instruments Article
Optimized Treatment and Recovery of Irradiated [18O]-Water in the Production of [18F]-Fluoride Antje Uhlending *, Harald Henneken, Verena Hugenberg and Wolfgang Burchert Institute for Radiology, Nuclear Medicine and Molecular Imaging, Heart and Diabetes Center North Rhine Westphalia, University Hospital, Ruhr University Bochum, 32545 Bad Oeynhausen, Germany;
[email protected] (H.H.);
[email protected] (V.H.);
[email protected] (W.B.) * Correspondence:
[email protected]; Tel.: +49-5731-97-3532 Received: 28 May 2018; Accepted: 22 June 2018; Published: 4 July 2018
Abstract: Enriched [18 O]-water is the target material for [18 F]-fluoride production. Due to its high price and scarce availability, an increased interest and necessity has arisen to recycle the used water, in order to use it multiple times as a target material for [18 F]-fluoride production. This paper presents an efficient treatment and reprocessing procedure giving rise to high chemical quality [18 O]-water, thereby maintaining its enrichment grade. The reprocessing is subdivided into two main steps. In the first step, the [18 F]-FDG (fluorodeoxyglucose) synthesis preparation was modified to preserve the enrichment grade. Anhydrous acetonitrile is used to dry tubing systems and cartridges in the synthesis module. Applying this procedure, the loss in the enrichment throughout the reprocessing is 90% of the [18 O]-water, while maintaining the
Instruments 2018, 2, 12; doi:10.3390/instruments2030012
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recycle >90% of the [18O]-water, while maintaining the enrichment grade with the prescribed method. For further radiation, themethod. [18O]-water quality radiation, needs to the possess a high quality chemical quality, enrichment grade with the prescribed For further [18 O]-water needs to [9]. the release specifications [9]. thereby attaining the release possess a high chemical quality,specifications thereby attaining 2. Materials and Methods 2. Materials and Methods 2.1.2.1. Overview of the Optimized Recovery Method Overview of the Optimized Recovery Method ForFor useuse in in thethe target, thethe [18 O]-water has to to bebe present with high chemical and microbiological target, [18O]-water has present with high chemical and microbiological 18 purity, as well as sufficient enrichment grade. After the bombardment, the irradiated purity, as well as sufficient enrichment grade. After the bombardment, the irradiated[[18O]-water O]-water is 18 F]-transfer lines into the synthesis modules. For a meaningful recovery, is usually transferred via [ 18 usually transferred via [ F]-transfer lines into the synthesis modules. For a meaningful recovery, an anadditional additionalrinse rinseofof transfer lines target conducted exclusively [18 O]-water. thethe transfer lines andand target waswas conducted exclusively with with [18O]-water. During 18 18 During the synthesis of [ F]-radiopharmaceutical, the irradiated [ O]-water was passed the synthesis of [18F]-radiopharmaceutical, the irradiated [18O]-water was passed throughthrough an anion anexchange anion exchange cartridge to separate [18 F]-fluoride fromthe the [[18 O]-water, which 18O]-water, cartridge to separate the the [18F]-fluoride from whichwas wascollected collected 16 separately. Residues of [ O]-water on the cartridge and in the tubing system of the module would lead separately. Residues of [16O]-water on the cartridge and in the tubing system of the module would 18 O]-water with [16 O]-water. Therefore, an improved synthesis to lead a significant contamination of the [ 18 16 to a significant contamination of the [ O]-water with [ O]-water. Therefore, an improved module preparation the maintenance the enrichment grade of the [18grade O]-water. A fractional synthesis module ensures preparation ensures the of maintenance of the enrichment of the [18O]-water. 18 distillation was performed for the purification of the [ O]-water. The first collected fraction contained A fractional distillation was performed for the purification of the [18O]-water. The first collected 18 O]-water was anfraction azeotropic [18 O]-water/acetonitrile mixture (10–15% of mixture the preparation). contained an azeotropic [18O]-water/acetonitrile (10–15% ofThe the[ preparation). The separated fromwas this azeotropic via an optimizedmixture molecular [18O]-water separated mixture from this azeotropic viasieve an procedure. optimized Microbiological molecular sieve contaminants removed viacontaminants UV-irradiation before the finalvia distillation, followed by a quality procedure. were Microbiological were removed UV-irradiation before the final 18 control of the recycled [ O]-water before its release for the next irradiation. A schematic overview 18 distillation, followed by a quality control of the recycled [ O]-water before its release for the of next theirradiation. whole recovery methodoverview is shown of below in Figure 1. A schematic the whole recovery method is shown below in Figure 1.
Figure 1. Overview of the optimized recovery method. Figure 1. Overview of the optimized recovery method.
