Carrier-free production and purification of lutetium-177 using chromatographic methods

Abstract

The present invention relates to a method for the production and purification of carrier-free Lutetium-177 using chromatography, in particular to a method for the production and purification of carrier-free Lutetium-177 with excellent separation capacity of Lutetium and Ytterbium without eluent concentration gradient using chromatography.

Description

Technical Field

[0001] This application claims priority and benefit to Korean Patent Application No. 10-2020-0183771, filed on December 24, 2020, the disclosure of which is incorporated herein by reference in its entirety.

[0002] This invention relates to a method for the production and purification of carrier-free lutetium-177 using chromatography, specifically to a method for the production and purification of carrier-free lutetium-177 using a single concentration eluent without an eluent concentration gradient and using chromatography with excellent separation capabilities for lutetium and ytterbium. Background Technology

[0003] Since 1990, the potential applications of β-ray-emitting nuclides in the lanthanide series in the medical field have attracted widespread attention. In particular, lutetium-177 (Lu-177) exhibits β-ray emission (E... βmax With its properties of Eγ = 498 keV and γ release (Eγ = 208 keV (11%) and 113 keV (6.4%)), it can be used for both treatment and diagnosis, and is therefore attracting much attention as a radioactive isotope for tumor treatment.

[0004] The primary medical application of Lu-177 is in research on monoclonal antibodies labeled with it for cancer treatment. A representative product is zevalin, used to treat lymphoma. Recently, with the development of Lu-177 prostate-specific membrane antigen (PSMA) for prostate cancer treatment and lutetium oxide octreotide (Lutathera) for neuroendocrine tumor treatment, the therapeutic value of using the radioisotope Lu-177 has been gradually increasing.

[0005] Lu-177 can be produced through the following direct and indirect production methods.

[0006] Direct production method: Lu-176+n→Lu-177+γ[ 176 Lu(n,γ) 177 Lu]

[0007] Indirect production method: Yb-176+n→Yb-177+γ→Lu-177+β - [ 176 Yb(n,γ)β 177 Lu]

[0008] For Lu-177 produced by the direct production method, the nuclear reaction cross-section of Lu-176 is 2090 barn, which is a very large value. Therefore, when 1 mg of Lu-176 is targeted at 1×10 14 At neutron flux levels, irradiation for one day can theoretically produce 70 GBq (1.8 Ci) of Lu-177. This corresponds to a Lu-176:Lu-177 ratio of 100:1.6, with 1.6% being radioactive isotopes and the remainder containing Lu-176 as a carrier. Extending the irradiation time generally yields radioactive isotopes corresponding to 1%–7% Lu-177.

[0009] For the indirect production method, the nuclear reaction cross-section of ytterbium-176 (Yb-176) is 2.85 barn. Under the conditions described above, Yb-177 yields approximately 975 MBq (26.36 mCi), and Lu-177 yields 85 MBq (2.3 mCi). In terms of isotope production, the indirect method yields only about 1% to 2% compared to the direct method.

[0010] Nevertheless, for use in pharmaceuticals, it is not recommended to use too many carriers other than therapeutic radioisotopes. This is because, in order to label pharmaceuticals with radioisotopes produced by the direct method, only a 20 to 100 times greater amount of the carrier material can be used, which poses risks to patients and can lead to treatment side effects.

[0011] Furthermore, the Lu-177 produced by the direct production method contains Lu-177m, a radioactive isotope, as a byproduct of the reaction. This equates to approximately 0.4% existing as a carrier, with a half-life of up to 160 days, potentially posing challenges for patient treatment and radioactive waste disposal.

[0012] The production of Lu-177 using the direct production method is significantly higher, but the disadvantage is that the carrier content is high and the generation of the side reaction Lu-177m inevitably leads to low medical value.

[0013] To address the problems described above, an indirect production method using an element different from the target element as a target was developed to separate Lu-177, the target material. Research on separation methods for carrier-free lutetium began in the 1950s.

