EP0213589B1 - Generator of technecium-99m, its preparation and use - Google Patents

Abstract

Silica gels modified with amino groups or magnesium silicates are suitable carrier materials for technetium-99m generators since they retain copper(II) ions well and thus produce a copper-free eluate.

Description

The invention relates to an improved technetium-99m generator based on carrier-adsorbed molybdenum-99, processes for producing such generators and their use for obtaining eluates which contain technetium-99m in the form of pertechnetate.

Technetium-99m is the most commonly used radioactive nuclide in nuclear medicine diagnostics. This is due to its core physical properties that are optimal for this application (short half-life of 6.0 hours, no corpuscular radiation, favorable γ energy of 140 keV). It can be easily and easily obtained from a molybdenum 99 / technetium 99m generator.

In the currently most widespread generator type, the molybdenum-99, from which the isotope technetium-99m is continuously formed by core decay, is adsorbed onto an aluminum oxide column as molybdenum-99-molybdate. Technetium-99m, which is chemically pertechnetate, is separated from Molydbän-99 by washing with isotonic saline. The so-called split molybdenum-99 is used almost exclusively as molybdenum-99. It is isolated from the fission product mixture that occurs during the core decay of uranium-235 and has a very high specific activity. This makes it possible to get high technetium-99m activity in small volumes of saline from a generator.

The introduction of split molybdenum made it possible to use only small amounts (1-2 g) of aluminum oxide in the generators, whereby the minimum amount of saline solution required for the elution of the technetium-99m could be limited to a few milliliters (approx. 5 ml).

The minimum requirements for a ready-to-use generator are summarized in DIN 6854 (January 1985). Thereafter, the elutable activity on Tc-99m should not be less than 70% when eluted at 24 hour intervals. The quality of the eluate is subject to certain requirements. It is of course desirable to fall below these limits as much as possible. This applies in particular to molybdenum-99, which is contained in the generator in high activities and which in the eluate would lead to unnecessary radiation exposure when used in humans due to the long half-life of 66.0 h.

It is known that Mo-99 / Tc-99m generators with split molybdenum, in particular in the case of higher Mo-99 activities, tend to lose yields or sometimes even breakdowns (EP-B 0 014 957). This effect is caused by organic impurities in the eluent, e.g. can get into the saline solution from plastic eluent containers.

In order to avoid these losses in yield, yield stabilizers are used. It is known that copper (II) ions have this stabilizing effect.

Here, however, there arises the difficulty that the small amounts of aluminum oxide are not sufficient to prevent the passage of the copper into the eluate in the long term.

German Offenlegungsschrift 1 929 067 describes adding copper (II) acetate to the eluent. A minimum amount of 0.001 percent by volume is required, which in the case of copper (II) acetate means 10 µg / ml = 3.5 µg Cu (II) / ml. For modern generators, unlike those on the priority day of the aforementioned German published application, which only contain a small amount of aluminum oxide, this is not sufficient - even when using the minimum copper (II) concentrations mentioned - to prevent the aforementioned passage of copper into the eluate. In addition, it has been shown that 3.5 µg Cu (II) / ml eluent cannot always ensure a stable, high yield.

In order to prevent the passage of copper ions into the eluate, a process was described in EP-B-0 014 957 which allows large amounts of copper (II) to be fixed on the aluminum oxide. However, this method requires an additional process step in the production of the generators and is therefore complex.

It has now been found that silica gels modified with amino groups and, if appropriate, magnesium silicates are advantageous carrier materials for technetium-99m generators which are capable of firmly binding copper (II) ions. The invention thus relates to technetium-99m generators based on carrier-adsorbed molybdenum-99, which are characterized by a content of an amino group-modified silica gel and, if appropriate, magnesium silicates.

It was also found that the amino group-modified silica gel is able to adsorb radioactive molybdenum-99. This means that the Mo-99 content in the eluate can be reduced to less than 1 µCi Mo-99 / Ci Tc-99m. One embodiment of the invention thus relates to a technetium-99m generator, the carrier material of which consists of silica group modified with amino groups. However, preferred embodiments of this invention additionally contain aluminum oxide and, if appropriate, magnesium silicates.

Generators according to the invention with a content of magnesium silicate expediently contain, in addition to the silica group-modified silica gel according to the invention, additionally aluminum oxide for the adsorption of Mo-99. For generators that contain more than one carrier material, it is fundamentally possible to mix the carrier materials and to fill the usual equipment with the mixture. However, since the different materials generally have a different grain size, special precautions, for example joint grinding, must be used to ensure that no "channels" remain open in the filling. It is therefore generally more convenient to fill the different materials in layers in the generators. "Layer by layer" can mean that the different materials are introduced in several, alternating layers, but it is advisable to introduce each material in the form of a single layer.

The amino group-modified silica gel is preferably introduced as the bottom layer in the generator column. A layer of aluminum oxide is then applied over this.

Use can also be made of the invention described in EP-B 0 014 957 by producing a generator in which the copper (II)-laden aluminum oxide is introduced in the top layer, including a layer of aluminum oxide and one below Layer of the carrier material according to the invention follows.

