A METHOD FOR PRE-ENRICHING OF AN ISOTOPE AND A PRE_ENRICHER

Abstract

l 8 The invention is in the field of a method of pre-enriching isotopes, a pre-enrichment system, an array of such enrichment systems, and a computer program for carrying out the method. It therefore also relates to preparations containing radioactive substances, which may be used in therapy or testing. Typically thereto a further enrichment step is required.

Description

l AMETHODFORPRE-ENRICHINGOFANISOTOPEANDAPRE_ENRICHER FIELD OF THEINVENTION The invention is in the eld of a method ofpre-enriching isotopes, a pre-enrichment sys- tem, an array ofsuch enrichment systems, and a computer program for carrying out the method. It therefore also relates to preparations containing radioactive substances, which may be used in therapy or testing. Typically, thereto a further enrichment step is required. BACKGROUND OF THEINVENTION Isotopes are distinct nuclear species ofthe same chemical element, wherein the chemical element is an element ofthe Periodic System ofElements (periodic table). Isotopes have the same atomic number, relating to the number ofprotons in their nuclei. And therefore isotopes have the same position in the periodic table. The number ofprotons is equal to the number of electrons in the neutral atom. The difference between isotopes ofthe same element lies in the number ofneutrons in their nuclei. Typically, isotopes of a given element have similar or the same chemical properties, however, they often have different physical properties. Examples of such isotopes are 40Ca, 44Ca, 46Ca,48Ca, 142Nd, 143Nd,144Nd, 145Nd, 146Nd,148Nd, 150Nd, 156Dy, 158Dy, 160Dy, 161Dy, 162Dy, 163Dy, and 164Dy. Isotopes are also referred to as nuclides. A nuclide is an individual nuclear species ofan atom with a specic number ofprotons and neutrons in the nucleus, as are the isotopes. The nuclide concept emphasizes nuclear properties over chemical properties, whereas the isotope concept emphasizes chemical over nuclear. Heavy, stable isotopes ofcalcium, in particular 46Ca and 48Ca, have a number ofmedical and scientic applications. The natural abundance is low, only 0.004% for 46Ca and 0.187% for 48Ca. Enrichmentup to a medium to high purity is possible using electromagnetic isotope separa- tion in a calutron (see below) or by laser separation. However, both methods have a relatively low efciency, which limits the production quantity, and drives up the costs. For instance, the annual worldwide production ofpure 48Ca is 10 g and the price is above 400 k / g. Calcium isotopes are an important target material to produce isotopically pure nuclides for medical purposes. In personalized medicine, patients are treated according to an individually tai- lored treatment regime. In nuclear medicine, this approach is realized by exploiting diagnostic techniques, such as non- invasive imaging by means ofPositron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT), together with individualized radi- otherapeutic treatment. The resulting combination became known as the theragnostic approach and uses the same molecular targeting vectors, labelled either with a diagnostic or therapeutic ra- dionuclide In addition, ideally, employed radionuclides represent a matched pair, wherein both are ra- dioisotopes ofthe same chemical element. Only a limited number ofmatching radionuclides are found suited for radio-theragnostic use. Ofthose the radionuclides of scandium, 44Sc / 43Sc and 47Sc, are most promising candidates. The emission oflow-energy B-particles from 47Sc is par- ticularly interesting for targeted radionuclide therapy of small tumors and cancer metastases. Moreover, the shorter half-life of47Sc (Tl / 2 = 3.35 d) is favorable for certain applications. Availability ofhigh activity 47Sc with adequate purity is important for future clinical applica- tions. The current bottleneck lies in the production ofpure 47Sc samples using enriched isotopes ofcalcium. The preferred production mode for 47Sc is through neutron capture on 46Ca: 46Ca(n,y)47Ca > 47Sc. The low natural abundance of46Ca, even 45x lower than for 48Ca, makes this process economically not viable. An alternative production mechanism starts with 48Ca and uses the 48Ca(p,2n)47Sc process. Using a proton beam with an energy of 17-24MeV on a CaCO3 target purities of85% for 47Sc have been achieved. Both 46Ca and 48Ca are used to measure cal- cium absorption mainly inwomen and children. In adults, calcium deciency is strongly related to increasing severity of osteoporosis. In children, calcium deciency is primarily related to the development of rickets. Finally, 44Ca has a natural abundance of2%. It is used the