[0014] In 1956, G.R. Choppin proposed in the journal *Journal of Inorganic Chemistry* (J. Inorg. Nucl. Chem) that cation exchange resin column separation using ammonium hydroxyisobutyrate (HIBA) solution under high temperature conditions was used for the separation of lanthanides and actinides. In 1994, P.S. Balasubramanian proposed that NH4+ substituted into the cation exchange resin be used for the separation of Lu-177. + Cd 2+ Zn 2+ Then, HIBA solution was used as the eluent for separation. The method described above may result in Cd residue after separation. 2+ Zn 2+ The probability that ions can also exist.

[0015] In US Patent 6,716,353B1, Lu-177 is separated under acidic conditions using a resin containing phosphate groups via an indirect production method. This method elutes Yb first and Lu later during column separation, thus having the disadvantage that the separated Lu may contain Yb, which could limit its use in pharmaceuticals.

[0016] In Germany, the method for obtaining carrier-free Lu-177 using DE102011051868.1 (Korea 10-2014-0071324) involves replacing hydrogen ions with ammonium ions in the cation exchange resin of the first column (free column), loading a dissolved target, and then using one of several solutes, such as hydroxyisobutyrate (HIBA), in the second column (main separation column) for separation and purification with an ammonium-containing solution. In this case, a third column (purification column) is used, for a total of three columns. The main separation column is not pretreated; eluent is introduced into the cation exchange resin, and repeated saturation and equilibration with the cation exchange resin are performed from the top to the bottom of the column. The separation of Lu occurs when the functional groups in the cation exchange resin and the eluent reach a saturated state, achieving a balance between them. This method requires time to reach saturation, thus consuming a significant amount of time during separation. To address this issue and improve separation efficiency, an elution gradient from low to high concentration is introduced.

[0017] Therefore, there is a need to develop methods that improve separation capacity to ensure that separated lutetium is free of ytterbium, and methods for lutetium separation and purification that do not require the application of an elution gradient to improve separation capacity and can remove cadmium ions after separation. Summary of the Invention

[0018] Technical issues

[0019] The present invention is proposed to solve the problems mentioned above. The purpose of the present invention is to provide a method for the separation and purification of lutetium-177, which uses a chromatographic method with significantly improved separation ability of lutetium and ytterbium compared with conventional separation and purification methods.

[0020] Solution to the problem

[0021] To address the technical problems described above, this invention provides a carrier-free method for separating lutetium-177 (Lu-177). This method is characterized by sequentially performing chromatographic analysis on a mixture containing ytterbium and lutetium-177 (Lu-177) compounds generated by neutron irradiation targeting a ytterbium-176 (Yb-166) compound using the following two-step column chromatography, wherein the first eluent is used as the mobile phase:

[0022] 1) Separation column: A column saturated with the stationary phase, using a cation exchange resin as the stationary phase and a first eluent containing one or more primary to quaternary ammonium ions and a chelate agent.

[0023] 2) Purification column: A purification column impregnated with water using the cation exchange resin as the stationary phase.

[0024] The first eluent can be used as the mobile phase.

[0025] According to a preferred embodiment of the present invention, lutetium-177 (Lu-177) is first eluted in the separation column, followed by ytterbium (Yb).

[0026] According to a preferred embodiment of the present invention, the first eluent may be a single eluent without a concentration gradient.

[0027] According to a preferred embodiment of the present invention, when lutetium-177 is eluted from the separation column, a first eluent containing the eluted lutetium-177 is introduced into the purification column, and

[0028] Next, when ytterbium is eluted from the separation column, the separated ytterbium can be introduced into a separate column by using a second eluent containing one or more primary to quaternary amino-onium ions and a chelate agent, and the ytterbium can be obtained by chromatography through the separate column.

[0029] In a preferred embodiment of the present invention, the cation exchange resin may contain one or more selected from sulfonic acid groups (-SO3H), phosphate groups (-OP(O)(OH)2, -P(O)(OH)2) and carboxyl groups (-C(O)OH).

[0030] In a preferred embodiment of the present invention, the amineonium ion may be an ion represented by the following chemical formula 1, or a secondary to quaternary amineonium ion or a mixture thereof comprising a heteroaliphatic ring or heteroaromatic ring containing 5 to 30 nitrogen atoms in the ring.

[0031] Chemical Formula 1:

[0032]

[0033] In the chemical formula 1,

[0034] R 1 R 2 R 3 and R 4 At least one of them is a substituted or unsubstituted C1-C8 linear or branched alkyl group, and the remainder is hydrogen, wherein R 1 R 2 R 3 and R 4 They are the same or different.

