DE2932948C2 - Process for the production of an ion exchanger and its use - Google Patents

Description

The invention relates to a method for producing an ion exchanger by reacting pyrogallol with excess formaldehyde and its use for separating ⁶⁸ gallium from its mother nuclide ⁶⁸ germanium by exchange chromatography.

In nuclear medicine diagnostics, as is well known, there is a need for the provision of ⁶⁸ gallium, which up to now has been obtained by the most varied of methods. So is z. B. from Int. J. Appl. Rad. Isotopes, Vol.12, p. 62 (1961), a generator now commercially available, with the help of which ⁶⁸ germanium is adsorbed on aluminum oxide and ⁶⁸ gallium is subsequently eluted with EDTA. The process with this generator has the disadvantage that different yields of ⁶⁸ GalIium are achieved, which are between 30 and 70%, based on ⁶⁸ Ge, and that the ⁶⁸ Ga obtained is present as an EDTA complex which is destroyed before further processing into radiopharmaceuticals must become. This process and the labeling of pharmaceuticals with the ⁶⁸ Ga obtained in this way is therefore very time-consuming and costly. -

From Int. J, Appl Rad Isotopes, Vol. 29, S, 120 (1978), the adsorption of ⁶⁸ Ge on antimony pertoxide is known, in which case the ⁶⁸ Ga is then eluted with sodium oxalate. This procedure results in too high a proportion of ⁶⁸ Ge err "« Ga eluate, e.g. 0.05%, based on eluted ⁶⁸ Ga. The oxalate complex must be destroyed here before further processing.

In J. Nucl. Med “Vol. 19, p. 925 (1978) describes the liquid extraction of ⁶⁸ GA with oxine / chloroform. This method is time-consuming and requires precise work during the extraction, so that this known method involves the risk of operating errors

Therefore, a ⁶⁸ Ge / ⁶⁸ Ga nuclide generator for ion exchange chromatography ^{is of interest, of which 68} Ga without the addition of chelating agents, e.g. B. with dilute mineral acids (preferably HCl, since it does not have to be separated from the pharmaceutical solution after neutralization), can be eluted.

A number of polyhydroxybenzene-containing ion exchangers which can selectively bind metal ions from acidic, aqueous solutions are now known from the literature. (GB-PS 8 06 871, DE-OS 2128 802. AT-PS 3 34 084, DE-OS 24 50 541, G. Cassidy, J Am. Chem. Soo, Vol. 71, No. 2, p. 402 [1949], GV Myasoedova et al, Zh. Analit Khim. 23, No. 4, p. 507 [1968].) Only the pyrogalloI / formaldehyde resin mentioned in the Russian literature and the condensate described in AT-PS 3 34 084 from hydrolyzable tannin concentrates and formaldehyde (hydrolyzable tannin concentrates contain gallic acid, ^{some of which also convert to pyrogallol when hardened between 300 and 400 °} C.), however, are not suitable for this purpose. Adsorb germanium from mineral acid solution aj.

For the use of such a pyrogallol-formaldehyde resin as a Ge carrier in a ⁶⁸ GeZ ⁶⁸ Ga-NUkHdgenerator, three requirements must be made:

1. The ion exchanger must have a high capacity for germanium (only a small excess of formaldehyde may be used in the condensation) so that the generator can be eluted 800-1000 times without a breakthrough of ⁶⁸ Ge.

2. The ion exchanger must have a reversible water content of at least 40%, so that a sufficiently rapid diffusion of the ToL'hternuclid ⁶⁸ Ga from the resin particles and thus a high yield is guaranteed.

3. The ion exchanger may only have an extremely low solubility in the eluant (this will achieved through long hardening times of the condensate), otherwise additional cleaning steps of the eluate become necessary.

However, these three requirements are only inadequately met by the ion exchangers known from the literature, since z. B. the exchanger known from the Russian work has too low a capacity due to an unfavorable ratio of pyrogallol to formaldehyde and z. B. the exchanger according to the Austrian patent 3 34 084 contains too little water, since apart from the formaldehyde solution no water is added and thus the diffusion of ⁶⁸ Ga is severely hindered. In the known exchangers, the solubility also leaves something to be desired.

An exchanger that fully meets the three requirements mentioned would therefore be highly desirable Exchanger is the aim of the invention

An arbitrarily repeatable, complexing agent-free separation of ⁶⁸ Ga from its mother nuclide ⁵³ Ge with high yield is made possible with the help of an ion exchanger, which ^{can be loaded with the mother nuclide 68} Ge and can be removed by elution, e.g. B. with dilute hydrochloric acid (preferably 2n-5n) ⁶⁸ Ga in

ionic form in high yield (of the order of 75%) with very low impurities of ⁶ ? Ge (of the order of 0.0003%)

The process of making an ion exchanger by reacting pyrogallol with excess Formaldehyde consists in being in the presence of water in a hot, with the Reaction partners compatible, inert to them and a suspension-forming medium under Stirring condenses, the condensation product hardens, that sucks hot inert medium and the hardened resin washes free from it and sieves. Formaldehyde is in in a slight molar excess of 5 to 15 mol%, preferably 10 mol%. Big amount of of formaldehyde reduce the exchange capacity, and smaller amounts lead to a disadvantageous one Increasing the solubility of the resin in water and acid. The use of an excess of formaldehyde So from 5 to 15% is pretty critical.