production of thePET isotope 44Sc in cyclotrons. While there is adequate supply, the cost is 25k / g for high purity calcium Isotope production, specically isotope enrichment, may further rely on a so-called calu- tron as mentioned. The calutron is a type ofmass spectrometer, which is an instrument in which a sample is ionized and then accelerated by electric elds and deected by magnetic elds. In the mass spectrometer ions ultimately collide with a plate and produce a measurable electric cur- rent. Since the ions ofthe different isotopes have the same electric charge but different masses, the heavier isotopes are deected less by the magnetic eld, causing the beam ofparticles to sep- arate into several beams by mass, striking the plate at different locations. The same principle may be used, not only to separate isotopes from one and another, but also to collect separated fractions thereof, with respective higher and lower concentrations of specic isotopes. Therewith enriched isotopes can be produced. Production ofthese isotopes is however slow and costly. As such the availability of certain isotopes, such as heavy isotopes, e.g. ofcalcium (48Ca, 46Ca and 44Ca), which are used in medical applications and scientic research, may form a problem, in particularwhen a calutron is not or less available. The present invention aims to resolve or at least reduce this availability problem. Further, isotopes may be treated with e.g. radiation to produce a desired (further) isotope. Typically, isotopes are separated from one and another in a further process step, and then trans- ported to a location ofuse. The present invention therefore relates to an improved method for pre-enrichment of iso- topes, a system for such enrichment, and further aspects thereof, which overcome one or more of the above disadvantages, withoutjeopardizing functionality and advantages. SUMMARY OF THE INVENTION The present invention relates in a rst aspect to a method ofpre-enriching an isotope, comprising providing a mixture comprising a rst salt comprising the to be enriched isotope rst cation of a rst chemical element, and a rst anion, and at least one further isotope cation of said chemical element, and at least one second salt comprising a second anion and a second cation, providing the salt in an enrichment system, the enrichment system comprising at least one cath- ode compartmentCC comprising a cathode (4), at least one anode compartmentAC comprising an anode (5), a bridging compartmentBC in uidic contact with the at least one cathode com- partment and the at least one anode compartment comprising a lter F, a heater for heating the respective compartments, a salt outlet (13) in uidic contact with the at least one cathode com- partment CC, and a salt inlet (12) in uidic contact with the at least one anode compartment AC, melting the salt, applying a voltage to the cathode and anode during an enrichment time at an en- richment current density, therewith providing ow ofthe molten salt, providing un-enriched mixture to the salt inlet, that is, with natural occurring quantities ofrespective isotopes, and op- tionally removing an isotope depleted mixture from the salt outlet (13), that is, with less heavier isotope than naturally occurring. In comparative cases likewise lighter isotopes, of interest, may be obtained at higher concentrations or quantities than naturally occurring. The present invention relates amongst others to a device for pre-enriching heavy calcium isotopes by counter current electromigration in a molten salt solution. It is noted that typically molten salts are highly corro- sive, so care has to be taken. The present mixture is found to be much less corrosive. Also, by using a mixture with a relatively low melting point, energy costs are much more acceptable. An enrichment factor ofve would already reduce the production time and cost by 80%.e.g. for Ca. In an exemplary embodiment a pre-enricher for 46Ca and 48Ca is developed. By enriching those isotopes by a factor 5-10, further enrichment to a higher purity is less cumbersome. The time re- quired for enrichment and costs would be reduced by a similar factor and in addition would re- duce the pressure on enrichment facilities. The present invention would typically start from natu- ral available material, such as Ca comprising 46Ca and 48Ca isotopes. The present method can performed in a reproducible and consistent manner, e.g. involving lling and extraction. There- with a target production of250g / year is easily achievable. In an example the present device also enriches 44Ca by about halfthe amount wherein 48Ca is enriched. Such is an additional ad- vantage. It is noted that in the