Introduction Liquid targets using top-of-foil loading concept have been succesfully employed for routine high current production of 18F and 13N at Cyclotope (Houston,TX), over the past ten years1,2. These targets are typically filled with 3.5 ml of water, then pressurized with helium gas at 22 bar and bombarded with 18MeV protons (70–100 µA). Average calculated saturation yield for produc-tion of 18F is ~7.8 GBq/µA (210 mCi/µA) using in-house recycled [18O]-water at approximately 93% enrichment. Reduction of beam power per unit of area is one of the advantages of a tilted entrance-foil geo-metry. Implementation of this target geometry on the ACSI TR19 cyclotron 25degrees upwards irradiation port results in an almost horizontal target entrance foil. A 6ml total cavity volume target allows variable liquid fill volumes of 1.2–4.5 ml for beam current operation from 30–120 µA, resulting in a very efficient use of the costly 18O-water. In a near horizontal installation as in the mayority of cyclotrons, the fill volume flexibility is drastically reduced, having a minimum fill volume of 3.3 ml. At the requirement of Laboratorios Bacon, Cyc-lotope modified the target design with a front mounted collimator compatible with the IBA Cyclone 18/9 cyclotron. A second requirement was to reduce the minimum fill volume for horizontally mounted targets to 2.5 ml or less, while maintaining saturation yield performance. To preserve compatibility with existing IBA targets, the target hardware was modified to operate in self-pressurization mode. This paper presents the results obtained with high and low volume Niobium target inserts (6ml and 4 ml) mounted near horizontally on the IBA Cyclone 18/9 cyclotron and operated in self-pressurization mode. We present pressure/current characteristics, target performance (saturation yield, produced activities, maintenance frequency, FDG yields, etc.). Material and Methods The following targets manufactured by Cyclotope were tested and routinely used for production at Laboratorios Bacon: 1-High Volume Target CY2 model (“American Standard”), 6ml Niobium cavity. 2-Low Volume Target, CY3a model (“Traful”), 4ml Niobium cavity. 3- Low volume Target, CY3b model (“Ferrum”), 4.1ml Niobium cavity. Results and Conclusion The advantages of self-pressurization mode (Laboratorios Bacon setup) are: - Using the vapor pressure as a performance parameter - heat removal by boiling/condensation cycle starts at lower temperature (beam cur-rent) . While, the advantages of the pre-pressurized targets (Cyclotope setup) are: - reduced pressure fluctuations - performance is basically unaffected by plumbing dead volume - flexibility to locate instrumentation farther away from radiation fields - less dependence on fill volume - potential target leaks can be detected before starting an irradiation No significant differences were found in target performance when operated in either pressu-rization mode. The self-pressurizing setup seems to require a sligthly lower fill volume (approxi-mately 5%). The maximum beam current was limited by the foil rupture pressure (~ 40 bar). Safe maximum operating pressure was determined as 30 bar. No foil rupture was experienced during nine months of daily irradiation of these targets in self-pressurizing mode at Laboratorios Bacon. The irradiation parameters and target performance for the different targets are shown in Tables 1 and 2 below. The low volume Traful and Ferrum targets have the best saturation activity vs. fill volume, A(sat)/V, relation. Both targets produce 310 ± 31GBq (8.4 ± 0.8 Ci) of high quali-ty fluoride (F-18) in two hours of irradiation at 70 µA. The low volume targets have a low operation pressure (20bar @ 70µA) when compared to the IBA (NIRTA XL) targets. The typical saturation activity for the low volume targets was 592 ± 59 GBq (16 ± 1.6 Ci) of F-18 at 70 µA, 8.5 GBq/µA (228 mCi/µA) using 2.7ml enriched O-18 water (98 % +). The maintenance interval (> 10 mA.h) is very conveniente to reduce personnel radiation dose. No reduction in FDG yields was observed during that operation interval. In contrast, operation of the high volume targets in pre-presurization mode at the Cyclotope facility results in a higher maximum beam current limit (135 µA) for the same operating pressure (25 bar). Nevertheless, more O-18 water will be required to irradiate at this high current (4.5 ml vs. 3.0 ml). In self-pressurizing mode, a higher filling volume will reduce the expansion volume and, in consequence, the maximum beam current.

