Patent Application
20210350946
The present invention relates to methods for recovering a parent radionuclide from a radionuclide generator. In particular, the methods of the invention relate to recovering germanium-68 from a germanium-68/gallium-68 generator.
Radionuclides, or radioisotopes, are widely used in nuclear medicine for the diagnosis and treatment of disease. However, one of the practical issues faced in nuclear medicine is the desirability to use metastable short-lived radionuclides and at the same time have the radionuclides ready on demand in a hospital or clinical setting.
To address this problem, radionuclide generator systems have been developed. The generator systems comprise a parent-daughter radionuclide pair contained in an apparatus, the parent radionuclide having a longer half-life than the daughter radionuclide. The daughter radionuclide activity is replenished continuously by decay of the parent radionuclide meaning that the daughter radionuclide can be extracted repeatedly. Storage, transportation and on-demand extraction of the daughter radionuclide is therefore possible.
Two of the most widely used radionuclide generators are Mo-99/Tc-99m and Ge-68/Ga-68 generators. Tc-99m, which is used in medical imaging, has a half-life of 6 hours, whereas Mo-99 has a half-life of 66 hours. Ga-68, which is used in PET scanning has a half-life of 68 minutes, whereas Ge-68 has half-life of 270.82 days. Other parent/daughter radionuclide pairs for radionuclide generators include W-188/Re-188, Zn-62/Cu-62, Rb-81/Kr-81m and Sr-82/Rb-82.
Historically, radionuclide generators were based on liquid-liquid extraction techniques and were given the nickname “cows”, based on the fact that the daughter radionuclide could be “milked” from the parent nuclide. Modern methods are typically based on solid phase-based column chromatography. A number of different systems using combinations of inorganic or organic solid phases and mobile phases have been proposed and are commercially available.
In a typical generator system, the parent radionuclide is specifically adsorbed to a stationary phase or support material e.g. within a chromatography column. The daughter radionuclide should have a lower affinity for the support material so that it can be readily removed (e.g. eluted) from the generator.
The stationary phase or support material of the generator is typically an ion exchange resin such as alumina, TiO2, SnO2 or SiO2. The mobile phase is a solvent that is able to elute the daughter radionuclide after it has been produced by decay of the immobilized parent radionuclide. With columns comprising silica-based resins as the stationary phase, diluted hydrochloric acid is often used as the mobile phase. For alumina columns, saline is usually used as the mobile phase.
A parent radionuclide that is loaded into a generator column can be produced by a number of methods. For example, the most common method of producing Mo-99 is through fission of uranium-235 in a nuclear reactor. Ge-68 may be produced by proton accelerators, e.g. by proton capture after proton irradiation of Nb-encapsulated gallium metal, by proton capture and double neutron knockout from gallium-69 (Ga-69(p,2n)Ge-68) or by accelerator-produced helium ion (alpha) irradiation of zinc-66 after double neutron knockout (Zn-66(a,2n)Ge-68).
While in principle the physical half-life of a parent radionuclide should allow utility of the generator for a time period that is much longer than the half-life of the parent radionuclide, the shelf life of a generator does not necessarily parallel the physical half-life of the parent radionuclide. Decreasing qualities of the generator itself, such as reduced daughter radionuclide yield, degradation of the stationary phase and in particular parent radionuclide breakthrough mean that the shelf life of a generator is significantly shorter than the lifetime potential of the parent radionuclide.
For example, Ge-68/Ga-68 generators have a typical shelf life of one year, which is similar to the physical half-life of Ge-68 (270.82 days). Accordingly, upon expiry, around 40% of the initial Ge-68 activity remains in the generator.
To date, an effective commercial process for the recovery of parent radionuclides from radionuclide generators has not been developed.
According to an aspect of the present invention there is provided a method for recovering a parent radionuclide from a radionuclide generator, the radionuclide generator comprising the parent radionuclide adsorbed to a stationary phase, the method comprising a series of elutions comprising:
According to another aspect of the present invention, there is provided method for recovering a parent radionuclide from a radionuclide generator comprising the parent radionuclide adsorbed to a stationary phase, the method comprising:
According to another aspect of the present invention, there is provided a parent radionuclide recovered according to the methods described herein.