The condensation is started by heating, to which is introduced the reaction mixture suitably in a hot, in the case of pyrogallol, preferably at 85 to 90 ⁰ C heated, hydrophobic, reaction. ', Wtnern against inert and compatible therewith, suspension forming medium purpose, preferably viscose Paraffin used, which forms a suspension with the aqueous solution whereby small resin particles are preformed. Much higher temperatures are disadvantageous insofar as the reaction medium foams, in particular if the boiling point of water is exceeded in the exothermic reaction. At much lower temperatures, the reaction takes place too slowly or not at all. Instead of paraffin, other inert high-boiling heat transfer media can also be used, e.g. B. hydrophobic glycol ethers, such as dibutyl ethers of ethylene glycol, but also 1,2- or IJ-dichlorobenzene or dibutyl ketones. The term paraffin also includes paraffin oils which are sold under the trade name thick or thin and whose composition and properties are specified in the DAB (German Pharmacopoeia).

Water must be present during the condensation, since subsequent water absorption, i. H. a Swelling of a resin condensed without the addition of water, too slow and too incomplete.

The preferred resin used! Iat a particle size 0.15 to 0.075 mm and preferably has a reversible water content of 45 to 50 wt .-% (determined by weight loss of the air-dried resin in the H + form vach 20 hours of heating at 110 ^c C and subsequently 48 hours of swelling of the dried resin in 2 /? HCl). A lower water content lowers the exchange capacity. A water content greater than 70% results in mechanically unstable and relatively soluble resins, so that a water content of 40 to 60% is suitable for the grain size fraction 0.15 to 0.075 mm.

Adding NaOH to the reaction medium leads to a pH of about 6.0-6.8. The setting too high a pH value leads to an undesirable increased solubility of the resin (pKa pyrogallol =?). A strongly acidic condensation is also possible, but less advantageous, since the reaction then becomes too fast and foaming of the Reaction medium conditional

The resin droplets formed still have to be hardened, which is expedient by 15 to 25 hours, preferably 20 h, long heating at about 110 to 130 ° C, preferably at 115 to 120 ° C, takes place

Since the freshly formed resin droplets have condensed on the surface and partially stick together, it proves particularly when processing smaller test batches on a laboratory scale It is often advantageous to mechanically comminute the process product prior to hardening, e.g. Am a commercially available homogenizer, as it is also used for the homogenization of tissue samples The homogenizer treatment is carried out for about 5 to 15 minutes, preferably about 10 minutes In the case of semi-technical and technical process implementation, which is due to better mixing is better controllable for the production of comparatively small grain sizes, can be based on the homogenization in usually be waived.

After hardening, the hot paraffin is sucked off and the resin washed until it is free of paraffin is used as washing liquids organic solvents such as chloroforhi and methanol.

Larger resin particles, for example 03 to 0.1 f mm, can also be used. The preferred smaller grain size of 0.15 to 0.075 mm, however, has the advantage that with the same column dimensions and with the same amount of eluant, approx. 40% ⁶⁸ Ge less appear in the ^ Ga eluate. The same degree of separation with resin particles from 03 to 0.15 mm particle size therefore requires larger columns and more eluent.

The exchange resin of the selected grain size is repeatedly in warm water at about 60 to 70 ° C slurried and decanted, whereupon it is expedient to equilibrate with 2N-HC1 Production of a ready-to-use ion exchanger. The resin obtained can be used under 2N-HC1 or dry be kept. It is not resistant to alkali.

If the hardening was preceded by homogenization, dust-like particles can be present that penetrate through Sieving and decanting are not easily removable. In this case, it proves useful that the Harz for a few hours, e.g. B. shake for 5 hours in 2N HCl on a commercially available shaker, whereupon it is decanted to obtain a ready-to-use ion exchanger.

The ion exchanger is filled into columns which, for laboratory tests, have a diameter of about 0.5 to 1.5 cm and about 5 to 6 cm high are filled with ion exchanger. Depending on the amount of exchange resin used, loading of up to 7.4 χ 10 "sec" ^{1 68} Ge can be carried out, with incubation times of 5 to 24 h being suitable for loading. The loading capacity is about 35 to 45, usually about 40 mg Ge / g ion exchanger. The eluent is suitably 2N-HCl, of which about 2-10 ml are used per elution, depending on the resin narrowing used. The achievable flow rates prove to be sufficient and amount to about 2 ml / min with a column diameter of about 1 cm and a filling height of about 5 cm.