present invention a relative mobility of different species, e.g. cati- ons, and anions, is not the same in the present mixture. Not the same implies that the relative mobility [m / sec] of said different species is, relative to another species, at least 1% larger or smaller, typically at least 5% larger or smaller, such as at least 10% larger or smaller. To some extent the present mobility may be compared to electrophoresis. Mobilities are typically rather small, e.g. in the order 10'9-10'6 m / s, e.g. depending on the cation, applied voltage, charge ofthe cation, Stokes radius, concentration, etc. A rst second saltmay be referred to as second salt, a subsequent second salt as third salt, and so on. The present rst salt is typically pre- sent in an amount of 10-70 atom%, in particular 20-50 atom%, more in particular 30-45 atom%, such as 38-42 atom%, the present second salt is typically present in an amount of 10-70 atom%, in particular 20-50 atom%, more in particular 30-45 atom%, such as 38-42 atom%, an optional present third and fourth salt may be typically each individually present in an amount of2-30 atom%, in particular 5-25 atom%, more in particular 10-20 atom%, such as 15-18 atom%, an op- tional fth and subsequent saltmay be typically each individually present in an amount of0.1-20 atom%, in particular 0.5-17 atom%, more in particular 1-15 atom%, even more in particular 3-13 atom%, such as 5-12 atom%. Ifnot mentioned otherwise, characteristics of species are taken at a temperature of20 0C (293 K) and at 100 kPa, or at the temperature ofthe respective melt, and pressure thereof. Spe- cic characteristics can easily be found in relevant text books, or on the intemet, such as an atomic mass, etc., and can be measured accordingly. In an exemplary embodiment in a bath ofmolten salt, a cathode and an anode are posi- tioned in two sub-reservoirs being connected by a barrier. In operation, the cathode attracts the positive metal ions, with the lighter isotope moving faster than the heavier one. At the anode the negative ions may form a gas (e.g. C12, Brz), which may be fed back to the cathode compartment to react with the metal. This forms a counter-current. In an embodiment, by carefully balancing the currents a net migration to the anode reservoir for the heavier isotopes and to the cathode res- ervoir for the lighter isotopes is created and after some time the heavier isotopes accumulate in the cathode reservoir. In a second aspect the present invention relates to a computer program comprising instruc- tions, the instructions when loaded and running on a computer causing the computer to carry out: providing a mixture comprising a rst salt comprising the to be enriched isotope rst cation ofa rst chemical element, and a rst anion, and at least one further isotope cation of said chemical element, and at least one second salt comprising a second anion and a second cation, providing the salt in an enrichment system, the enrichment system comprising at least one cath- ode compartmentCC comprising a cathode (4), at least one anode compartmentAC comprising an anode (5), a bridging compartmentBC in uidic contact with the at least one cathode com- partment and the at least one anode compartment comprising a lter F, a heater for heating the respective compartments, a salt inlet (11) in uidic contact with the at least one cathode com- partment CC, and a salt inlet (12) in uidic contact with the at least one anode compartment AC, melting the salt, applying a voltage to the cathode and anode during an enrichment time at an en- richment current density, therewith providingow ofthe molten salt, providing un-enriched mixture to the salt inlet, and optionally removing an isotope depleted mixture from the salt outlet (13). In a third aspect the present invention relates to a systemA pre-enrichment system com- prising at least one cathode compartmentCC comprising a cathode (4), at least one anode com- partmentAC comprising an anode (5), a bridging compartmentBC in uidic contact with the at least one cathode compartment and the at least one anode compartment comprising a lter F, a heater for heating the respective compartments, a salt inlet (11) in uidic contact with the at least one cathode compartment CC, and a salt inlet (12) in uidic contact with the at least one anode compartment AC. In a fourth aspect the present invention relates to 27. An array (n*m) ofpre-enrichment systems according to any of claims 20-26, wherein in the array an enriched mixture outlet (13) of an ith pre-enrichment system in a row is in uidic contact with a mixture inlet (11) ofan i+1th pre-enrichment system in the same row, wherein ie [1,n-1].

Images