[0035] In a preferred embodiment of the present invention, the substituted C1-C8 straight-chain or branched alkyl group is replaced by a hydrophilic functional group.

[0036] Furthermore, in a preferred embodiment of the present invention, the hydrophilic functional group may be independently selected from one of the following groups: hydroxyl group, carbonyl group, amine group, carboxyl group, ester group, alkoxy group, amide group, imine group, oxime group, thiol group, sulfide group, sulfoxide group, thioketone group, and thioester group.

[0037] In a preferred embodiment of the present invention, the ammonium ion may be a primary ammonium ion.

[0038] In a preferred embodiment of the present invention, the chelating agent may be C2-C4. 12Monocarboxylic acid, dicarboxylic acid, tricarboxylic acid, or tetracarboxylic acid are compounds or their salts that contain other hydrophilic functional groups besides the carboxyl group.

[0039] In a preferred embodiment of the present invention, the chelating agent may be 2-hydroxyisobutyric acid (2-HIBA).

[0040] In a preferred embodiment of the present invention, the concentration of the chelating agent in the first eluent may be 0.01M to 0.5M.

[0041] In a preferred embodiment of the present invention, the concentration of the chelating agent in the second eluent may be 0.01M to 1.0M.

[0042] In a preferred embodiment of the present invention, the concentration of amine ions in the first eluent may be 0.1M to 1.0M.

[0043] The effects of the invention

[0044] The method for separating lutetium-177 according to the present invention improves separation capability without the use of gradient eluent, thus enabling the production of carrier-free lutetium-177. This reduces the amount of expensive cation exchange resin used and the amount of waste generated, and allows for the separation of carrier-free lutetium-177 in a short time.

[0045] Furthermore, since it uses an eluent without a concentration gradient, it has the advantage of being able to recover the eluent and simplifying the separation and purification process. Attached Figure Description

[0046] Figure 1 The diagram illustrates the structure of a device for separating lutetium-177 according to a preferred embodiment of the present invention.

[0047] Figure 2 Chromatograms of stable isotopes of lutetium and ytterbium separated by saturating an eluent containing ammonium ions and hydroxyisobutyric acid (HIBA) in a separation column packed with cation exchange resin.

[0048] Figure 3 Chromatograms of lutetium and ytterbium radioisotopes separated by saturating an eluent containing ammonium ions and hydroxyisobutyric acid (HIBA) in a separation column packed with cation exchange resin.

[0049] Figure 4Chromatogram of stable isotopes of lutetium and ytterbium separated in a cation exchange resin column saturated with an eluent containing methylamine cations and hydroxyisobutyric acid (HIBA).

[0050] Figure 5 Chromatograms of stable isotopes of lutetium and ytterbium separated by saturating an eluent containing ethylamine cations and hydroxyisobutyric acid (HIBA) in a separation column packed with cation exchange resin.

[0051] Figure 6 Chromatograms of stable isotopes of lutetium and ytterbium separated by saturating an eluent containing ethanolamine cations and hydroxyisobutyric acid (HIBA) in a separation column packed with cation exchange resin.

[0052] Figure 7 Chromatograms of stable isotopes of lutetium and ytterbium separated by saturating an eluent containing diethylamine cations and hydroxyisobutyric acid (HIBA) in a separation column packed with cation exchange resin.

[0053] Figure 8 Chromatograms of stable isotopes of lutetium and ytterbium separated by saturating an eluent containing ethylenediamine cations and hydroxyisobutyric acid (HIBA) in a separation column packed with cation exchange resin.

[0054] Figure 9 Chromatogram of stable isotopes of lutetium and ytterbium separated by saturating an eluent containing methylamine cations and hydroxyisobutyric acid (HIBA) in a separation column packed with a silica-supported cation exchange resin. Detailed Implementation

[0055] The method for separating lutetium-177 according to the present invention improves separation capacity without the use of gradient elution solutions, thus enabling the production of carrier-free lutetium-177. This also reduces the amount of expensive cation exchange resin used and the amount of waste generated, and allows for the separation of carrier-free lutetium-177 in a short time.

[0056] Furthermore, since it uses an eluent without a concentration gradient, it has the advantage of being able to recover the eluent and simplifies the separation and purification process.

