Method of manufacturing non-carrier-added high-purity 177Lu compounds as well as non-carrier-added 177Lu compounds

Abstract

The present invention relates to a column chromatographic method of manufacturing non-carrier-added high-purity .sup.177Lu compounds for medicinal purposes. In the method in accordance with the invention a cation exchanger and a suitable chelating agent are used. With the method in accordance with the invention it is possible for the first time to provide non-carrier-added high-purity .sup.177Lu compounds in milligram amounts for pharmaceutical-medicinal purposes from .sup.176Yb compounds irradiated with thermal neutrons, the radionuclides .sup.177Lu and .sup.176Yb being present in an approximate mass ratio of 1:10.sup.2 to 1:10.sup.10 for purification.

Claims

1. A method of manufacturing non-carrier-added high-purity .sup.177Lu compounds for medicinal purposes from .sup.176Yb compounds irradiated with thermal neutrons, wherein the end products of neutron irradiation, which contain a mixture of .sup.177Lu and .sup.176Yb in a mass ratio of 1:10.sup.2 to 1:10.sup.10, are used as base materials, wherein base materials that are insoluble in water, are converted into a soluble form, and wherein the method comprises the following steps: a) loading a first column packed with cation exchange material, with the base materials dissolved in an acid selected from the group consisting of HNO.sub.3, HCl, HF, H.sub.2SO.sub.4 and acetic acid; and containing .sup.177Lu and .sup.176Yb in a mass ratio of 1:10.sup.2 to 1:10.sup.10; exchanging the protons of the cation exchange material for ammonium ions, using an NH.sub.4Cl solution; and washing the cation exchange material of the first column with water; b) linking the outlet of the first column with the inlet of a second column that is packed with a cation exchange material; c) applying a gradient of water and a first chelating agent selected from the group consisting of: α-hydroxyisobutyrate, citric acid, citrate, butyric acid, butyrate, EDTA, EGTA and ammonium ions, starting at 100% of H.sub.20 to 0.2 M of the first chelating agent on the inlet of the first column, to elute .sup.177Lu compounds from the first and second column; d) determining the radioactivity dose at the outlet of the second column in order to recognize the elution of .sup.177Lu compounds; and collecting a first .sup.177Lu eluate from the outlet of the second column in a vessel; and protonating the chelating agent to inactivate same for the complex formation with .sup.177Lu ions; e) loading a final column packed with a cation exchange material by continuously conveying the first .sup.177Lu eluate of step d) to the inlet of the final column; washing out the first chelating agent with diluted mineral acid of lower concentration than 0.1 M; removing traces of other metal ions from the first .sup.177Lu solution by washing the cation exchange material of the final column with mineral acid of various concentrations in a range of 0.1 to 2.5 M; and f) eluting the .sup.177Lu ions from the final column with a highly concentrated mineral acid of 3 to 12 M; collecting the high purity .sup.177Lu eluate in a vaporizer unit and removing the mineral acid by vaporization.

2. The method in accordance with claim 1, characterized in that between steps d) and f) the following steps are performed: d.1) continuously conveying the first .sup.177Lu eluate of step d) to the inlet of a third column packed with cation exchange material, the cation exchange material being present in protonated form due to the loading with the first .sup.177Lu eluate; exchanging the protons of the cation exchange material for ammonium ions, using an NH.sub.4Cl solution; and washing the cation exchange material of the third column with water; d.2) linking the outlet of the third column with the inlet of a fourth column packed with a cation exchange material; d.3) applying a gradient of water and a second chelating agent selected from the group consisting of: α-hydroxyisobutyrate, citric acid, citrate, butyric acid, butyrate, EDTA, EGTA and ammonium ions, starting at 100% of H.sub.20 to 0.2 M of the second chelating agent, on the inlet of the third column to elute .sup.177Lu compounds from the third and fourth column; and d.4) determining the radioactivity dose at the outlet of the fourth column in order to recognize the elution of .sup.177Lu compounds; and collecting a second .sup.177Lu eluate from the outlet of the third column in a vessel; and protonating the chelating agent to inactivate same for the complex formation with .sup.177Lu ions.