The following distribution coefficients (KD) can be achieved:

KD _Oe =
KD _Oa =

⁶⁸ Ge ^ activity on exchanger ⁶⁸ Gc activity in the supernatant

⁶⁸ Ga activity on the exchanger ⁶⁸ Ga activity in the supernatant = 2000 to 12000

- 0.05 to 012

For special purposes, it has been found possible to use the ion exchanger prepared according to the invention in 'to graft onto carrier materials in the usual known manner.

It proves to be particularly advantageous that a small amount of time is required for the elution, which is in the order of magnitude of, for. B. 3 to 5 minutes. Since the elution is preferably carried out with hydrochloric acid, the ⁶⁸ Ga is in the chloride form and can easily be further processed. The eluate contains less than 3 x 10- ^{4% 68} Ge, based on ⁶³ Ga, and is free from other metals. The yield of ⁶⁸ Ga is 75% ± 5%, and the elution can be repeated as often as desired.

The ion exchanger produced according to the invention thus has a high adsorption capacity for germanium and a low adsorption capacity for gallium, especially when using a 2N HCl solution, and the eluate is free of complexing agents, e.g. B. EDTA, which make it difficult to ^{further process the 68 Ga into radiopharmaceuticals.}

The following examples are intended to explain the invention in more detail.

with 2N-HCL dust-like particles that are difficult to separate, which had formed as a result of the homogenization were shaken in for about 5 hours 2N-HCl removed on a shaker and then decanted off. The resin was under 2N HCl kept. The loading capacity of the ion exchanger was 38 mg Ge per g exchanger. Of the The water content of the exchanger was 45%.

Example 2

VsrwaHwiin '* ei «s! Onsfisiisisüschsrs s! S
Nuclide generator 68Ge / ^M Ga

The ion exchange resin produced according to the invention was incubated with a 0.5 η hydrochloric acid solution of carrier-free ⁶⁸ Ge for 5 hours, 0.25 g resin being ^{loaded with 3.7 10 10} see ^'68 Ge.

The distribution coefficients were as follows:

⁶⁸ Ge activity on the exchanger

example 1

Production of pyrogallol formaldehyde ion exchange resin

About 700 ml of paraffin (thick) were ^{heated to 85 to 90 °} C. in a heating bath which was equipped with side baffles and a stirrer. A solution of 0.4 mol (50.4 g) pyrogallol, 80 ml H ₂ O, 48 ml formaldehyde (37%) (0.44 mol) and 2 ml 1N NaOH was added with vigorous stirring. The resulting suspension was stirred for 1.5 hours at the specified temperature. Fine resin droplets formed, the surface of which had already condensed and some of which were sticking to one another. The batch was therefore comminuted for 10 minutes with a homogenizer, as is normally used for homogenizing tissue samples, after which the final hardening of the particles was brought about ^{by heating at 115 to 120 ° C. for 20 hours.}

After hardening, the hot paraffin was suctioned off and the resin repeatedly with chloroform and Washed paraffin-free methanol. It was then sieved, with typical yields for such a Approach are as follows:

Grain size yield

mm (g)

■ iie activity in the supernatant

⁶⁸ Ga activity on the exchanger
⁶⁸ Ga activity in the supernatant

= 2000

0.1

> 0.3
0.3-0.15
0.15-0.075

27.6

27.6

5.0

The resin mii a particle size 0.15 to 0.075 mm was suspended several times in warm water of 60 to 70 ⁰ C and decanted equilibration took place, the resin was transferred into a chromatographic column of 0.5 cm diameter, provided with a glass frit at the bottom and was already filled with 3 times the amount (750 mg) of inactive resin (free of ⁶⁸ Ge) as a collecting layer (total height of the column 6.0 cm).

The exchange column obtained was rinsed with 50 ml of 2N HC1 and was then ready for use, with it It has been found to be useful to use a glass frit as the top closure in order to achieve a Avoid swirling up the resin when adding the eluent. 2N-HCl served as eluent, 2.5 ml per elution.

In order to be able to make a statement about the operating time, an example 2 was described Generator subjected to a permanent elution (5.5 liters of 2N HC1 were continuously with a flow rate of 0.29 ml / min passed through the resin bed).

This amount Hci only 0.09% of the initially adsorbed 68Ge were eluted However, there was a migration of ⁶⁸ Ge of the incubated resin layer into the trapping layer. The breakthrough of the column (sudden increase in ⁶⁸ Ge in ⁶⁸ Ga-ElUaO after 12-151 2N-HCl after 12-151 2N-HC1 was calculated based on the measured migration speed. This corresponds to 4800-6000 eluations. Under practical conditions (3-4 eluations with 24 ml each per day and a flow rate of 0.7 ml / min) is possible with an operating time of 1600-2000 eluations

65 count.