[0057] Implementation

[0058] As mentioned above, conventional lutetium separation methods have the following drawbacks: it is difficult to obtain high-purity lutetium-177, separation requires multiple separation columns and takes a long time, and a concentration gradient is required as the eluent.

[0059] Therefore, in order to solve the problems mentioned above, the inventors devoted themselves to research and development, and finally came up with this invention.

[0060] This invention utilizes an indirect production method targeting ytterbium-176 (Yb-176) to replace the direct production method that uses lutetium-176, an isotope of lutetium-177 (Lu-177), as the target for neutron irradiation. When using the direct production method, the proportion of lutetium-177 in the generated lutetium is approximately 2%, resulting in a very high carrier content. Compared to the direct production method, while the indirect production method produces less lutetium-177, it also produces less of other isotopes and significantly fewer byproducts. Therefore, when lutetium is separated from the mixture with high purity, it offers superior effectiveness as a marker for medical applications.

[0061] The simplified reaction formula for the neutron capture reaction in the indirect production method is as follows.

[0062] 176 Yb+n→ 177 Yb+γ→ 177 Lu+β - [ 176 Yb(n, γ)β 177 Lu]

[0063] This invention specifically relates to a method for separating lutetium-177 generated from ytterbium (ytterbium-176, ytterbium-177) via the neutron capture reaction. The separation method employs chromatography, and this invention demonstrates that the separation capability of the chromatogram varies significantly with adjustments to the stationary and mobile phases of the column, thereby providing a time- and cost-effective method for separating carrier-free lutetium-177.

[0064] The method for separating carrier-free lutetium-177 according to the present invention is a method for separating a mixture of ytterbium and lutetium-177 (Lu-177) compounds generated by irradiating neutrons in a ytterbium-176 (Yb-166) compound by using the following two-step column chromatography according to the above-described indirect production method.

[0065] 1) Separation column: A column packed with cation exchange resin as the stationary phase is saturated with a first eluent containing one or more primary to quaternary ammonium ions and a chelate agent;

[0066] 2) Purification column: The cation exchange resin is used as the stationary phase and impregnated with water.

[0067] The mobile phase in the separation column is the first eluent.

[0068] For the chromatography in the separation column, ammonium ions (NH4+) are added along with the chelating agent to adjust the pH of the eluent, instead of the ammonium ions (NH4+) used in the traditional lutetium separation method. + ), or together with ammonium ions, it contains primary to tertiary ammonium ions substituted with one or more alkyl groups (NR4). + R can be one or more of alkyl or hydrogen groups, which allows for fine-tuning of the polarity of the eluent.

[0069] When using amineonium ions, the theoretical plate of the separation column can be increased, thereby increasing the retention time of lutetium-177 and ytterbium. Therefore, it offers the advantages of achieving the same separation capability as conventional lutetium separation methods while shortening the column length, and reducing the amount of cation exchange resin used.

[0070] The amineonium ion may be an ion represented by the following chemical formula 1, or a secondary to tertiary amineonium ion containing 5 to 30 nitrogen atoms in a heteroaliphatic or heteroaromatic ring, or a mixture of two or more thereof.

[0071] Chemical Formula 1:

[0072]

[0073] In the chemical formula 1,

[0074] R 1 R 2 R 3 and R 4 At least one of them is a substituted or unsubstituted C1-C8 linear or branched alkyl group, and the remainder is hydrogen, wherein R 1 R 2 R 3 and R 4 They are the same or different.

[0075] Wherein, substituted alkyl means that a reactive functional group is bonded to at least one of the carbon atoms of the alkyl group, and the reactive functional group is preferably a hydrophilic functional group.

[0076] Preferably, the hydrophilic functional group may be independently selected from one of the following groups: hydroxyl group, carbonyl group, amine group, carboxyl group, ester group, alkoxy group, amide group, imine group, oxime group, thiol group, sulfide group, sulfoxide group, thioketone group, and thioester group.

[0077] More preferably, it refers to the hydroxyl group.

[0078] The residence time in a lutetium-ytterbium column tends to follow the order of ammonium ions < primary ammonium ions < hydroxyl primary ammonium ions < secondary ammonium ions < tertiary ammonium ions < quaternary ammonium ions, depending on the ions contained in the eluent. This is consistent with the trend of column separation time.