3. The method in accordance with claim 2, characterized in that after elution of the .sup.177Lu compounds in steps d) and d.4) the first and second column as well as the third and fourth column are washed using higher concentrations of chelating agents to elute Yb ions from the cation exchange material, and Yb eluates obtained that essentially contain .sup.176Yb ions, are collected separately for the purpose of re-using them as base material for the manufacture of .sup.177Lu.

4. The method in accordance with claim 1, characterized in that .sup.176Yb oxides insoluble in water are converted into a water-soluble form by the use of 1 M to 12 M of HNO.sub.3 or H.sub.2SO.sub.4.

5. The method in accordance with claim 1, characterized in that loading of the cation exchange materials is done using an acid concentration of 0.01 M to 2 M of HNO.sub.3 or HCl.

6. The method in accordance with claim 1, characterized in that the cation exchange material is selected from the group consisting of: macroporous and gel-like polystyrene based cation exchange resins and silicate based cation exchange resins.

7. The method in accordance with claim 1, characterized in that gram amounts of base materials are used and milligram amounts of .sup.177Lu are produced.

8. The method in accordance with claim 1, characterized in that yields of several TBq of .sup.177Lu and specific activities of approximately 3.9 TBq of .sup.177Lu per mg of lutetium are obtained.

9. The method in accordance with claim 1 wherein the use of cation exchange chromatography with a cation exchange resin as stationary phase and a chelating agent as mobile phase results in the manufacture of milligrams of high-purity, non-carrier-added .sup.177Lu compounds from grams of .sup.176Yb matrix.

10. A method of manufacturing non-carrier-added high purity .sup.177Lu compounds for medicinal and/or diagnostic purposes from .sup.176Yb compounds irradiated with thermal neutrons, wherein the end products of neutron irradiation, which essentially contain a mixture of .sup.177Lu and .sup.176Yb in a mass ratio of 1:10.sup.2 to 1:10.sup.10, are used as base materials, wherein base materials that are insoluble in water, are converted into a soluble form, and wherein the method comprises the following steps: a) loading a first column packed with cation exchange material, with the base materials dissolved in an acid selected from the group consisting of HNO.sub.3, HCl, HF, H.sub.2SO.sub.4 and acetic acid; and containing .sup.177Lu and .sup.176Yb in a mass ratio of 1:10.sup.2 to 1:10.sup.10; exchanging the protons of the cation exchange material for ammonium ions, using an NH.sub.4Cl solution; and washing the cation exchange material of the first column with water; b) linking the outlet of the first column with the inlet of a second column that is packed with a cation exchange material; c) applying a gradient of water and a chelating agent selected from the group consisting of: α-hydroxyisobutyrate, citric acid, citrate, butyric acid, butyrate, EDTA, EGTA and ammonium ions, starting at 100% of H.sub.20 to 0.2 M of the chelating agent on the inlet of the first column; d) determining the radioactivity dose at the outlet of the second column in order to recognize the elution of .sup.177Lu compounds; and collecting a first .sup.177Lu eluate from the outlet of the second column in a vessel; and protonating the chelating agent to inactivate same for the complex formation with .sup.177Lu ions; e) continuously conveying the first .sup.177Lu eluate of step d) to the inlet of a third column packed with cation exchange material, the cation exchange material being present in protonated form due to the loading with the first .sup.177Lu eluate; exchanging the protons of the cation exchange material for ammonium ions, using an NH.sub.4Cl solution; and washing the cation exchange material of the third column with water; f) linking the outlet of the third column with the inlet of a fourth column packed with a cation exchange material; g) applying a gradient of water and a chelating agent selected from the group consisting of: α-hydroxyisobutyrate, citric acid, citrate, butyric acid, butyrate, EDTA, EGTA and ammonium ions, starting at 100% of H.sub.20 to 0.2 M of the chelating agent, on the inlet of the third column; h) determining the radioactivity dose at the outlet of the fourth column in order to recognize the elution of .sup.177Lu compounds; and collecting a second .sup.177Lu eluate from the outlet of the fourth column in a vessel; and protonating the chelating agent to inactivate same for the complex formation with .sup.177Lu ions; i) loading a fifth column packed with a cation exchange material by continuously conveying the acidic .sup.177Lu eluate of step h) to the inlet of the fifth column; washing out the chelating agent with diluted mineral acid; removing traces of other metal ions from the .sup.177Lu solution by washing the cation exchange material of the fifth column with mineral acid of various concentrations in a range of 0.01 to 2.5 M; and j) eluting the .sup.177Lu ions from the fifth column with concentrated mineral acid of 3 M up to 12 M; collecting the high purity .sup.177Lu eluate in a vaporizer unit and removing the mineral acid by vaporization.