2.2. Improved Synthesis Preparation for Maintaining the Enrichment Grade 2.2. Improved Synthesis Preparation for Maintaining the Enrichment Grade The use of [16O]-water to rinse the transfer lines during the cleaning process and the The use ofof [16the O]-water to rinse the transfer lines the cleaning and the preparation preparation synthesis modules resulted in during a significant loss ofprocess the enrichment grade in the of collected the synthesis modules resulted in a significant loss of the enrichment grade in the collectedon 18 18 18 [ O]-water. During the synthesis, [ O]-water was recovered by trapping [ F]-fluoride 18 18 18 [ an O]-water. During the synthesis, [ O]-water was recovered by trapping [ F]-fluoride on an anion anion exchange cartridge (Chromafix 30-PS-HCO 3 by Macherey-Nagel) and subsequent elution exchange cartridge (Chromafix 30-PS-HCO by Macherey-Nagel) and itself subsequent elution with an 3 with an aqueous potassium carbonate solution [10]. The cartridge was also preconditioned aqueous carbonate solutionof [10]. cartridgereduce itself was also preconditioned 5 mL of with 5 potassium mL of [16O]-water. Residues theThe [16O]-water the enrichment grade of with the recollected 16 O]-water reduce the enrichment grade of the recollected [18 O]-water. [16[O]-water. Residues of the [ 18O]-water. First attempts to remove the water residues from the cartridge with a stream of helium First to remove the water from the cartridge with1). a stream helium gas still gasattempts still revealed a significant lossresidues of the enrichment grade (Table A clearof improvement in the revealed a significant loss of the enrichment grade (Table 1). A clear improvement in the retention of retention of the enrichment grade was achieved by an additional flushing of the red tubing system theinenrichment grade was achieved by an additional flushing of the red tubing system in Figure 2 Figure 2 with anhydrous acetonitrile [11]. Additionally, the anion exchange cartridge was rinsed with anhydrous acetonitrile [11]. Additionally, the anion exchange cartridge was rinsed with 1 mL of with 1 mL of anhydrous acetonitrile after conditioning. After performing the above-mentioned anhydrous after conditioning. After performing the above-mentioned steps, the [12]. synthesis steps, theacetonitrile synthesis module was prepared according to common literature procedures A flow module was prepared according to common literature procedures [12]. A flow chart representing the chart representing the tubing system is shown in Figure 2. tubing system is shown in Figure 2.
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Table 1. Influence of the synthesis preparation on the enrichment grade.
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Table 1. Influence of the synthesis preparation on the enrichment grade.
Common Drying Module Cartridge InfluenceSynthesis of the synthesis preparation on+the enrichmentDrying grade. Module + Cartridge Enrichment GradeTable 1.Common Enrichment Synthesis Drying Module + Cartridge Dryingwith Module + Cartridge Preparation with Helium Flow Acetonitrile Grade Preparation with Helium Flow with Acetonitrile Enrichment Common Synthesis Drying Module + Cartridge Drying Module + Cartridge [%] 74.0–80.0 84.0–88.0 95.0–96.5 74.0–80.0 84.0–88.0Flow Grade[%] Preparation with Helium with95.0–96.5 Acetonitrile [%] 74.0–80.0 84.0–88.0 95.0–96.5
Figure 2. Schematic partial representation of the tubing system.
Figure 2. Schematic partial representation of the tubing system. 2.3. Purification by Fractional Distillation FigureDistillation 2. Schematic partial representation of the tubing system. 2.3. Purification by Fractional
The distillation is a simple separation process that can be used for the cleaning and separation of liquids with points below 150 °C. A fractionated commercial is The is Fractional aboiling simple separation process that can bedistillation used forin the cleaning glassware and separation 2.3.distillation Purification by Distillation used for the purification of the collected [18O]-water [13]. The distillation unit (Figure 3a) consists of ◦ of liquids with boiling points below 150 C. A fractionated distillation in commercial glassware is distillation a simple separation that can usedafor the vacuum-coated cleaning and separation aThe heating jacket, ais500 mL flask (a 1–2 mLprocess flask can also bebe used), 30 cm Vigreux 18 O]-water used for purification of the collected [150 [13]. The distillation distillation (Figure 3a) consists of a of the liquids with boiling points below °C. mL A fractionated inunit commercial glassware column, a thermometer (20–150 °C), a 100 distillate receiver with vent stopcock, and a specialis heatingused jacket, a 500 mL flask (a 1–2 mL flask can also be used), a 30 cm vacuum-coated Vigreux column, 18 distillation cooling attachment (Figure 3b). This [13]. special apparatus anof for the purification of the collected [ O]-water Thesemi-micro distillationscale unit (Figure 3a)allows consists ◦ C), a a thermometer (20–150 100 mL distillate receiver with vent stopcock, and a special distillation improved separation of the fractions, thereby obtaining a lower volume loss. a heating jacket, a 500 mL flask (a 1–2 mL flask can also be used), a 30 cm vacuum-coated Vigreux
coolingcolumn, attachment (Figure 3b). This special semi-micro scale apparatus an improved a thermometer (20–150 °C), a 100 mL distillate receiver with allows vent stopcock, and a separation special cooling obtaining attachmenta lower (Figurevolume 3b). This special semi-micro scale apparatus allows an of the distillation fractions, thereby loss. improved separation of the fractions, thereby obtaining a lower volume loss.
