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Introduction 61Cu (T1/2 = 3.33 hr, Eβ= 1.22 MeV, 61.4 %) is an attractive isotope for positron emission tomography (PET) radiopharmaceutical agents such as ATSM and PTSM. Various separation processes have been reported for the production of 61Cu on a medium cyclotron using 13–22 MeV protons on natural and enriched 64Zn target materials [1,2]. This work, investigates production of 61Cu using both natural and enriched 64Zn targets and its separation. Three types of resins were used to assess for their efficiency and speed to separate the desired 61Cu from the 66,67,68Ga and 64Zn and for the recycling of 64Zn target material. The effective specific activity of purified 61Cu, was determined by ICP-MS and its titration with various polyaza and polycarboxylate complexing ligands. Material and Methods 1. Production and Separation Targets were irradiated by proton beam of IBA cyclotron 18/18MeV via the 64Zn(p,α) 61Cu and natZn(p,x) 61Cu reactions using an enriched 64Zn foil(15×15×0.05mm, ~50 mg) and natural foil (diameter 25 mm, 0.05 mm,~ 60 mg). Thirty minute irradiations were conducted with incident proton energies between 11.7–12.0 MeV and beam currents of 20 and 40 µA. Irradiated Zn targets were dissolved in 8M HCl at 150 oC then evaporated to dryness. Trace water to the resultant residue (twice) and resultant solutions evaporated to dryness. The residue was re-dissolved in 2ml of 0.01M HCl before loading onto a Cu-resin column (FIG. 1) Zn and Ga isotopes were collectively eluted using 30 ml of 0.01M HCl. The Cu was then removed using 1.5 ml of 8M HCl and passed directly onto a cation exchange followed by an anion exchange column. An additional 3 ml of 8M HCl was used to rinse the cation exchange column and ensure quantitatively removal of Cu (II) ions. The Cu was finally eluted from the anion exchange column using 3 ml of 2M HCl. The Cu solution was heated up at 150 oC until evaporated to dryness and 61Cu final product dissolved in 400–800 μL of 0.01M HCl. 2. Specific activity of 61Cu The specific activity (GBq/µmol) of the purified 61Cu was determined by ICP-MS and compared with that determined using dota, nota and di-amsar complexing ligands. For each 61Cu production run aliquot of final solution (100 µL) was left to decay before dilut-ing to 10 mL with 10% HNO3. Decayed samples were sent to ChemCentre (Curtin University) for ICP-MS analysis. Each sample was analysed for Cu, Al, Ca, Co, Fe, Ga, Ni, Si, and Zn, which are known to compete with Cu2+ for ligand complexation. Effective specific activity of the 61Cu was deter-mined by titrating various known concentration of ligands with 61Cu solution. The method is detailed in the literature [3]. Briefly, varying concentrations of each ligand was prepared in 0.1M sodium acetate buffer pH 6.5 to a total volume 20 µL. Fixed concentration of diluted 61Cu (0.01M HCl) in 10 µL was added to each ligand solution. The mixtures were vortexed then left to incubate at the room temperature for 30 mins. Two uL aliquots were withdrawn (in triplicate) from each reaction mixture and spot-ted on ITLC –SA. [Mobile phase: 0.1M NaCl: 0.1M EDTA (9:1) for Cu2+ and diamsar mixtures: Rf <0.2 Cu-diamsar; Rf > 0.8 free Cu2+ and 0.1M sodium acetate pH 4.5: H2O: MeOH: ammonium hydroxide (20:18:2:1 v/v) for Cu2+ dota and nota mixtures: Rf >0.8 Cu-dota and Cu-nota Rf < 0.2 free Cu2+]. Complexation of the 61Cu with each ligand was complete within 30 mins at room temperature. Concentration of Cu2+ was deter-mined from the 50% labelling efficiency. Results and Conclusion 1. Production and Separation The radioisotopes production from natZn target must be minimized by the optimum proton energy to reduce a radiation dose in the final product. The excitation functions of 66,67,68Ga ,65Zn and 61Cu are shown in FIG. 2. Proton beam energy of 11.7 MeV was used for both Zn targets to minimise the production of Ga isotopes and prevent formation of 65Zn. For the enriched 64Zn target (99.30%) higher proton energy could be used for the production of 61Cu allowing for increased yields and reduce radio contaminants. Previously, we used anion and cation exchange resin as described in the literature to separate the 61Cu [1]. Unfortunately the literature method was too long (up to 3 hours) and requiring high concentration of HCl and long evaporation times compromising achievable yields [4]. Thieme S. et al., 2013 [2] reported the successful use of Cu-resin for the separation of Cu radioisotopes and it was of interest to the current work to test this material for the separation of 61Cu in our hands. A cation, anion exchange and Cu-resin were combined into closed system to separate the 61Cu within 30 mins (FIG. 1). The system is designed to contain the transfer of solutions be-tween each column using simple plunger to force solution through and between each column. This system afforded an easy, reliable and fast separation of 61Cu that could be completed within 30 min. 2. Specific activity The specific activity of 61Cu was determined using ICP-MS and by titration with three ligands is summarized in TABLE 1. The ICP-MS data show values ranging from 9.2 to 32.4 GBq/μmol for 8 production runs. Specific activity determine using nota and dota were in all cases lower than the ICP MS data indicating some interference from the other metal ion contaminates such as Fe(ii/Iii), Ni (II), Ca (II), Zn (II), Ga (III). The specific activity determine using diamsar, which is known to be highly selective for Cu(II) (and Zn(II) and Fe(III)) in the presence of alkali and alkaline earth ions gave values significantly higher effective specific activity than that obtained using ICP MS. Variations in values can be explained by presence of contaminating metal ions.