11. The method in accordance with claim 10 wherein the use of cation exchange chromatography with a cation exchange resin as stationary phase and a chelating agent as mobile phase results in the manufacture of milligrams of high-purity, non-carrier-added .sup.177Lu compounds from grams of .sup.176Yb matrix.

Description

(1) Further advantages and features are to be seen from the description of an example and from the drawings:

(2) FIG. 1 shows a schematic structure of an exemplary apparatus for performing the method in accordance with the invention;

(3) FIG. 2 shows a column chromatogram of the separation of .sup.177Lu and ytterbium, recorded on the outlet of column S1 of FIG. 1;

(4) FIG. 3 shows a column chromatogram of the separation of .sup.177Lu and ytterbium, recorded on the outlet of column S2 of FIG. 1; and

(5) FIG. 4 shows an SF-ICP mass spectrum of the non-carrier-added .sup.177Lu end product (n.c.a. .sup.177Lu) obtained in accordance with the invention as compared to c.a. .sup.177Lu in accordance with the prior art.

(6) In the following, the exemplary structure of an apparatus for performing the method in accordance with the invention is described, thereby referring to FIG. 1:

(7) For reasons of radiation protection, the process is performed in an environment shielded by lead and/or plexiglass. This may be a hot cell or a different suitable system. In view of the fact that the product is used as pharmaceutical agent, the environment is to be classified into corresponding cleanliness classes in accordance with the demands of pharmaceutical manufacture (good manufacturing practice, GMP of the EU). In this case, the ambient condition in the hot cell has to conform to class C or higher.

(8) The hot cell has suitable double door systems to the environment where auxiliary systems for production, such as HPLC pumps, syringe pumps or other conveying systems, and the control system are accommodated.

(9) The system has several individual components such as chromatographic columns (VS1, S1, VS2, S2 and S3), flasks (F1 to F6) and pumps (P1 to P7) that are connected with each other via capillaries and valves.

(10) Depending on their function, the pumps may be configured as vacuum pumps, syringe pumps, HPLC pumps, peristaltic pumps, or according to other principles of operation. In the present example, the pumps (P1) and (P2) are configured as HPLC pumps. They convey different concentrations (from 0.01 M to 10 M) and flow rates (from 0.05 ml/min to 100 ml/min) of H.sub.2O, HIBA and NH.sub.4Cl. The pumps (P3), (P4), (P5), (P6) convey different concentrations (from 0.01M to 10 M) and flow rates (from 0.05 ml/min to 100 ml/min) of further reagents such as HCl, HNO.sub.3, H.sub.2O and air. In the preferred configuration, pumps P3 to P6 are syringe pumps or plunger pumps. However, they may be implemented by further valves to form a pump system in the configuration of a syringe pump. Pump 7 (P7) is a vacuum pump configured to be able to apply a variable negative pressure (from 1 mbar to 1000 mbar) to the system.

(11) The components marked by (N2) (without numbers of their own) are inert gas sources, preferably nitrogen and argon, through which pressure of between 0.1 bar to 5 bar or even higher, depending on the configuration of the system, can be applied to the system.