The graphic shows the elution behavior of a Generator that was manufactured according to the information in Example 2, and that over a period of 100

Days was eluted approx. 60 times with 2.5 ml of 2N HCl each time, ion exchanger condensed in paraffin. From-

The ion exchanger yielded less per elution than the yield of smaller particles was slightly higher.

10 μ £ pyrogallol washed out (minimum lethal dose _R · ; \ a

applied iv in the dog 80-100 mg / kg; H. M, Rauen * ^p

Biochemical Pocket Book, Part II, Springer Verlag, 5,400 ml of dibutyl ketone (5-nonanone, m.p. -5.9 ° C, b.p.

1964). 187 ⁰ C, density 0.82 g / ml) were heated to 85 ° C and

ο. . - _ a solution of 25.2 g pyrogallol with vigorous stirring,

^p 40 ml H ₂ O, 24 ml formaldehyde 37% and 1 ml

Example! I was added with the same amounts of the In NaOH. The batch was on for 1.5 hours

Reäktionspartner repeated, except that the paraffin io stirred at 85 ⁰ C. After 10 minutes of homogenizer operation *

(viscous) heated to 65 to 70 "C when the batch treatment and 18 hours of curing at 115 ⁰ C

was stirred for 3 hours, and the result was then that the grain size yield was twice as high

same product as in Example 1, which is also used as in 0.15-0.075 mm with the same germanium bond cable

Example 1 described has been worked up. capacity and the same water content as in

η · · | ₄ 15 paraffin condensed resin. However, 5-nonanone has

P has an intense odor and is about five times more expensive than

An experiment as in Example 1, but paraffin or 1,2-dichlorobenzol

with paraffin preheated to 103 ^° C. had the following: The drawings show the elution behavior of the

Result. The aqueous formaldehyde / pyrogallol solution described in Example 2 ⁶⁸ gallium nuclide generators

could not be added all at once, io tors,

but had to be in portions of approx. 10 ml over 40 resin beds

Minutes are introduced distributed, because the approach _0O .5cm, level 6.0 cm (corresponding to Ig

air-dried exchange resin after each reagent addition with a short delay),

foamed violently. After another hour of loading

Stirring at 103 ^° C. resulted in a coarse-grained resin. the 25 _{3J χ} ·, ₀ , _{0 sec} „, _{68Ge trä free} (corresponding to 1 μ _έ

an extended (25 minutes) homogenizer cycle Q _e \

act had to be subjected to. The resulting eluant

Ion exchanger showed the same binding capacity of ₂ n HCI

compared to germanium, but a 10% lower elution amount

th water content than that according to Example 1 at 85-90 ⁰ C >>> 25 ml

condensed product. Investigated period:

B e i s ρ i e 1 5 100 days after manufacture.

_. ... ,,,. Elution frequency in this period:

If the test conditions are otherwise equivalent to Example 1, 60 times
90 ⁰ C hot paraffin was used through 90 ⁰ C hot 35

^ -Dichlorobenzene (mp -16.7 °, bp 172.9 ° C, density Fig. 1 shows the yield of <«Ga in% in 2.5 ml of eluate,

1.29 g / ml, non-flammable) replaced. There was a in based on adsorbed ⁶⁸ Ge and

with respect to the germanium binding capacity and the FIG. 2 shows the contamination at 68Ge in% in 2.5 ml

Water content of identical product in comparison to the eluate, based on eluted ⁶⁸ Ga.

1 sheet of drawings

Claims (8)

Patent claims: 1. Process for the production of an ion exchanger by reacting pyrogallol with Excess formaldehyde, characterized in that in the presence of water in a hot, with the reactants compatible, inert to them and a suspension-forming medium condensed with stirring, the condensation product hardens, the hot inert medium sucks off and the hardened one Resin washes free from it and sieves 2. The method according to claim 1, characterized in that one is compatible, inert, suspension-forming Medium paraffin used 3. The method according to claim 2, characterized in that condensation is carried out at 85 to 90 ° C 4. The method according to claim 1, characterized in that there is a condensation at a pH from pH 6 to 6.8 carries out 5. The method according to any one of claims i to 4, characterized in that the fresh condensation product is cured at 115 to 120 ⁰ C for 15 to 25 hours. 6. The method according to claim 5, characterized in that the Konduisationsprodukt before mechanically comminuted after hardening 7. Use of the ion exchanger according to claim 1 for the separation of ⁶⁸ GaIIiUm from its parent nuclide ^ germanium by exchange chromatography. 8. Use narh Ans cloth 7, the ion exchange resin having a particle size of 0.15 up to 0.075 mm