Patent Number: 047822317
Section: summary

This invention relates to a standard component .sup.99m Tc elution generator useful for medical purposes and consisting of prefabricated component parts. The fundamental part of the generator is formed by the main generator-ampoule-column made from materials with low radiactivation ability by neutrons. It serves first as the reactor irradiation ampoule and after suitable adjustment directly as proper generator column. The ampoule-column is filled with the target material--elution matrix, that contains high amounts of molybdenum (up to 40% by weight) consisting of water insoluable molybdates or polymolybdates releasing easily .sup.99m Tc technetium generated in the column by radioactive decay of mother .sup.99 Mo, formed in the matrix structure by neutron activation. The filling of the ampoule-column serves originally as target material for reactor irradiations and afterwards it is directly used as the proper elution matrix of the generator. The high content of molybdenum in the target material-elution matrix makes possible the utilization even of low to medium power reactors for neutron activation. The production possibility of the main generator column as completely inactive material already before the reactor irradiation facilitates substantially the post-irradiation assembly procedure. In such a way the manufacturer can supply not only the complementary components but even the main generator ampoule-column as inactive parts, that can be produced highly effective in large batches and kept for a long time on stock. BACKGROUND OF THE INVENTION .sup.99m Tc is a widely used radionuclide in radiopharmaceutical and nuclear medicine applications. The particular medical advantage of this radionuclide is its very short half-life of about 6 hours. However, the short half-life creates manufacture and delivery problems, because the radionuclide must be used very soon after it is produced. For this reason, .sup.99m Tc is preferably supplied to hospitals on demand by an on-site generator, through disintegration of isotopic molybdenum (.sup.99 Mo) and chemical separation of the .sup.99m Tc product. High purity and high activity are important, so that the .sup.99m Tc product may be used immediately as a pertechnate, in the preparation of radionuclide tracer compounds, etc. Current medical technology requires the use of radionuclide generators which can supply radioactive levels of at least 4 GBq, most often 8-12 GBq, and in some cases as high as 40 GBq per generator. Of radionuclide the generators now in use, elution generators are the most advantageous because they provide for rapid, efficient, and simple production of the desired radionuclides. However, in practice, most elution generators rely on aluminum oxide as a sorption material, which has a sorption capacity of only several percent by weight of molybdenum. This limits the activity of the generator to only several hundred MBq when natural isotopes of molybdenum are irradiated by a medium neutron flux ranging approximately between 10.sup.17 and 10.sup.18 n/m.sup.2 s. This level of activity is insufficient for medical applications. Known elution generators must therefore rely on either (a) the irradiation of enriched .sup.98 Mo as a target material for a high-intensity neutron flux; or (b) a carrier-free .sup.99 Mo isotope obtained by fission of uranium. These known devices and processes require a large capital investment; high energy and labor costs; a complex series of processing and purification steps involving highly radioactive components; the separation of .sup.99 Mo from uranium fission products, which are about twenty times more active than the useable radionuclide. Thus, for many applications the advantages of known elution generators have been outweighed by the practical and economic disadvantages, and other types of generators have been sought. Methods of .sup.99m Tc production allowing its separation from low specific activity parent .sup.99 Mo are to be used. For example, a sublimation of .sup.99m Tc may be obtained from a suitable .sup.99 Mo compound. Or, .sup.99m Tc products may be extracted from a strongly alkaline aqueous solution of a molybdate of .sup.99 Mo by methylethylketone. These processes permit the production of .sup.99m Tc products of medically sufficient activity from low to medium neutron flux irradiation within the range of about 5.times.10.sup.16 to 5.times.10.sup.17 n/m.sup.2 s. However, these chemical methods are substantially more complex, time-consuming, and labor intensive than a common elution generator. They may not be economically and conveniently practiced within a self-contained on-site apparatus. Instead, a centralized manufacturing and processing center will generally