Figure 3. (a) Distillation unit; (b) special distillation cooling attachment.
Figure (a)Distillation Distillation unit; cooling attachment. Figure 3. 3.(a) unit;(b) (b)special specialdistillation distillation cooling attachment.
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2.4. Separation of the [18O]-Water from the Azeotropic Mixtures by Means of a Molecular Sieve 2.4. Separation of the [18 O]-Water from the Azeotropic Mixtures by Means of a Molecular Sieve The idea of the separation of [18O]-water from organic solvents using a desiccant (including The ideasieves) of the has separation [18 O]-water solvents using a desiccant (including molecular already of been describedfrom in theorganic literature [14]. We adapted this method for the 18 molecular sieves) has already been described in the literature [14]. We adapted this method for thean purification of the first distilled fractions, which contain an [ O]-water/acetonitrile mixture with 18 purification ofcontent the firstof distilled an [ O]-water/acetonitrile mixture by with an acetonitrile 50–80%fractions, (10–15%which of the contain preparation). Separation of the [18O]-water further 18 O]-water by further acetonitrile content of 50–80% (10–15% of the preparation). Separation of the [ distillation is not possible [15]. A simple and suitable routine method for an almost complete distillation [15]. from A simple and suitable routine method for ansieve almost recoveryisofnot thepossible [18O]-water azeotropic mixtures using molecular 3Åcomplete is brieflyrecovery described 18 18O]-enrichment of below the [ O]-water from azeotropic using molecular sieveof3Å is [briefly described grade. below [16]. [16]. Special attention hadmixtures been paid to the preservation the 18 O]-enrichment grade. Special A attention had been paid to the preservation condensation unit (Figure 4) consistingofofthea [ three-necked flask with a thermometer, a A condensation consisting three-necked flask with a thermometer, a stopcock, A stopcock, an inlet unit pipe(Figure with a4)diameter ofof10a mm, and a heating jacket has been constructed. ancooling inlet pipe with a diameter of 10 was mm, connected and a heating jacket has been constructed. A cooling trap with trap with ice cooling to the diaphragm vacuum pump via PTFE tubing iceconnections cooling waswith connected to the diaphragm vacuum pump via PTFE tubing connections with a piston a piston and a three-way stopcock. and a three-way stopcock. The use of a molecular sieve containing [16O]-substitute groups led to a significant loss of 16 O]-substitute groups led to a significant loss of The use ofgrade. a molecular sievethe containing enrichment Therefore, molecular[ sieve has to be pretreated before use. Dust and enrichment Therefore, thesieve molecular sieve has to be beforedouble use. Dust and breakage breakage grade. from the molecular 3Å was removed bypretreated washing with distilled water. For from the molecular sieve 3Åsieve waswas removed washing distilled water. For activation, the molecular dried by under argonwith flowdouble in the condensation unit atactivation, a maximum thetemperature molecular sieve was under argon in the condensation unitwith at a maximum of 300 °C.dried Subsequently, theflow molecular sieve was mixed [18O]-watertemperature of about 50% 18 O]-water of about 50% enrichment of enrichment 300 ◦ C. Subsequently, the molecular sieve was mixed with [ grade, and dried again at about 200 °C. Further handling and storage was carried out grade, and dried again at about 200 ◦ C. Further handling and storage was carried out under argon. under argon. ForFor thethe separation of the [18 O]-water from the azeotropic [18 O]-water/acetonitrile mixture, 150 g150 of g separation of the [18O]-water from the azeotropic [18O]-water/acetonitrile mixture, theofpreconditioned 3Å molecular sieve was added to 150 gtoof150 thegmixture, and allowed to stand under the preconditioned 3Å molecular sieve was added of the mixture, and allowed to stand 18 O]-water molecules 18 argon for 24 h. After 24 h, most of the [ had been absorbed by the molecular under argon for 24 h. After 24 h, most of the [ O]-water molecules had been absorbed sieve. by the After decantation the acetonitrile, theofresidual amount of the acetonitrile removed by drying for molecular sieve.of After decantation the acetonitrile, residualwas amount of acetonitrile was 1 hremoved at 40 ◦ C by under a membrane vacuum, and subsequently under aand weak argon stream for a drying for 1 h at pump 40 °C under a membrane pump vacuum, subsequently under another min. stream Following this, the5cold was cleaned andcold placed ice water. theplaced recovery weak 5argon for another min.trap Following this, the trapinwas cleanedFor and in ice 18 18 of water. the [ O]-water, the molecular sieve was heated 3 h under sieve atmospheric pressure For the recovery of the [ O]-water, theformolecular was heated for in3 ahweak under stream of argonpressure at a maximum temperature 200 ◦atC.aThe pure [18temperature O]-water was in the atmospheric in a weak stream of of argon maximum of collected 200 °C. The pure 18 18 18 cold trap. The solvent content of the recollected [ O]-water is usually >1%, and can be returned to is [ O]-water was collected in the cold trap. The solvent content of the recollected [ O]-water theusually distillation. >1%, and can be returned to the distillation.