According to another aspect of the present invention, there is provided method for recycling a parent radionuclide from a first radionuclide generator for reuse in a second radionuclide generator, the method comprising,
Applicant surprisingly found that the described series of elutions are effective in disengaging or decoupling the parent radionuclide from the stationary phase of a radionuclide generator. The methods of the invention make it possible to recover the parent radionuclide with high yield (≥88%), high chemical and radiochemical purity, and in a form suitable for the production of new radionuclide generators.
In some embodiments, the mineral acid may comprise hydroiodic acid (HI) and/or hydrobromic acid (HBr). In particular for the recovery of Ge-68, avoiding the use of HCl is preferable to avoid the formation of volatile gaseous germanium compounds such as GeCl4. Methods of the invention comprising HI and HBr mineral acid allow the parent radionuclide to be recovered safely and efficiently without the formation of GeCl4 which would create a significant contamination hazard and lower the overall process yield. On the other hand, methods using ethanol and dilute hydrochloric acid as eluents were found to obtain significantly lower yields and clogging of the column was found to be a major obstacle.
This summary of the invention does not necessarily describe all features of the invention.
These and other features of the invention will become more apparent from the following description in which reference is made to the appended drawings wherein:
The term “radionuclide” refers to an atom with excess nuclear energy making it unstable and that undergoes radioactive decay. Radionuclides are also known as radioactive nuclides, radioisotopes or radioactive isotopes. Radioactive decay may produce a new stable nuclide, or a new unstable radionuclide, which may undergo further decay. The term “parent radionuclide” in the context of the present invention refers to a radionuclide that decays into a new radionuclide, or “daughter radionuclide”. Examples of parent radionuclides and their daughter radionuclides include Mo-99/Tc-99m, Ge-68/Ga-68 and W-188/Re-188.
The term “radionuclide complex” refers to any compound or salt comprising the radionuclide. In the methods of the present invention, the parent radionuclide may be present in the eluates as a radionuclide complex. For example, the parent radionuclide may elute bound to part of the stationary phase (e.g. 68Ge-laurylgallate, 68Ge-silica), or may react with the mineral acid and elute as a new complex (e.g. 68GeCl4, 68GeI4). The radionuclide complexes obtained from elution with HI and Br, i.e. GeI4 (melting point 144° C.) and GeBr4 (melting point 26° C. and boiling point 186° C.), are stable at room temperature and non-volatile. The parent radionuclide may be isolated as a radionuclide complex which may be used directly for loading into a new radionuclide generator.
The term “radionuclide generator” refers to a system containing a parent radionuclide which decays into a daughter radionuclide, where the half-life of the parent is longer than the half-life of the daughter. The decay of the parent to the daughter is continuous and the daughter radionuclide can be extracted repeatedly. Radionuclide generators typically comprise an ion exchange column in which the parent radionuclide is bound (adsorbed) to a stationary phase in the column. The daughter radionuclide can be obtained by eluting the stationary phase with a mobile phase to release the daughter radionuclide from the stationary phase. The radionuclide generator may be partially depleted. By partially depleted, it is meant that the parent radionuclide has undergone decay, but the generator is not completely exhausted of activity.
Common stationary phases for radionuclide generators include oxidic substrates such as silica (SiO2), alumina (Al2O3), zirconia (ZrO2), titanium oxide (TiO2), tin oxide (SnO2), tantalum oxide (Ta2O5), vanadium oxide (V2O5) and niobium oxide (Nb2O3). Common mobile phases for eluting daughter radionuclides from the stationary phase include hydrogen chloride (HCl) and saline.
The terms “elution”, “eluting”, “eluent” and “eluate” are known in the art. Elution and eluting refers to the process of washing or rinsing the stationary phase with a mobile phase to extract or separate a substance or material from the stationary phase. “An elution” refers to a single wash or rinse of the stationary phase with the mobile phase. The “eluent” is the mobile phase that the stationary phase is washed with and the resulting solution containing the extracted substance and the mobile phase which is obtained from the elution or eluting is the “eluate”.
Pausing an elution to increase the contact time between the eluent and the stationary phase is also known in the art. When an elution is paused, discharge of the eluent is prevented such that the eluent remains in contact with the stationary phase. In other words, the stationary phase is soaked with the eluent. The “soak time” or “contact time” in the context of the invention refers to the amount of time that the eluent (e.g. mineral acid) is in contact with the stationary phase when an elution is paused. The “total soak time” refers to the sum of the soak times of each of the one or more elutions.