[0079] As the amine order increases, i.e., quaternary ammonium ions have lower polarity than primary ammonium ions, lanthanides remain in the cation exchange resin for a longer period under equilibrium, ultimately leading to a prolonged column retention time. Therefore, chromatography containing high-order ammonium ions increases elution time compared to using eluents containing low-order ammonium ions.

[0080] Conversely, as the number of cycles decreases, the ammonium ions have a higher material polarity than primary or quaternary ammonium ions. Therefore, the equilibrium is more favorable to the mobile phase than to the cation exchange resin used as the stationary phase, thus reducing column residence time.

[0081] The equilibrium relationship and binding affinity between the cation exchange resin (stationary phase) and the eluent (mobile phase) of each ytterbium and lutetium ion differ, ultimately forming the theoretical plates for each ion.

[0082] When the mobile phase is altered by changing the ammonium ions in the mobile phase, the individual ytterbium and lutetium ions will cause changes in the equilibrium relationship and binding affinity between the eluent and the stationary phase, resulting in differences in separation capabilities.

[0083] Compared with conventional methods using eluents containing ammonium ions, the lutetium-177 separation method according to the present invention has significantly improved lutetium separation capability, and therefore has the advantage of obtaining high-purity carrier-free lutetium-177 even if lutetium is obtained through indirect production methods.

[0084] In a preferred embodiment of the present invention, the amineonium ion preferably comprises a primary amineonium ion or a hydroxyl-substituted primary amineonium ion, more preferably, it comprises a primary amineonium ion substituted with an alkyl group having fewer carbon atoms or an amineonium ion in which the hydroxyl group of the amine is substituted, i.e., methylamine cation, ethylamine cation and ethanolamine cation.

[0085] In this case, compared to cases involving a high number of ammonium ions, a first elution time of less than 2 hours is more suitable, and the separation ability is better when using primary amines, and the elution between lutetium and ytterbium is clearly distinguished with a short elution time, which is more advantageous.

[0086] In a preferred embodiment of the present invention, the concentration of the chelating agent in the first eluent can be 0.01M to 0.5M, and the concentration of ammonium ions can be 0.01M to 1.0M.

[0087] When the concentrations of the chelating agent and ammonium ions are below 0.01 M, the elution time becomes longer. Conversely, when the concentration exceeds 0.5 M, the elution time shortens rapidly, making it difficult to separate lutetium-177 from ytterbium.

[0088] Furthermore, preferably, the chelating agent can be C2-C4. 12 Compounds or their salts that contain other hydrophilic functional groups besides the carboxyl group in monocarboxylic acid, dicarboxylic acid, tricarboxylic acid, or tetracarboxylic acid.

[0089] For example, the chelating agent may be selected from 2-hydroxyisobutyric acid (2-HIBA), 3-hydroxybutyric acid (3-HIBA), 3-hydroxypropionic acid, tartaric acid, lactic acid, citric acid, and glycolic acid.

[0090] More preferably, the chelating agent may be 2-hydroxyisobutyric acid (2-HIBA). When 2-hydroxyisobutyric acid (2-HIBA) is used as a chelating agent, it has the advantage of being easy to separate and remove compared with other compounds because its structure readily forms weak chelates with metal ions.

[0091] Furthermore, the types of cation exchange resins used as stationary phases in separation and purification columns may be the same or different in the two columns.

[0092] The cation exchange resin may contain one or more of the following: sulfonic acid group (-SO3H), phosphate group (-OP(O)(OH)2 or -P(O)(OH)2) and carboxyl group (-C(O)OH).

[0093] Furthermore, the cation exchange resin preferably uses a polymer, inorganic material, or a mixture of polymer and inorganic material as a support and contains one or more of the sulfonic acid group, phosphoric acid group, and carboxyl group selected above.

[0094] More preferably, the cation exchange resin can be one or more resins selected in polymeric form from substances having sulfonic acid groups. However, it is not necessarily limited to this, and a suitable cation exchange resin can be selected from those commonly used in this art, depending on the polarity, pH, and separation conditions of the eluent.