Orientadores: Marco Aurélio Zezzi Arruda, Ljubica Tasic / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-23T02:17:28Z (GMT). No. of bitstreams: 1 Mataveli_LidianeRaquelVerola_D.pdf: 1935019 bytes, checksum: 059066ee53b01850e2858460ba23617e (MD5) Previous issue date: 2013 / Resumo: Este trabalho consistiu em estudos de metalômica comparativa de sementes de soja transgênica (T) e não-transgênica (NT). Para tanto, as sementes de soja T e NT foram comparadas, em um primeiro, momento levando-se em conta: concentração total dos elementos, comportamento dos elementos durante extração utilizando-se fracionamento sequencial, e bioacessibilidade dos elementos após procedimento de digestão gastrointestinal simulada (in vitro). As análises preliminares foram feitas utilizando-se ICP-MS com analisador de massas quadrupolar, e as análises posteriores utilizando espectrometria de massas de alta resolução com plasma acoplado indutivamente (HR-ICP-MS). Foram determinados 25 elementos em concentrações variando de ng g até %. Foi observado que as sementes de soja T e NT exibem diferenças estatisticamente significantes nas concentrações de Cu, Fe e Sr, sendo os dois primeiros apresentando maiores concentrações na semente T, e, o último, com maior concentração nas sementes de soja NT. Estes resultados também se refletiram nos conteúdos desses elementos em extratos aquosos e resíduos obtidos por meio de fracionamento sequencial. Ainda, os experimentos de bioacessibilidade realizados mostraram que as frações bioacessíveis de Cu, Fe, e outros elementos (Mn, S, Zn) contribuíram em maior porcentagem para a concentração total dos elementos nas sementes de soja T do que para as sementes de soja NT. Posteriormente, foi dada continuidade aos estudos utilizando cromatografia líquida bidimensional off line para as amostras de sementes de soja, sendo a primeira dimensão constituída de cromatografia de exclusão por tamanho (SEC,) e a segunda dimensão constituída de cromatografia de troca aniônica (AEX). Na primeira dimensão cromatográfica foram identificadas três frações contendo metais por meio da hifenação SEC-ICP-MS: a primeira correspondendo a massas molares entre 38,1 e 181,1 kDa, a segunda correspondendo a massas molares entre 8,2 e 17,2 kDa, e a terceira fração correspondendo a massas molares entre 0,4 e 3,8 kDa. As três frações identificadas foram separadas, liofilizadas, e separadas novamente utilizando a cromatografia de troca aniônica. Foram detectados metais em todas as frações separadas por SEC: três sub-frações da primeira fração, uma sub-fração na segunda fração e três sub-frações na terceira fração. Os eluatos foram coletados, liofilizados, digeridos e levados ao espectrômetro de massas com fonte de ionização por electrospray (ESI-MS) para identificação de proteínas. Foram identificadas 33 e, entre elas, duas proteinas previamente relacionadas a metais foram encontradas: seed lipoxygenase 1 e b-conglycinin. Após a separação na segunda dimensão cromatográfica, as sub-frações resultantes foram liofilizadas e submetidas a uma terceira dimensao de separacao, utilizando a eletroforese em gel de poliacrilamida unidimensional (SDS-PAGE). As bandas obtidas por SDS-PAGE foram recortadas e digeridas a fim de analisar os metais presentes nas mesmas, destacando os resultados obtidos para Fe, onde o mesmo foi quantificado nas bandas da sub-fração onde o pico deste elemento foi encontrado nas análises por AEX-ICP-MS. Ainda, as bandas foram digeridas tripticamente a fim de identificar as proteínas presentes, e, novamente, proteínas associadas a metais foram identificadas: chain A lipoxygenase-3 (Soybean) complex with 13(S)-hydroperoxy- 9(Z),11(E)-octadecadienoic acid; beta-amylase [Glycine max]; seed lipoxygenase-1, lipoxygenase [Glycine max], seed lipoxygenase-2 (PISUM SATIVUM) e beta-conglycinin / Abstract: This work consisted of comparative metallomics studies of transgenic (T) and nontransgenic (NT) soybean seeds. To that end, T and NT seeds were compared at first taking into account: the total concentration of the elements, the elements behavior during extraction using sequential fractionation, and bioacessibility of the elements after simulated gastrointestinal digestion procedure (in vitro). Preliminary analyzes were done using ICP-MS with quadrupole mass analyzer, and the subsequent analysis using high-resolution inductively coupled plasma mass spectrometry, (HR-ICP-MS). 