The term “concentrated” in the context of “concentrated acid” or “concentrated mineral acid” refers to the maximum concentration of an acid in an aqueous solution, or within 10% of the maximum % concentration. For example, the maximum concentration of HCl owing to its solubility in water is around 38%. The maximum concentration of HI is around 57%. The maximum concentration of HBr is around 48%. The term “diluted” in the context of “dilute acid” refers to an acid concentration below the maximum concentration, or a concentration lower than 10% below the maximum percentage concentration.
The term “elution regime” in the context of the recovery methods of the present invention refers to the series of elutions carried out on the stationary phase of a radionuclide generator. A schematic of the fundamental elution regime according to the invention is shown in
The term “laurylgallate”, otherwise known as dodecyl gallate or Dodecyl 3,4,5-trihydroxybenzoate, refers to the chemical compound having formula C19H30O5.
The term “chemical purity” can be defined as the proportion (e.g. percentage) of the desired chemical or compound in a sample.
The term “radiochemical purity” refers to the amount of total radioactivity in a sample which is present as the desired radionuclide.
In the context of the present invention, “yield” of the parent radionuclide refers to the amount of parent radionuclide recovered compared to the total amount of parent radionuclide present in the generator. The yield of the radionuclide can be measured in terms of radioactivity e.g. in becquerels (Bq).
The term “isolating” in the context of isolating the parent radionuclide as described in the present invention refers to separating or extracting the parent radionuclide from a matrix (e.g. an alcohol, mineral acid or aqueous eluate). Isolation (extraction) techniques include, but are not limited to, liquid-liquid extraction and solid-phase extraction. The Applicant has developed an efficient liquid-liquid extraction for mineral acid and aqueous eluates containing a parent radionuclide using chlorinated organic solvents such as chloroform. The parent radionuclide extracts can then be dissolved in dilute HCl (e.g. 0.001N-1N) ready for loading into a new generator. However, the isolation (extraction) method may also be performed by replacing chloroform with any other chlorinated hydrocarbon that is non-miscible with aqueous solvents, for example, carbon tetrachloride (CCl4) or dichloromethane (CH2Cl2). The extraction can also be performed with other non-water miscible organic phases in which the germanium halides are soluble, for example, benzene, toluene, carbon disulfide.
The use of the word “a” or “an” when used herein in conjunction with the term “comprising” may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one” and “one or more than one.” Any element expressed in the singular form also encompasses its plural form. Any element expressed in the plural form also encompasses its singular form. The term “plurality” as used herein means more than one, for example, two or more, three or more, four or more, and the like.
As used herein, the terms “comprising,” “having,” “including” and “containing,” and grammatical variations thereof, are inclusive or open-ended and do not exclude additional, un-recited elements and/or method steps. The term “consisting essentially of” when used herein in connection with a composition, use or method, denotes that additional elements, method steps or both additional elements and method steps may be present, but that these additions do not materially affect the manner in which the recited composition, method or use functions. The term “consisting of” when used herein in connection with a composition, use or method, excludes the presence of additional elements and/or method steps. A use or method described herein as comprising certain elements and/or steps may also, in certain embodiments consist essentially of those elements and/or steps, and in other embodiments consist of those elements and/or steps, whether or not these embodiments are specifically referred to.
As used herein, the terms “about” or “around”, when used to describe a recited value, means within 10% of the recited value, unless otherwise stated.
The present invention will be further illustrated in the following examples.
Partially depleted Ge-68/Ga-68 generator columns were obtained for preliminary testing. A series of elutions with ethanol and dilute hydrochloric acid (up to 6N) were performed. It was found that it was not possible to use hydrochloric acid of concentrations above 6N due to the formation of highly volatile 68GeCl4 (boiling point 84° C.).
Recovery yields of Ge-68 in the order of 50-70% were achieved. It was found that the generator column became clogged easily, preventing efficient elution.