[0095] Furthermore, the separation method of the present invention is characterized in that the separation column is saturated with the eluent before injection. Pre-containing the separation column in the eluent provides the advantage of easy separation even with a single eluent, without using an eluent with a concentration gradient. When separation is performed without pre-saturation with the eluent, separation occurs simultaneously with the eluent flow equilibrating the column, thus increasing the total separation time and forcing the use of an eluent with a concentration gradient.

[0096] According to a preferred embodiment of the present invention, lutetium can be eluted first in the separation column, followed by ytterbium elution.

[0097] Furthermore, the eluted lutetium can be introduced into the purification column as the elution solution itself. Subsequently, the eluted ytterbium can be purified using a separate column, different from the aforementioned purification column.

[0098] Figure 1 A diagram is provided to briefly illustrate the structure of the apparatus for carrier-free lutetium-177 separation according to the present invention. (Refer to...) Figure 1 It can be confirmed that purification column 1, used to purify lutetium eluted first from the separation column, and purification column 2, used to purify ytterbium eluted subsequently, are set up separately.

[0099] In a preferred embodiment of the invention, preferably, the lutetium and ytterbium mixture to be introduced into the separation column can be dissolved in hydrochloric acid or nitric acid to form M. 3+ (Cl - )3 or M 3+ (NO3 - The compound is then heated to remove excess acid and dissolve it in water. However, the form of the mixture introduced into the column can be selected in a manner that is conventionally used and in which conventional creativity can be exercised to replace or change it to a certain extent.

[0100] Furthermore, lutetium-177 purified by a purification column can be obtained in the form of the desired compound using conventional methods, and such methods are within the scope that can be implemented by those skilled in the art.

[0101] The present invention will now be described in further detail with reference to the embodiments. However, it should be understood that the scope of the present invention is not limited to the following embodiments, and the content disclosed in the embodiments is merely exemplary in order to enable a more specific understanding of the present invention.

[0102] <Example>

[0103] Comparative Example 1

[0104] In a separation column (a cylindrical column with a diameter of 10 mm and a height of 70 mm) filled with a stationary phase cation exchange resin containing sulfonic acid groups, 2-hydroxyisobutyric acid (2-HIBA) (0.07 M) was added as a chelating agent, and 25% ammonia water was added to prepare an aqueous solution with a pH of 4.2 as the first eluent. The solution was injected into the column until it was completely saturated.

[0105] In a research nuclear reactor, 50 mg of ytterbium oxide (Yb₂O₃) is added at a concentration of 1 × 10⁻⁶. 14 Irradiated with neutrons in a neutron beam for 5 days. The resulting ytterbium oxide-lutetium mixture (Yb₂O₃- 177 Lu₂O₃ was dissolved in saturated hydrochloric acid (c-HCl, 11.4 M) to prepare a metal chloride (MCl, where M is any metal ion) state. The prepared sample was heated to remove excess acid, and 1 ml of water was added to prepare YbCl₃-. 177 LuCl3 aqueous solution.

[0106] The YbCl3- 177 LuCl3 aqueous solution was eluted into the separation column at a rate of 1.5 ml / min.

[0107] First, the eluent containing the eluted lutetium-177 compound is injected into a purification column (a cylindrical column with a diameter of 5 mm and a height of 20 mm) filled with the same cation exchange resin as the separation column and saturated with water.

[0108] The purification column containing lutetium-177 was washed with a cleaning solution to remove organic and inorganic components from the eluent. Next, lutetium-177 was recovered from the purification column using a recovery solution containing a strong acid. After heating the recovery solution to 150°C to remove the acid, it was dissolved in 1 ml of 0.01 M hydrochloric acid to obtain high-purity, carrier-free lutetium-177.

[0109] The elution time in the separation column needs to be more than 40 minutes.

[0110] The elution of lutetium and ytterbium was determined by a gamma-ray detector, and the chromatograms for each case are shown in [image / image / etc.]. Figure 3 middle.

[0111] Comparative Example 2:

[0112] The same procedure as in Example 1 was followed, but the mixture of ytterbium oxide and lutetium oxide that had not been irradiated with neutrons was treated in the same way to prepare a mixture of ytterbium chloride and lutetium chloride, which was then used as a sample for the same separation and purification process.

[0113] The eluted lutetium and ytterbium were determined using a UV detector, and the chromatogram was plotted on... Figure 2 middle.