25 elements were determined at concentrations ranging from 1 ng g up to %. It was observed that T and NT soybean seeds exhibit statistically significant differences in the concentrations of Cu, Fe and Sr, the first two having higher concentrations in the T seeds, and the last with the highest concentration in soybeans NT. These results were also reflected in the contents of these elements in aqueous extracts and residues obtained through sequential fractionation. Also, the contributions of bioaccessible fractions of Cu, Fe and other elements (Mn, S, Zn) to the total content of the elements in T soybean seeds were higher than those found in NT soybean seeds. Subsequently, studies were continued using bidimensional liquid chromatography, the first dimension consisting of size exclusion chromatography (SEC) and the second dimension of anion exchange chromatography (AEX). In the first chromatographic dimension three fractions containing metals were identified using hyphenation SEC-ICP-MS, the first corresponding to molar masses between 38.1 and 181.1 kDa, the second corresponding to molar masses between 8.2 and 17.2 kDa and the third fraction corresponding to molar masses between 0.4 and 3.8 kDa. The three identified fractions were separated and lyophilized, and again separated using anion exchange chromatography (AEX). Metals were found in all the separated fractions by SEC: three sub-fractions of the first fraction, a subfraction in the second fraction and three sub-fractions in the third fraction. These peaks were collected, lyophilized, digested and taken to the mass spectrometer for protein identification. 33 proteins were identified, and, among them, two proteins previously related to metals were found: seed lipoxygenase 1 and b-conglycinin. After chromatographic separation in the second dimension, the resultant subfractions were lyophilized and subjected to a third separation dimension using onedimensional polyacrylamide gel electrophoresis (SDS-PAGE). After the separation, the bands were cut out and digested to examine the metals contained therein, highlighting the results obtained for Fe, which was quantified in the bands of the sub-fraction where the peak of the element is found in the analysis by ICP-AEX - MS. Also, the bands were digested triptically to identify the proteins, and once again proteins associated to metals were identified: 3-lipoxygenase A chain (Soybean) complex with 13 (S)-Hydroperoxy-9 (Z), 11 ( E)-octadecadienoic acid, beta-amylase [Glycine max]; seed lipoxygenase-1, lipoxygenase [Glycine max] seed lipoxygenase-2 (Pisum sativum) and beta-conglycinin / Doutorado / Quimica Analitica / Doutora em Ciências

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Com o aumento das exigências regulatórias e estabelecimento de limites mais restritos para impurezas elementares em fármacos e excipientes usados em formulações farmacêuticas, ocorreu uma busca por técnicas analíticas capazes de quantificar elementos em níveis traço e assegurar a qualidade e a segurança dos medicamentos. A espectrometria de massas com plasma acoplado indutivamente (ICP-MS) é uma técnica multielementar, que apresenta alta sensibilidade e é empregada com eficiência na análise de elementos traço em diferentes matrizes. O ICP-MS, acoplado a um sistema separador como o cromatógrafo líquido de alta eficiência (HPLC), possibilita a especiação de elementos químicos, o que é importante, pois a toxicidade pode estar diretamente ligada à forma química do elemento, como ocorre para o Hg e As. Neste sentido, os objetivos deste trabalho foram desenvolver e validar um método de análise simples, rápido e com alta sensibilidade, para determinação de 15 impurezas elementares: As, Cd, Cr, Cu, Ni, Pb, V, Ir, Pd, Pt, Rh, Ru, Hg, Os e Mo, em diferentes fármacos e excipientes, em níveis que atendam aos novos critérios estabelecidos pelos órgãos regulatórios, avaliar a utilização da cela de reação dinâmica (DRC) para eliminação de interferências espectrais na determinação de As, Cr e V, realizar a especiação de As e Hg, e aplicar esta metodologia para análise de diversas amostras comprovando sua robustez, versatilidade e vantagens para utilização