Ge-68/Ga-68 generator columns were obtained from ITG (ITM Isotopen Technologien Munchen AG). The generator column specifications were as follows—column material: silica gel modified with laurylgallate (CAS: 166-52-5); primary package: PEEK column; secondary package: lead containers; lead shielding: 36-50 mm thickness; shelf life: 12 months or 250 elutions; eluent for obtaining daughter Ga68: sterile 0.05 M aqueous hydrochloric acid solution; nominal Ge-68 activity at manufacture 0.3 GBq-2 GBq. The generator columns selected for testing had a range of ages (see Table 3).
The generator columns were dried and any residual hydrochloric acid was removed by flowing pressurized air through the column.
The elution regimes and acid soak times as carried out on the generators tested are shown in Tables 1-6 below.
The elutions were carried out as follows. The column was eluted with methanol (10-20 mL) at room temperature and the methanol eluate collected. Elutions with concentrated hydroiodic acid (57%) and/or hydrobromic acid (48%) (4-15 mL) at room temperature were performed and each acid elution was followed by elution with milli Q (MQ) water (10-20 mL) at ˜100° C. The mineral acid and aqueous eluates were collected. During each elution with hydroiodic acid and/or hydrobromic acid, the elution was paused halfway so that the column remained in contact with the acid (soaking) for the indicated time period. The elution regime of methanol, and hydroiodic acid/hydrobromic acid followed by a water flush was repeated as necessary.
Table 7 shows the activity recovered for each generator compared to the acid soak time. It was found that the mineral acid elution itself was not as effective at carrying activity (eluting the parent radionuclide) as the water elution that followed each mineral acid elution.
The methanol eluates were evaporated to near dryness and the remaining Ge-68 extracts were dissolved in an excess of dilute hydrochloric acid (0.05 M). The hydroiodic/hydrobromic eluates and the aqueous eluates were each mixed with chloroform and the chloroform phases containing 68GeI4 and/or 68GeBr4 were retained. The chloroform phases were evaporated to dryness and the extracts dissolved in a small quantity of methanol and then diluted with an excess of hydrochloric acid (0.05 M). The resulting hydrochloric acid solution containing Ge-68 as 68GeI4 and/or 68GeBr4 was loaded into a new Ge-68/Ga-68 generator column. The new generator columns containing the recycled Ge-68 were confirmed to be effective in producing the Ga-68 daughter radionuclide using the standard method of eluting with dilute hydrochloric acid (0.05 M).
Although commercial Ge-68/Ga-68 generators are typically prepared by loading the column with 68GeCl4 in dilute hydrochloric acid, it was found that higher homologues such as 68GeI4 and 68GeBr4 behave identically to 68GeCl4 as regards loading new generator columns.
The yield of Ge-68 obtained from each elution regime was assessed by measuring the radioactivity of each eluate emerging from the generator column using a CRC®-55tR Dose Calibrator (Captintec, Inc.).
The total activity recovered (% yield) as a function of the number of elutions is shown in
Without wishing to be bound by theory, it is thought that elution with alcohol, e.g. methanol, removes Ge-68 in chelate form with laurylgallate, as well as laurylgallate itself, from the generator. It was found that the first methanol elution from each elution regime removed a significant yield of Ge-68, whereas subsequent methanol elutions were substantially diminished in activity relative to the first alcohol elution.
In contrast, it is thought that the mineral acid elution (e.g. HI and/or HBr) is complementary to the alcohol elution and primarily targets Ge-68 bonded to silica. Removal of Ge-68 from the silica matrix is thought to be crucial for high yield recovery. The method exemplified in the present application for a generator with a silica stationary phase may be applied to all oxidic substrates commonly used for radionuclide generator columns, for example, alumina (Al2O3), zirconia (ZrO2), titanium oxide (TiO2), tin oxide (SnO2), tantalum oxide (Ta2O5), vanadium oxide (V2O5) and niobium oxide (Nb2O3).
All citations are hereby incorporated by reference.
The present invention has been described with regard to one or more embodiments. However, it will be apparent to persons skilled in the art that a number of variations and modifications can be made without departing from the scope of the invention as defined in the claims.
The scope of the claims should not be limited by the preferred embodiments set forth in the examples but should be given the broadest interpretation consistent with the description as a whole.
| Number | Date | Country | |
|---|---|---|---|
| 62926263 | Oct 2019 | US |