[0114] Example 1

[0115] The procedure was carried out in the same manner as in Comparative Example 2, except that the first eluent was replaced with a solution containing the same concentration of methylaminium ions as primary ammonium ions.

[0116] Lutetium was eluted starting at 77 minutes and proceeded for approximately 20 minutes. To facilitate the recovery of ytterbium as the target substance, at the 120-minute mark, a second elution buffer (0.2 M HIBA aqueous solution adjusted to pH 4.2 using methylamine ontium) was used for elution.

[0117] Similarly, the chromatograms obtained using the same detector are shown in Figure 4 middle.

[0118] Example 2

[0119] The procedure was carried out in the same manner as in Comparative Example 2, except that the first eluent was replaced with a solution containing the same concentration of ethylaminium ions as primary ammonium ions.

[0120] The elution of lutetium began at 70 minutes and proceeded for approximately 20 minutes. To facilitate the recovery of ytterbium as the target substance, the elution was replaced at 110 minutes with a second elution buffer (0.2 M HIBA aqueous solution adjusted to pH 4.2 using ethylamine ontium) at a higher concentration than the first elution buffer.

[0121] Similarly, the chromatograms obtained using the same detector are shown in Figure 5 middle.

[0122] Example 3

[0123] The procedure was carried out in the same manner as Comparative Example 2, except that the first eluent was replaced with a solution containing the same concentration of ethanolaminium ions, which are hydroxyl-substituted as primary ammonium ions.

[0124] The elution of lutetium began at approximately 120 minutes and proceeded for approximately 24 minutes. To facilitate the recovery of ytterbium as the target substance, at the 177-minute mark, the elution was replaced with a second elution buffer (0.2 M HIBA aqueous solution adjusted to pH 4.2 using ethanolamine ontium) at a higher concentration than the first elution buffer.

[0125] Similarly, the chromatograms obtained using the same detector are shown in Figure 6 middle.

[0126] Example 4

[0127] The procedure was carried out in the same manner as in Comparative Example 2, except that the first eluent was replaced with a solution containing the same concentration of diethyl aminium ions as secondary ammonium ions.

[0128] The elution results showed that no lutetium was eluted after 4 hours.

[0129] The elution with the second eluent (0.2M HIBA aqueous solution adjusted to pH 4.2 using diethylamine ontium) showed that lutetium began to elute at 70 minutes, but it was confirmed that the elution was mixed with ytterbium.

[0130] The chromatogram obtained using the same detector is shown in Figure 7 middle.

[0131] Example 5

[0132] The procedure was carried out in the same manner as in Comparative Example 2, except that the first eluent was replaced with a solution containing the same concentration of amino-substituted ethylenediamine ions as primary ammonium ions.

[0133] Elution with the first eluent resulted in the separation of lutetium and ytterbium within 15 minutes. On repeat experiments, ytterbium was also detected in a portion of the lutetium fraction.

[0134] The chromatogram obtained using the same detector is shown in Figure 8 middle.

[0135] Example 6

[0136] The procedure was carried out in the same manner as Comparative Example 2, but a silica support was used as the cation exchange resin, and the first eluent was a solution containing the same concentration of methylaminium ions as primary ammonium ions instead of ammonia.

[0137] Elution was performed with the first eluent, and lutetium was identified after 4 minutes of elution, and it was eluted after approximately 7 minutes. The metal components of the separated eluent were then identified, and a portion of ytterbium was also identified.

[0138] The chromatogram obtained using the same detector is shown in Figure 9 middle.

[0139] Table 1 below shows the elution times for lutetium and ytterbium when eluted according to the methods of the Examples and Comparative Examples.

[0140] Table 1

[0141]

[0142] As shown in Table 1, replacing ammonium ions with primary amineonium or hydroxyl-substituted primary amineonium ions in the eluent according to the separation methods of Examples 1 to 3, although the elution time was prolonged, a significant time interval existed between lutetium and ytterbium, thus confirming that clear separation occurred. The disadvantage of Example 4 is that while the separation capability was further improved by using secondary amineonium ions, the elution time was nearly doubled.

[0143] Example 5 found that using amineonium ions with two amino groups actually resulted in a poorer separation ability compared to ammonium ions.