In this master’s thesis the hydrolytic degradation in 18O-water solutions of six drug substances has been studied. The aim was to develop a mass spectrometric method for easier identification of degradants, since hydrolysis in 18O-water will generate degradants with higher mass compared with hydrolysis in regular water. The degradation was carried out in both acidic and basic conditions. About 10 % degradation was aimed for in the study and the storage time and conditions were adjusted to accommodate that. The samples were then analyzed with UPLC-MS. Separation was achieved on either an Acquity BEH C18 or HSS T3, 100 x 2.1 mm, 1.7 μm column. The mobile phases consisted of water and acetonitrile with the addition of 0.1 % formic acid. Structures for the detected degradants were proposed based on the molecular ion data from the regular and 18O-experiments. Most of these degradants have previously been reported. Structures for some previously unreported degradants are also proposed. These structures should need to be confirmed with future studies. The usefulness of the 18O-method has been evaluated and it was concluded that it is valuable to use as a complement to the generic hydrolytic experiment. In this study, the extra information gained from the 18O-experiment was used to confirm a number of proposed structures. It was also crucial in the rejection of two proposed structures for degradants of duloxetine. The method is most useful when confirming water involvement in reactions, for example in drug degradation. It is also a good alternative for obtaining structural information if the laboratory does not own a high-resolution MS.

Introduction Liquid targets using top-of-foil loading concept have been succesfully employed for routine high current production of 18F and 13N at Cyclotope (Houston,TX), over the past ten years1,2. These targets are typically filled with 3.5 ml of water, then pressurized with helium gas at 22 bar and bombarded with 18MeV protons (70–100 µA). Average calculated saturation yield for produc-tion of 18F is ~7.8 GBq/µA (210 mCi/µA) using in-house recycled [18O]-water at approximately 93% enrichment. Reduction of beam power per unit of area is one of the advantages of a tilted entrance-foil geo-metry. Implementation of this target geometry on the ACSI TR19 cyclotron 25degrees upwards irradiation port results in an almost horizontal target entrance foil. A 6ml total cavity volume target allows variable liquid fill volumes of 1.2–4.5 ml for beam current operation from 30–120 µA, resulting in a very efficient use of the costly 18O-water. In a near horizontal installation as in the mayority of cyclotrons, the fill volume flexibility is drastically reduced, having a minimum fill volume of 3.3 ml. At the requirement of Laboratorios Bacon, Cyc-lotope modified the target design with a front mounted collimator compatible with the IBA Cyclone 18/9 cyclotron. A second requirement was to reduce the minimum fill volume for horizontally mounted targets to 2.5 ml or less, while maintaining saturation yield performance. To preserve compatibility with existing IBA targets, the target hardware was modified to operate in self-pressurization mode. This paper presents the results obtained with high and low volume Niobium target inserts (6ml and 4 ml) mounted near horizontally on the IBA Cyclone 18/9 cyclotron and operated in self-pressurization mode. We present pressure/current characteristics, target performance (saturation yield, produced activities, maintenance frequency, FDG yields, etc.). Material and Methods The following targets manufactured by Cyclotope were tested and routinely used for production at Laboratorios Bacon: 1-High Volume Target CY2 model (“American Standard”), 6ml Niobium cavity. 2-Low Volume Target, CY3a model (“Traful”), 4ml Niobium cavity. 