Figure 4. Condensation unit for the recovery of [18O]-water from azeotropic mixtures. Figure 4. Condensation unit for the recovery of [18 O]-water from azeotropic mixtures.
2.5. Determination of the Degree of Enrichment via Pycnometry The effects on the enrichment grade of the individual process steps were examined via pycnometry [17,18]. With an increased amount of [18O] in [16O]-water, an increase of the density of
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2.5. Determination of the Degree of Enrichment via Pycnometry The effects on the enrichment grade of the individual process steps were examined via pycnometry [17,18]. With an increased amount of [18 O] in [16 O]-water, an increase of the density of the [18 O]-water mixture is observed. The increase of the density is dependent on the increase of the amount of [18 O] present in the [18 O]-water.
ρ[18 O]-water(T) = ρ[16 O]-water(T) × (20.0153/18.0153) [g/mL] for pure [18 O]-water
()
(20.0153/18.0153) is the molecular weight ratio of [18 O]-water to [16 O]-water. Since the number of atoms is proportional to the volume, the enrichment grade is dependent on the density (ρ = m/V) at constant temperature. ρ sample = (w[18 O]water × ρ[18 O]water) + (w[16 O]water × ρ[16 O]water)
()
At a constant volume measurement (using the same pipette), the enrichment grade can be determined by the mass ratio of [18 O]-water to [16 O]-water. The density of the [18 O]-water can be determined experimentally, and the enrichment grade can be calculated using the following formula: wsample
h
18
m 18 O water O = 9× − 9[%] m[16 O]water i
m [16 O]-water (T) = mass of [16 O]-water at certain temperature and pipette m [18 O]-water (T) = mass of [18 O]-water sample at certain temperature and pipette w: enrichment grade in % 9 = 1/K, K = (20.0153/18.0153) − 1; K: constant from the difference of the molecular weights. Hence, the enrichment grade is determined by simple weighing in combination with volume measurement, whereas the density is temperature dependent. 3. Results For the validation of the purification procedures and the quality control of the purified [18 O]-water, the following parameters (Table 2) have been investigated. Table 2. Examination parameters for the quality control of [18 O]-water. Parameter
Method
Device
Relative pycnometry
Libra, pipette
Solvent content
Gas chromatography
Trace 1310 Thermo Fischer, FID
Aromatic compounds
UV-Spectroscopy
Genesys 10 S Thermo Fisher
Ions
Conductivity measurement
Vario Cond, WTW, 0.001-200 µS/cm
Radioactive nuclide
Gamma measurement, multi-channel-analyzer
Germanium Detector GC 1200-7500 SL Canberra
[18 O]-Enrichment
grade
Using fractionated distillation, a separation of the [18 O]-water from the solvent mixture in the first step was possible, in both good quantity and sufficient quality (Table 3). About 80% of the used [18 O]-water can be recycled in the first step. The process was established in common laboratory scales of 1 to 2 L. No differences in the yields of activity during [18 F]-fluoride production and the radiochemical yields of [18 F]-FDG in the following radiosynthesis were observed, comparing the use of recycled
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[18 O]-water to fresh [18 O]-water. After more than 10 times of use and purification, no accumulation of any impurity, in particular of radionuclides, has been detected. Furthermore, during irradiation in the cyclotron, the recycled [18 O]-water showed no pressure increase in the target, normally observed when additional solvent residues are present. It has also been found that purification by fractional distillation does not diminish the enrichment grade. In summary, following the above-mentioned recycling process, used [18 O]-water can be recovered without any loss in the enrichment grade. Table 3. Quality of the recovered [18 O]-water. Parameter
Unit
Collected[18 O]-H2 O
Main Fraction
First Fraction
Residue
Specification
Volume
%
100
80
15
5
-
Conductivity
µS/cm
1200
0.9
133
3000