[0144] In Example 6, it was confirmed that using a silica support as the stationary phase actually reduced the separation capability.

[0145] Industrial availability

[0146] The method for separating lutetium-177 according to the present invention improves separation capacity without the use of gradient elution solutions, thus enabling the production of carrier-free lutetium-177. This also reduces the amount of expensive cation exchange resin used and the amount of waste generated, and allows for the separation of carrier-free lutetium-177 in a short time.

[0147] Furthermore, since it uses an eluent without a concentration gradient, it has the advantage of being able to recover the eluent and simplifies the separation and purification process.

Claims

1. A carrier-free method for separating lutetium-177, characterized in that, A mixture containing ytterbium and lutetium-177 compounds generated by neutron irradiation targeting ytterbium-176 was subjected to the following two-step column chromatography: 1) Separation column: A column saturated with the stationary phase, using a cation exchange resin as the stationary phase and a first eluent containing primary ammonium ions and a chelating agent; 2) Purification column: The cation exchange resin is used as the stationary phase and impregnated with water. In this process, a first eluent is used as the mobile phase, which is a single eluent without a concentration gradient.

2. The carrier-free lutetium-177 separation method according to claim 1, characterized in that, Lutetium-177 was first eluted in the separation column, followed by ytterbium.

3. The carrier-free lutetium-177 separation method according to claim 2, characterized in that, When lutetium-177 is eluted from the separation column, a first eluent containing the eluted lutetium-177 is introduced into the purification column. When the separation of lutetium-177 or the elution of ytterbium is completed in the separation column, a second eluent containing one or more primary to quaternary ammonium ions and a chelating agent is used as the mobile phase, and the separated ytterbium is introduced into a separate column for chromatography to obtain ytterbium.

4. The carrier-free lutetium-177 separation method according to claim 3, characterized in that, The concentrations of chelating agents and primary to quaternary ammonium ions in the second eluent are higher than those in the first eluent.

5. The carrier-free lutetium-177 separation method according to claim 1, characterized in that, The cation exchange resin contains one or more of the following groups in an organic, inorganic, or organic-inorganic mixture support: sulfonic acid group (-SO3H), phosphate group (-OP(O)(OH)2 or -P(O)(OH)2), and carboxyl group (-C(O)OH).

6. The carrier-free lutetium-177 separation method according to claim 1, characterized in that, The primary amine ion has a C1-C8 straight-chain or branched alkyl group that is substituted or unsubstituted with a hydrophilic functional group.

7. The method for separating carrier-free lutetium-177 according to claim 6, characterized in that, The hydrophilic functional groups are each independently selected from one of the following groups: hydroxyl, carbonyl, amino, carboxyl, ester, alkoxy, amide, imino, oxime, mercapto, thioether, sulfoxide, thioketone, and thioester.

8. The method for separating carrier-free lutetium-177 according to claim 1, characterized in that, The chelating agent is C2-C. 12 Compounds or their salts that contain other hydrophilic functional groups besides the carboxyl group in monocarboxylic acids, dicarboxylic acids, tricarboxylic acids, or tetracarboxylic acids.

9. The method for separating carrier-free lutetium-177 according to claim 8, characterized in that, The chelating agent is 2-hydroxyisobutyric acid, also known as 2-HIBA.

10. The carrier-free lutetium-177 separation method according to claim 1, characterized in that, The concentration of the chelating agent in the first eluent is 0.01M to 0.5M.

11. The carrier-free lutetium-177 separation method according to claim 1, characterized in that, The concentration of amine ions in the first eluent is 0.01M to 1.0M.

12. The carrier-free lutetium-177 separation method according to claim 3, characterized in that, The concentration of the chelating agent in the second eluent is 0.1M to 1.0M.

13. The carrier-free lutetium-177 separation method according to claim 1, characterized in that, In the purification step via the purification column, A second eluent containing carrier-free lutetium-177 eluted from the separation column is introduced into the purification column, and includes: Step a) Using an organic or inorganic acid with a concentration of 0.1M to 2M as the mobile phase, the mixture of chelating agent and amine contained in the first eluent is eluted; and Step b), next, an organic or inorganic acid with a concentration of 3M to 12M is used as the mobile phase to elute carrier-free lutetium-177.

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