1 and 2 show schematically and not necessarily to scale two embodiments of the invention:
In FIG. 1, (1) means the column into which the carrier material is filled, the direction of elution (from top to bottom) being indicated by the arrow. (2) and (3) mean the layers of different carrier materials, in a preferred embodiment aluminum oxide as layer (2) and amino group-modified silica gel as layer (3).

FIG. 2 designates a corresponding arrangement with three layers, three different materials (2), (3) and (4) being used. In a preferred embodiment of this aspect of the invention, (4) means a layer of copper (II) -loaded aluminum oxide, (2) aluminum oxide and (3) amino group-modified silica gel and optionally magnesium silicates.

The technical design of nuclide generators is known and is described, for example, in German Patent Specification 1,614,486 (or the corresponding US Pat. No. 3,369,121) or GB Pat. No. 1,186,587. Details can therefore be dispensed with here.

The amount of carrier material depends on the dimensioning of the generator and the load; it can be easily determined by simple preliminary tests.

Amino group-modified silica gels are customary as support materials for chromatographic processes. A preferred form contains the amino groups in the form of 1,3-propylamine groups. However, other carrier materials, for example those with secondary or tertiary amino groups, such as those used as adsorbents for acidic compounds, are also possible.

Suitable as magnesium silicate are naturally occurring products such as forsterite, entstatite, serpentine, serpentine asbestos, talc, antigorite or meerschaum as well as corresponding synthetic products, the magnesium ortho-, di- or polysilicates, the latter with chain, ribbon or layer (sheet) ) Structure included. Such materials are used for example for chromatographic processes.

The invention is explained in more detail in the following examples.

The following carrier materials were used for the production of generator columns: aluminum oxide S, acidic, superactive; Riedel de Haen; ^(R) LiChroprep NH₂ for liquid chromatography, Merck, hereinafter "silica gel". Physiological saline containing different amounts of copper (II) chloride and dihydrate was used as the eluent. The copper (II) determination was carried out colorimetrically, the lower detection limit being 0.1 ppm.

example 1

By elution under the same conditions, it was determined to what extent the carrier materials are capable. Capture copper (II) ions. Eluates No. 1-8 were copper-free in all cases. As Table 1 below shows, the silica gel can trap copper (II) much better than the aluminum oxide.

Example 2

105 mg of silica gel are packed in a glass column and 1.0 g of aluminum oxide are layered on top. The column is loaded with Mo-99 and eluted daily with physiological saline containing 20 µg CuCl₂ 2R₂0 per ml. Before the addition of the copper (II) chloride, the saline solution was sterilized together with the PVC film that is usually used for packaging in an autoclave. It is known that organic impurities get into the eluent, which can lead to severe reductions in yield.

For comparison, one glass column was filled with 1.2 g of aluminum oxide and another with 105 mg of silica gel and 1.0 g of aluminum oxide. These comparative generators were eluted with copper-free eluent contaminated with organic contaminants.

The content of technetium-99m, molybdenum-99 and, to the extent that the eluent contains copper (II), the proportion of copper (II) is measured in the eluates. The results are summarized in Table 2. The yield of Tc-99m is given in%, based on the Mo-99 activity, the molybdenum-99 content in ppm, based on the Tc-99m activity and the copper (II) content in ppm.

Table 2 shows:

• 1. The use of silica gel lowers the Mo-99 content in the eluate below 1 ppm.
• 2. By using silica gel, copper (II) can be added to the eluent, as a result of which the yield of Tc-99m remains uniformly high without any significant amounts of copper (II) being detectable in the eluate.
• 3. By using silica gel, the copper (II) content in the eluent can be increased beyond the minimum proportion of 20 ppm.

Example 3

Generator columns were produced using the method of EP-B 0 014 957. However, some also contained silica gel as the bottom layer. These were loaded with Mo-99 and eluted daily with physiological saline. Table 3 shows the results.

Table 3 shows the reduction of the Mo-99 content in the eluate even when using the design according to EP-B 0 014 957. Cu (II) could not be found in any eluate.

Claims (6)

1. A technetium-99m generator which is based on molybdenum-99 adsorbed on a carrier and is eluted with solutions containing copper(II), which contains a silica gel modified with amino groups.
2. A generator as claimed in claim 1, wherein, in an elution column (1), the carrier containing the molybdenum-99 is arranged as the upper layer (2) and the silica gel modified with amino groups is arranged as the lower layers (3).
3. A generator as claimed in claim 1 or 2, which additionally contains a magnesium silicate.
4. A generator as claimed in claim 1, 2 or 3 wherein, in an elution column (1), aluminum oxide charged with copper(II) is arranged as the upper layer (4), aluminum oxide is arranged as the middle layer (2) and silica gel modified with amino groups is arranged as the lower layer (3).
5. A process for the preparation of a generator as claimed in any one of claims 1 to 4, which comprises using a silica gel modified with amino groups as carrier.
6. The use of a generator as claimed in any one of claims 1 to 4 for obtaining an eluate containing technetium-99m.

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