3- Low volume Target, CY3b model (“Ferrum”), 4.1ml Niobium cavity. Results and Conclusion The advantages of self-pressurization mode (Laboratorios Bacon setup) are: - Using the vapor pressure as a performance parameter - heat removal by boiling/condensation cycle starts at lower temperature (beam cur-rent) . While, the advantages of the pre-pressurized targets (Cyclotope setup) are: - reduced pressure fluctuations - performance is basically unaffected by plumbing dead volume - flexibility to locate instrumentation farther away from radiation fields - less dependence on fill volume - potential target leaks can be detected before starting an irradiation No significant differences were found in target performance when operated in either pressu-rization mode. The self-pressurizing setup seems to require a sligthly lower fill volume (approxi-mately 5%). The maximum beam current was limited by the foil rupture pressure (~ 40 bar). Safe maximum operating pressure was determined as 30 bar. No foil rupture was experienced during nine months of daily irradiation of these targets in self-pressurizing mode at Laboratorios Bacon. The irradiation parameters and target performance for the different targets are shown in Tables 1 and 2 below. The low volume Traful and Ferrum targets have the best saturation activity vs. fill volume, A(sat)/V, relation. Both targets produce 310 ± 31GBq (8.4 ± 0.8 Ci) of high quali-ty fluoride (F-18) in two hours of irradiation at 70 µA. The low volume targets have a low operation pressure (20bar @ 70µA) when compared to the IBA (NIRTA XL) targets. The typical saturation activity for the low volume targets was 592 ± 59 GBq (16 ± 1.6 Ci) of F-18 at 70 µA, 8.5 GBq/µA (228 mCi/µA) using 2.7ml enriched O-18 water (98 % +). The maintenance interval (> 10 mA.h) is very conveniente to reduce personnel radiation dose. No reduction in FDG yields was observed during that operation interval. In contrast, operation of the high volume targets in pre-presurization mode at the Cyclotope facility results in a higher maximum beam current limit (135 µA) for the same operating pressure (25 bar). Nevertheless, more O-18 water will be required to irradiate at this high current (4.5 ml vs. 3.0 ml). In self-pressurizing mode, a higher filling volume will reduce the expansion volume and, in consequence, the maximum beam current.

In this project the photodegradation of 3,5-diamino-6-chloro-N-(2-(methylamino)ethyl)pyrazine-2-carboxamide was studied. A hypothetical degradation pattern for the compound was proposed and the aim of the project was to study the formed secondary photodegradants and to, if possible, structure elucidate some of these compounds. In order to do this, the parent compound was photodegraded in two steps, where a primary photodegradant was isolated using semi-preparative supercritical fluid chromatography (SFC) and then further degraded into the secondary photodegradants. The photodegradation was first carried out in aqueous solution, where the parent compound was irradiated in UV-A light of 300-400 nm. This resulted in a primary photodegradant with a molecular ion of m/z = 227, where the chloride in position 6 of the pyrazine group had been replaced by a hydroxyl group. During the large scale photodegradation, prior to the preparative purification, the yield of primary photodegradant was very low due to the photodegradation being dependent on both sample volume and concentration and due to the primary photodegradant also being unstable in aqueous solution at room temperature. Due to the above mentioned difficulties the parent compound was photodegraded in methanol instead of water in order to avoid the freeze-drying process where a lot of the primary photodegradant was lost. This resulted in a primary photodegradant with a molecular ion of m/z = 241, where the chloride had been replaced by a methoxy group instead of a hydroxyl group. This compound was more stable which allowed workup by rotary evaporation, instead of freeze-drying, before the preparative purification. This primary photodegradant was isolated using semi-preparative SFC on a Viridis® BEH Prep OBD TM column (250 x 30 mm, 5 µm) and a Luna HILIC column (250 x 30 mm, 5 µm) with MeOH/NH3 100/1 v/v as organic modifier. About 1.2 mg material was isolated and further photodegradation tests in ordinary water and 18O-water were conducted. Some secondary photodegradants were observed in LC-MS analyses, and their element compositions were proposed by accurate mass results. Fundamental structures for these compounds were proposed. Further structural investigational analyses are needed for confirmation in the future.