(12) Component (1) is configured for breaking ampoules and in addition for the conversion of an ytterbium oxide into ytterbium nitrate. In this example, the two separate functions are configured as integration of functions.

(13) Component (2) is a vaporizer unit for drying up the lutetium solution. Component (3) is a system for accommodating the final product, such as, for example, a glass vial. Within the scope of an integration of functions, the components (2) and (3) can be configured as one structural component.

(14) All valves in the example are depicted so as to be switchable in each direction. The position of the valves is selected so that the number thereof is minimized. As is obvious to a person of average skill from FIG. 1, other valve configurations, particularly for joining or separating functions, are easily conceivable.

(15) Flasks (F1), (F2), (F3), (F4), (F5), (F6) are containers for receiving solutions. Preferred are flasks of glass having a volume adapted to the requirements of the method in accordance with the invention. Particularly for larger volumes the preferred embodiment is a plastic container.

(16) The column system exemplarily shown in the preferred embodiment comprises so-called pre-columns (VS 1) and (VS 2) through which loading is carried out. The main columns (S1) and (S2) which in the example form the actual separation columns, are attached to the pre-columns, so that the respective partner columns (VS1) and (S1) or (VS2) and (S2) can be connected to a column system.

(17) The entire fluid scheme of the exemplary apparatus for performing the invention is depicted in FIG. 1, irrespective of the actual configuration, also the configuration within hot cells. A preferred embodiment is the positioning of components (2) and (3) in a separate shielded device so as to enable the follow-up process, i.e. filling up the amounts of .sup.177Lu intended for the customer, all in one device. For logical reasons, the components (2) and (3) are integrated in one system. A further preferred embodiment is the location of component (3) in a separate shielded unit, so that the entire process takes place in one unit and merely the vial (3) for receiving the product is positioned in a pharmaceutically more sophisticated environment.

(18) For control of the process, activity sensors are used in the example that each are positioned at the end of columns (S1), (S2) and (S3) in order to monitor the process of separation.

EXAMPLE

(19) The present invention is a manufacturing process in which .sup.177Lu n.c.a. is extracted from reactor-irradiated .sup.176Yb. For this purpose, the irradiated ampoule is opened in an ampoule cup and transferred into a conversion vessel (F1). The .sup.176Yb may be present as an insoluble oxide. For the extraction of the .sup.177Lu that occurred during irradiation, the base material has to be converted into a soluble form. In the present example, this may be achieved by the use of 1 M to 12 M of HNO.sub.3, if need be, by heating.

(20) Through the dilution to a lower acid concentration of between 0.01 M and 1.5 M of HNO.sub.3 the solution can be loaded onto a pre-column system (VS1) as first column. By loading, the column material, a macroporous cation exchanger on a polystyrene basis, of the pre-column system is converted into a negative H.sup.+ form (protonated form) for separation. Through the use of NH.sub.4Cl the column material of the pre-column system is converted into its NH.sub.4.sup.+ form. Subsequently, the pre-column system VS1 is washed with water and connected with the separation column S1 as second column.

(21) Separation is conducted by way of the pump P1 at high flow rates (10-50 ml/min). For this purpose, a gradient of water and of α-hydroxy-isobutyrate (HIBA) used as chelating agent in the example, which is optimized for the separation in a VS1/S1 system, is set based on 100% of H.sub.2O to 0.2 M of HIBA and separation is run through the pre-column system VS1 and the separation column S1. The separation is monitored by way of dose rate sensors. As soon as the .sup.177Lu is eluted from the column S1, the eluate is collected in the collection flask F2.

(22) The separation of .sup.177Lu and ytterbium is depicted as a chromatogram in FIG. 2. The ordinate indicates the eluted % amount of the .sup.177Lu and ytterbium, respectively, applied onto the column while the abscissa indicates the retention time in minutes. The massive peak rise of the ytterbium is due to the fact that shortly after a maximum of the lutetium peak a shift was made to a high concentration of HIBA, so that the ytterbium can be obtained within a reasonable time and in an acceptable volume.

