrile (400 μL). Nitrogen was used to drive the solution from the QMA cartridge into the reactor vessel. Under a steady flow of nitrogen and vacuum, 3 × 0.5 mL acetonitrile azeotropic drying steps were included to obtain [F]fluoride. 18 The [F] fluoride was dried at 110 °C for about 20 min. The precursor (10.2 mg) in acetonitrile (1.7 mL) was dried [ 18 [F] fluoride was added and the reaction mixture was heated at 110° C. for 3 min. The crude product was diluted with 2 M NaOH (2.0 mL) and aqueous ascorbic acid (3.8 mL) and allowed to stand for 3 min. The crude product was then loaded onto a tC18 SPE cartridge (Waters, product no. WAT036800) and purified using the method described below.

[0080] The SPE cartridge was washed with aqueous ascorbic acid (13.4 mL) to wash away acetonitrile, NaOH, and hydrophilic chemical and radiochemical impurities. The SPE cartridge was then washed with 40% acetonitrile (11.9 mL) to remove hydroxy impurities. After this, the first SPE cartridge was connected in series to a second SPE cartridge (Waters, product no. WAT036800) and the two were washed with an additional 40% acetonitrile (22.2 mL) to remove [ 18 The [F]flurpiridaz was transferred to the second cartridge, while the more lipophilic chemical and radiochemical impurities were captured on the first SPE cartridge. The second SPE cartridge was then washed with additional 40% acetonitrile (5.1 mL). The second cartridge was then washed with aqueous ascorbic acid (20.1 mL) and eluted with a 45% ethanol solution (7 mL) to yield [F]flurpiridaz. 18 [F]flurpiridaz was eluted into a product vial, which consisted of 45 mL of ethanol (approximately 7% v / v) and ascorbic acid (35 mg / mL).

[0081] Table 1 summarizes the results of the synthesis.

[0082] [Table 1]

[0083] [Example 2] Ascorbic acid-free SPE purification 18 Radiosynthesis of [F]flurpiridaz The same procedures outlined in Example 1 were followed to dilute the crude product, wash the SPE cartridge, and make up the product vial, using water instead of ascorbic acid.

[0084] Table 2 summarizes the results of the synthesis.

[0085] [Table 2]

[0086] FIG. 2 shows chromatograms of the SPE purified product with and without ascorbic acid.

[0087] The results of Examples 1 and 2 show that including ascorbic acid as part of the purification step results in better process yields (i.e., less radiolysis of the product during purification) and better RCP. It is desirable for the RCP to be at least 95% upon product discharge.

[0088] [Example 3] Ascorbic acid titration To ensure that the pH of the solution obtained by combining the initial ascorbic acid solution with phosphoric acid is below pH 3, the specifications of the initial ascorbic acid solution and the vial of the second acid must be matched. This is illustrated by the following two scenarios. The specifications of the initial ascorbic acid solution and the vial of the second acid, as well as the pH of the combined solution, are detailed in Table 3.

[0089] [Table 3]

[0090] [Example 4] Manufacturing process for a typical 27.3 L batch of ascorbic acid (20.0 mg / mL) vials Vials containing initial aqueous solutions of ascorbic acid and base suitable for use in the methods disclosed herein can be prepared using the process as outlined below.

[0091] 1. Dissolve 122.85 g of sodium hydroxide in 3277.15 g of water for injection on a magnetic stirrer for 10 minutes. 2. Dissolve 546.0 g of L-(+)-ascorbic acid in 22.5 kg of water for injection on a magnetic stirrer for 20 minutes. Bubble nitrogen gas through the solution while mixing and protect from light. 3. Add the sodium hydroxide solution to the ascorbic acid solution. Begin mixing immediately after combining the solutions, or preferably while combining the solutions. Mix for 10 minutes while bubbling nitrogen gas through the solution. The solution no longer requires protection from light. 4. Measure the pH of the solution. The pH should be between 5.8 and 6.5. 5. Adjust final batch volume by qs to 27.3 L with water for injection. 6. Mix for 15 minutes while bubbling with nitrogen. 7. Filter the solution through a 0.2 μm filter to reduce bioburden. 8. Dispense into 100 mL Type I glass vials: Degas empty vial with nitrogen until full of nitrogen (typically 2 seconds), dispense ascorbic acid (20.0 mg / mL) into vial, degas vial headspace (typically 2 seconds), stopper and cap.