supply technetium 99m produced by sublimation or extraction to local hospitals and clinics. Although miniaturized extraction and sublimation generators are available for on-site hospital use, they remain complex and expensive. The technology of known .sup.99m Tc generators is discussed in R. E. Boyd, Recent Developments in Generators of .sup.99m Tc Radiopharmaceutical and Labeled Compounds, IAEA (Vienna: 1973), p. 1-26; R. E. Boyd, Technicium 99m Generators--The Available Options, Int. J. Appl. Rad. & Isot. (New York: 1982), Vol. 33, p. 801-2; and V. J. Molinsku, A Review of .sup.99m Tc Generator Technology, Int. J. Appl. Rad. & Isot. (New York: 1982), Vol. 33, p. 811-19. Other practitioners have sought to improve elution generators by replacing the aluminum oxide sorption material with a sorption matrix. The matrix is intended to recover greater amounts of molybdenum from which .sup.99m Tc can be eluated, thus improving efficiency and yield. J. V. Evans, P. W. Moore, M. S. Shying, & J. M. Soddeau, "A New Generator For .sup.99m Tc," Third World Congress on Nuclear Medicine and Biology, pp. 1592-5 (Paris: 1982). The Evans device uses a sorption matrix of zirconium molybdate obtained from irradiated molybdenum oxide that is dissolved in a lye solution, precipitated by zirconium nitrate, and dried at 105.degree. C. The approximate chemical composition of this sorption material is ZrO.sub.2.MoO.sub.3.xH.sub.2 O, having a molybdenum concentration of approximately 25% by weight. Through a hydration and shaping process, the material achieves elution of .sup.99m Tc from .sup.99 Mo with an efficiency of 70-90%. In experiments performed by the inventors in addition to zirconium molybdate also with titanium molybdate and polymolybdates of both elements containing 10-40% by weight molybdenum (with preferred content 20-30%) elution efficiencies 40-80% have been achieved. In contrary to previous authors (Evans et al) the elution matric was not made from already previously irradiated radioactive material dried at 105.degree. followed by hydration but in our case the elution matrix has been made from completely inactive material and dried at lower temperatures, prior to its activation by neutrons in the reactor. The drying has been performed at 40.degree.-50.degree. C., lasting many hours, in some cases even drying at room temperature (approximately. 20.degree. C.), lasting many days, has been used. The grain size of the matrix material usually has been in the range 50-140 /um. The inactive matrix prepared in such a way has been directly used as target material for the exposure to neutron activation in the reactor prior to elution. SUMMARY OF THE INVENTION It is an object of the invention to overcome or minimize a number of disadvantages of known .sup.99m Tc devices. These disadvantages include: (a) the limited availability of enriched .sup.98 Mo and of reactors with a high neutron flow; (b) the practical and economic difficulties inherent in elution devices based on .sup.99 Mo obtained from fission products; (c) MAAE control and disposal of used fission material and fission byproducts; (d) the risk of radioactive contamination; (e) the complexity and cost of sublimation and extraction processes and devices; (f) transport and delivery problems involving .sup.99m Tc products, activated generators, and fully assembled generators; (g) reliance on a neutron flow exceeding 10.sup.18 n/m.sup.2 s to achieve elution generator activity above 2 GBq from n, gamma reaction with .sup.99 Mo; and (h) the need for special sterilization procedures. According to the invention, these problems are alleviated or eliminated by an elution generator made of independent component parts. The major component is a main column which serves first as an irradiation ampoule for activation of the target material, and then is adjusted for immediate use as an elution column containing the activated material serving directly as elution matrix. The main column is preferably cylindrical and is provided with a supply means and a discharge means, such as tubes or hoses. It is composed of a corrosion-resistant material that is relatively inert with respect to neutrons, such as aluminum, zirconium, or quartz. The column is filled with target material containing at least 10% molybdenum by weight, so that efficent selective elution of .sup.99m Tc from .sup.99 Mo will result. Powdered or granular molybdates are generally used, such as polymolybdates of zirconium and/or titanium. The particles are held within the column by a porous material that is relatively unaffected by neutrons, such as a porous sinter of silicon or zirconium oxide, graphite, felt, quartz, or an aluminum fiber composite. The porous material allows the elution solution to pass