(23) The chelating agent still contained in the eluate of column S1, HIBA in the present example, is protonated through the addition of acid and thus is rendered inactive. After the .sup.177Lu has been collected, the ytterbium is eluted from the first and second column through the use of higher concentrated HIBA and collected separately for the purpose of recycling.

(24) Through addition of an acid into F2 the eluate of S1 can be run on a second pre-column system VS2. In the example, the eluate is applied through nitrogen pressure to the pre-column system VS2 as third column still while further eluate is being collected. In so doing, the addition of an acid into the flask F2 is required either at regular intervals or continuously. In loading, the column material of the system VS2 likewise is converted into its H.sup.+ form. For conversion of the undesired H.sup.+ form into the NH.sub.4.sup.+ form preferred for the separation, the VS2 system is washed with NH.sub.4Cl and subsequently with water. The pre-column system VS2 is then connected with the separation column S2 as fourth column.

(25) The further separation is conducted by way of an HPLC pump P2 at medium flow rates (1-10 ml/min). For this purpose, a gradient of water and HIBA optimized for separation in a VS2/S2 system as mentioned above is set and separation is run through the pre-column system VS2 and the separation column S2.

(26) The separation is monitored by way of dose rate sensors. As soon as the .sup.177Lu is eluted from the column S2, the eluate is collected in the collection flask F3. The chelating agent HIBA still contained in the eluate, is protonated through the addition of acid and thus is rendered inactive. After the .sup.177Lu has been collected, the ytterbium is eluted from columns VS2 and S2 through the use of higher concentrated HIBA, and collected separately for the purpose of recycling.

(27) FIG. 3 shows a section of a column chromatogram on column S2 in which again the dose rate is plotted against the retention time in minutes. Similar to FIG. 2 the ytterbium peak (now merely being very small) in FIG. 3 only appears to be shortly (with a retention time of approximately 135 min) after the lutetium peak as shortly after the maximum of the lutetium peak (approximately 115 min) a shift to a high concentration of HIBA was made. Otherwise, the ytterbium during the separation would appear only after several hours, which would unduly retard the process since it is, of course, useful to recycle the ytterbium, in particular .sup.176Yb.

(28) The eluate of column S2 is loaded from the collection flask F3 to a final column S3 as fifth column. For this purpose, while still being collected, the eluate is applied through nitrogen pressure from the collection flask F3 to column S3. In so doing, the addition of an acid into the flask F3 is required at regular intervals. After terminating loading of the final separation column S3, the column is liberated of HIBA by washing with diluted acid. Through selectively flushing the column S3 with acid of various concentrations a further separation of traces and impurities, respectively, of other metals is made possible.

(29) After final purification on the column S3 the .sup.177Lu is eluted into a vaporizer unit 2 by way of highly concentrated acid. The acid is removed through vaporization. The step also serves for sterilizing the end product at the same time.

(30) The .sup.177Lu n.c.a. can now be absorbed in the desired solvent and in the desired concentration. After a final determination of the activity obtained and quality check the produced .sup.177Lu is filled into a vial 3 according to customer requirements.

(31) Typically, the non-carrier-added .sup.177Lu compound obtained by way of the present method is characterized in that in a SF-ICP mass spectrum merely exhibits a peak at an atomic mass of 177, whereas c.a. .sup.177Lu essentially exhibits three main peaks at atomic mass units of 175, 176 and 177. Such difference is shown in the mass spectrum of FIG. 4. The ordinate indicates the isotope distribution on a scale of relative frequency of 0 to 12. With the abscissa of FIG. 4 the atomic mass is indicated. The mass spectroscopic method used was the sector field mass spectrometry with inductively coupled plasma [Sector Field Inductively Coupled Plasma—Mass Spectrometry, SF-ICP-MS].