[0092] It will be readily understood by those skilled in the art that the embodiments of the present invention described herein are capable of broad utility and application. Thus, although the present invention is described in detail herein in connection with exemplary embodiments, it should be understood that this disclosure is an explanation and example of the embodiments, and is made to provide an enabling disclosure of the exemplary embodiments. The disclosure is not intended to be construed as limiting the embodiments of the present invention or excluding any other such embodiments, adaptations, variations, modifications, and equivalent configurations. The scope of the present invention is defined by the appended claims. [Explanation of symbols]

[0093] 1 vial of initial aqueous solution of ascorbic acid and base 2 vials of phosphoric acid 3 SPE Cartridges 4 SPE Cartridges

Claims

**Claim 1** A method for stabilizing a radiolabeled compound during purification of the radiolabeled compound, comprising: The method for stabilizing the radiolabeled compound includes a method for preparing an aqueous ascorbic acid solution having a pH of 2.0 to 4.0, The method for preparing the aqueous ascorbic acid solution having a pH of 2.0 to 4.0 is Preparing an initial aqueous solution of ascorbic acid and a base, the initial aqueous solution having a pH of 5.0 to 8.0; Combining the initial aqueous solution with a second acid to obtain an ascorbic acid solution having a pH of 2.0 to 4.0; Combining at least a portion of the aqueous ascorbic acid solution with the radiolabeled compound; comprising Before combining the initial aqueous solution with a second acid to obtain an ascorbic acid solution having a pH of 2.0 to 4.0, the initial solution is stored for a period of at least 12 hours. A method for stabilizing a radiolabeled compound. **Claim 2** The method for stabilizing a radiolabeled compound according to claim 1, wherein the initial solution has a pH of 5.8 to 6.

5. **Claim 3** The method for stabilizing a radiolabeled compound according to claim 1, wherein the ascorbic acid concentration in the initial solution is 1 mg / mL to 100 mg / mL. **Claim 4** The method for stabilizing a radiolabeled compound according to claim 1, wherein the base in the initial solution is selected from sodium hydroxide, sodium carbonate, and mixtures thereof. **Claim 5** The method for stabilizing a radiolabeled compound according to claim 4, wherein the base is sodium hydroxide. **Claim 6** The method for stabilizing a radiolabeled compound according to claim 1, wherein the second acid is a mineral acid. **Claim 7** The method for stabilizing a radiolabeled compound according to claim 6, wherein the mineral acid is selected from phosphoric acid, nitric acid, sulfuric acid, hydrochloric acid, and mixtures thereof. **Claim 8** The method for stabilizing a radiolabeled compound according to claim 7, wherein the mineral acid is phosphoric acid. **Claim 9** The purification is purification of the radiolabeled compound by solid phase extraction (SPE) or high performance liquid chromatography (HPLC), and The step of combining the aqueous ascorbic acid solution having a pH of 2.0 to 4.0 with the radiolabeled compound is a) mixing at least a portion of the aqueous ascorbic acid solution having a pH of 2.0 to 4.0 with the radiolabeled compound before loading the radiolabeled compound onto an SPE cartridge or an HPLC column, or b) loading the radiolabeled compound onto an SPE cartridge or an HPLC column and washing the SPE cartridge or the HPLC column with at least a portion of the aqueous ascorbic acid solution having a pH of 2.0 to 4.0, or c) mixing a portion of the aqueous ascorbic acid solution having a pH of 2.0 to 4.0 with the radiolabeled compound before loading the radiolabeled compound onto an SPE cartridge or an HPLC column, loading the radiolabeled compound onto an SPE cartridge or an HPLC column, and washing the SPE cartridge or the HPLC column with a portion of the aqueous ascorbic acid solution having a pH of 2.0 to 4.0 A method for stabilizing a radiolabeled compound according to claim 1, which is carried out by the above.

10. A method for stabilizing a radiolabeled compound according to claim 1 or 9, wherein the purification is carried out in an automatic purification system.

11. A system for purifying a reaction mixture containing a radiolabeled compound, comprising: (i) a flow path, and (ii) a plurality of valves oriented along the flow path, each of the plurality of valves being selectively fluidly connected to one of several components, the plurality of valves including, the components including a) a composition vial for receiving a reaction mixture, b) a vial of an initial aqueous solution of ascorbic acid and a base, the initial aqueous solution having a pH of 5.0 to 8.0, the vial, c) a vial of a second acid, d) one or more SPE cartridges, and e) one or more solvent vials A system.

12. The system according to claim 11, wherein the initial solution and / or the second acid is as described in any one of claims 2 to 8.

13. A method for stabilizing a radiolabeled compound during the purification of a radiolabeled compound using the system according to claim 11, the method comprising: (i) combining the second acid with an initial ascorbic acid solution to obtain an aqueous ascorbic acid solution having a pH of 2.0 to 4.0, (ii) transferring the reaction mixture containing the radiolabeled compound from the composition vial to at least one of the one or more SPE cartridges; (iii) eluting the compound purified from the SPE cartridge (iv) including, a) prior to step (ii), mixing at least a portion of the aqueous ascorbic acid solution having a pH of 2.0 to 4.0 with the reaction mixture; b) after step (ii) and prior to step (iii), washing the one or more SPE cartridges with at least a portion of the aqueous ascorbic acid solution having a pH of 2.0 to 4.0; or c) prior to step (ii), mixing a portion of the aqueous ascorbic acid solution having a pH of 2.0 to 4.0 with the reaction mixture, and after step (ii) and prior to step (iii), washing the one or more SPE cartridges with at least a portion of the aqueous ascorbic acid solution having a pH of 2.0 to 4.0; further including, the initial solution is stored for a period of at least 12 hours before combining the initial solution with a second acid to obtain an ascorbic acid solution having a pH of 2.0 to 4.