freely. The main column can be hermetically sealed for radiation sterilization during activation by the neutron flow. Before exposure in the reactor, the ends of the column are hermetically sealed, such as by fusing, aluminum packing, or screw-type closures with aluminum packing. In addition, the entire column can be wrapped with aluminum foil to prevent bacterial contamination after removal from the reactor and to provide an aseptic connection with other components of the apparatus. After irradiation, the sealed ends of the column are breached and the supply and discharge tubes are attached in a sterile manner. The opposing ends of the supply and discharge tubes are sealed or plugged, so that the interior of the column is maintained in a sterile condition. The column, together with connecting means, is placed in a container for transportation to the user, preferably of lead or uranium deprived of .sup.235 U. The primary container is placed in another secondary protective container which is hermetically sealed. The other components of the assembled device, also sterilized and protected against contamination, comprise a vessel containing an apyrogenous elution solution, preferably 0.9% NaCl by weight, in sterile connection with the supply tube; a protective column filled with a sorbent, preferably zirconium oxide or aluminum oxide, and connected to the discharge tube; a piercing head with a connecting hose from the discharge tube; and evacuated bottles for the eluate connected to the piercing head. The apparatus also comprises a laboratory screening container and a support base for the assembled components. The apparatus can be delivered assembled or unassembled. Unassembled delivery is preferable, because the main column can then be separately manufactured, processed, and delivered. Table I shows the activity of the new elution generator at different column volumes and different neutron flows, when used with a target material containing 25% molybdenum by weight in a sorption matrix at a bulk weight of 1 g/ml. The activities are related to .sup.99 Mo and to a reference date 72 hours after a prior continuous irradiation for 90 hours. TABLE I ______________________________________ .sup.99 Mo ACTIVITY OF .sup.99m Tc GENERATOR IN GBq neutron flow is in n/m.sup.2 s; volume is in ml; dimensions are in cm. MAIN COLUMN .sup.99 Mo ACTIVITY IN GBq VOL- HEIGHT W AT GIVEN UME GIVEN DIAMETER NEUTRON FLUX .times. 10.sup.17 ml 1.0 cm 1.5 cm 2.0 cm 5 .times. 10.sup.-1 1 2 5 ______________________________________ 3 3.8 1.7 -- 0.5 1 2.5 6.5 5 6.4 2.8 -- 1 2 4 11 10 12.7 5.6 3.2 2 4 8 22 20 -- 11.3 6.4 3.5 8 17 43 30 -- -- 9.5 5 12 25 65 ______________________________________ When the main column is made of zirconium, both it and the elution matrix are activated. Due to the 10:1 ratio of Zr to Mo by weight, and due to the activating cross sections, the irradiation time, and the lethal time, the main column exhibits .sup.97 Zr activity with a half-life of 17 hours, and which is not more than double the .sup.99 Mo activity at the time of irradiation. At the reference time of 72 hours, .sup.97 Zr activity is roughly 20% of the .sup.99 Mo activity. The column also exhibits a .sup.95 Zr activity having a half-life of 64 days in equilibrium with .sup.95 Nb having a half-life of 35 days, representing roughly 10% the activity of .sup.99 Mo after irradiation and 20% at the reference time. These conditions create no significant or substantial hazards or problems with respect to construction and screening of the generator. When the main column is made of aluminum, the total radioactivity is lower, as only the target material is activated. The half-life of .sup.28 Al is 2.2 minutes, and therefore nuclear-clean aluminum creates no lingering radioactive byproducts from the neutron irradiation, and no column activity remains at the reference time. Column contaminants can be activated by neutron irradiation, and in addition aluminum itself may become activated by fast neutrons via .sup.27 Al/n,alfa/.sup.24 Na reaction to natrium (.sup.24 Na). Natrium has a half-life of 15 hours. From an irradiation point of view the most preferable column material is quartz, where only very small amounts of .sup.31 Si (half-life=2.6 hours) are activated. Quartz is also chemically inert and is low in contaminants; but quartz columns tend to be fragile. A neutron flux of 10.sup.16 n/m.sup.2 s corresponds to an irradiation dose of 360 kGy during one hour. All microorganisms and their latent forms are destroyed by irradiation at all doses exceeding 360 kGy. Thus, irradiation for more than one hour in a moderate neutron flow, as disclosed herein, serves the dual even purpose of target sorption material activation and reliable column sterilization.