0. Method.

14. The method according to any one of claims 1, 9 or 13, wherein the aqueous ascorbic acid solution having a pH of 2.0 to 4.0 is not present in the purified radiolabeled compound.

15. The method according to any one of claims 1 to 9 or 13, wherein the ascorbic acid solution having a pH of 2.0 to 4.0 has a pH of 2.0 to 3.2, 2.0 to 3.0, or 2.1 to 2.

6.

16. The method according to claim 9 or 13, wherein the radiolabeled compound is a radiopharmaceutical.

17. The system according to claim 11, wherein the radiolabeled compound is a radiopharmaceutical.

18. The radiolabeled compound is (i) an F-18 labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof; (ii) a C-11 labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof; (iii) a C-14 labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof; (iv) an I-123 labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof; (v) an I-124 labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof; (vi) an I-125 labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof; (vii)I-131 labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (viii)Br-75 labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (ix)Br-76 labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (x)Br-77 labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (xi)Br-78 labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (xii)O-15 labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (xiii)N-13 labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (xiv)P-32 labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (xv)Cu-62 labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (xvi)Ga-67 labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (xvii)Ga-68 labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (xviii)Rb-82 labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (xix)Sr-89 labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (xx)Tc-99m labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (xxi)In-111 labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (xxii)Sm-153 labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (xxiii)Re-186 labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (xxiv)Tl-201 labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, or a combination thereof The method according to claim 16, comprising

19. The radioactive labeled compound is (i)F-18 labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (ii)C-11 labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (iii)C-14 labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (iv)I-123 labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (v)I-124 labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (vi)I-125 labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (vii)I-131 labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (viii)Br-75 labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (ix)Br-76 labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (x) Br-77-labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (xi) Br-78-labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (xii) O-15-labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (xiii) N-13-labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (xiv) P-32-labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (xv) Cu-62-labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (xvi) Ga-67-labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (xvii) Ga-68-labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (xviii) Rb-82-labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (xix) Sr-89-labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (xx) Tc-99m-labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (xxi) In-111-labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (xxii) Sm-153-labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (xxiii) Re-186-labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, (xxiv) Tl-201-labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof, or a combination thereof The system according to claim 17, comprising

20. The method according to claim 18, wherein the radiolabeled compound comprises an F18-labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof.

21. The system according to claim 19, wherein the radiolabeled compound comprises an F18-labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof.

22. The method according to claim 20, wherein the radiolabeled compound is [F-18]FDG (2-deoxy-2-[18F]fluoro-D-glucose), [F-18]FMAU (2'-deoxy-2'-[18F]fluoro-5-methyl-1-beta-D-arabinofuranosyluracil), [F-18]FMISO ([18F]fluoromisonidazole), [F-18]FHBG (9-(4-[18F]-fluoro-3-[hydroxymethyl]butyl)guanine), [18F]FES (16a-[18F]-fluoro-17b-estradiol) [F-18]AV-45, [F-18]AV-19, [F-18]AV-1, [F-18]flutemetamol, [F-18]flurpiridaz, [F-18]K5, [F-18]HX4, [F-18]W372, [F-18]VM4-037, [F-18]CP18, [F-18]ML-10, [F-18]T808, [F-18]T807, 2-[F-18]fluoromethyl-L-phenylalanine, [F-18]fluciclatide, GE-212, GE-226, or a combination thereof.

23. The system according to claim 21, wherein the radiolabeled compound is [F-18]FDG (2-deoxy-2-[18F]fluoro-D-glucose), [F-18]FMAU (2'-deoxy-2'-[18F]fluoro-5-methyl-1-beta-D-arabinofuranosyluracil), [F-18]FMISO ([18F]fluoromisonidazole), [F-18]FHBG (9-(4-[18F]-fluoro-3-[hydroxymethyl]butyl)guanine), [18F]FES (16a-[18F]-fluoro-17b-estradiol) [F-18]AV-45, [F-18]AV-19, [F-18]AV-1, [F-18]flutemetamol, [F-18]flurpiridaz, [F-18]K5, [F-18]HX4, [F-18]W372, [F-18]VM4-037, [F-18]CP18, [F-18]ML-10, [F-18]T808, [F-18]T807, 2-[F-18]fluoromethyl-L-phenylalanine, [F-18]fluciclatide, GE-212, GE-226, or a combination thereof.

24. The radiolabeled compound is [F-18]flurpiridaz: 【Chemical 1】 The method according to claim 22, comprising: **Claim 25**: The radioactive labeling compound is [F-18] flurupiridaz: 【Chemical 1】 The system according to claim 23, comprising: **Claim 26** a) (i) A flow path, and (ii) A plurality of valves oriented along the flow path, each of the plurality of valves being selectively fluidly connected to one of several components A cassette comprising: b) One or more composition vials, c) A vial of an initial aqueous solution of ascorbic acid and a base, the initial aqueous solution having a pH of 5.0 to 8.0, d) A vial of a second acid, e) One or more SPE cartridges, and f) One or more solvent vials A kit comprising:

Images