em rotina. Foram avaliadas cinco estratégias de preparo de amostra: digestão em micro-ondas sistema fechado e digestão em micro-ondas - sistema aberto, digestão em banho-maria, diluição direta em meio ácido e extração utilizando ponteira de ultrassom. Através de ensaios de recuperação e materiais de referência certificados, os melhores resultados (84 a 101%) foram obtidos com a digestão das amostras em sistema fechado de micro-ondas e extração por ponteira de ultrassom. Os limites de detecção variaram entre 0,001 ng g-1 (103Rh) e 0,083 ng g-1 (75As). Em seguida, a metodologia analítica foi empregada para determinação dos elementos em estudo em 74 amostras de fármacos e excipientes. O elemento mais frequentemente encontrado foi o Cu, seguido por Cr, Mo, Ni, Pd e V. Já os elementos químicos Ir, Pt, Os e Ru não foram detectados. Cabe destacar que as concentrações de Pd, Rh, As, Cd, Cr, Cu, Ni, V e Mo encontraram-se acima do limite preconizado pela farmacopeia americana em algumas amostras. A análise por especiação química de As mostrou que as amostras possuíam apenas as formas inorgânicas e mais tóxicas. Em relação ao Hg, apenas uma amostra apresentou níveis detectáveis deste elemento, mas a concentração estava abaixo do limite estabelecido pela farmacopeia americana. / Due to quality and safety reasons, regulatory requirements and establishment of more restricted limits for elemental impurities in drugs and excipients are increasing. These regulations promoted a search for simple and robust analytical techniques for quantification of trace elements. Inductively coupled plasma mass spectrometry (ICP-MS) is an attractive technique for this purpose, presenting multielement and high sensitivity capabilities. ICP-MS can be hyphenated to separation techniques such as high-performance liquid chromatography (HPLC), enabling chemical speciation analysis. Speciation analysis may reveal the chemical form of the element that may be more directly related to the toxicity. In this sense, the objectives of this work were to develop and validate a simple, fast and highly sensitive method for the determination of 15 elemental impurities: As, Cd, Cr, Cu, Ni, Pb, V, Ir, Pd, Rh, Ru, Hg, Os and Mo, in different drugs and excipients, at levels that meet the new criteria established by the regulatory agencies. We also evaluated the use of the dynamic reaction cell (DRC) to eliminate spectral interferences for As, Cr And V. Finally, for As and Hg, speciation methods were applied. All analysis were performed focusing on robustness, versatility and sample high-throughput. We tested five sample preparation strategies: closed microwave system digestion, microwave digestion - open system, water bath digestion, direct acid dilution and ultrasound probe extraction. Recovery studies in ordinary samples and reference certified materials were observed with the closed microwave digestion system and ultrasound probe extraction (84 and 101%). Detection limits ranged from 0.001 ng g-1 for 103Rh to 0.083 ng g-1 for 75As. The analytical methodology was then applied for the determination of the elements in study in 74 samples of drugs and excipients. The most frequently found element was Cu, followed by Cr, Mo, Ni, Pd and V. The chemical elements Ir, Pt, Os and Ru were not detected. It should be mention that the concentrations of Pd, Rh, As, Cd, Cr, Cu, Ni, V and Mo were above the limit recommended by the American pharmacopeia in some samples. Only inorganic arsenic (most toxic forms) was found in samples by applying speciation analysis. Regarding Hg, only one sample had detectable levels of this element, but the concentration was below the limit established by the American pharmacopeia

Le germanium est un métalloïde « stratégique » dans l’industrie high-tech, notamment pour la transition énergétique et le secteur des communications. Étant distinctement sidérophile, lithophile, chalcophile et organophile, le Ge possède un fort potentiel comme traceur géochimique. Ces travaux de thèse visent à améliorer la compréhension de la géochimie du cycle du Ge et des facteurs qui contrôlent son incorporation dans les minéraux et les gisements métalliques. Les cibles de cette étude concernent le gisement filonien à Zn de Saint-Salvy (Massif Central, France), le gisement filonien à Cu de Barrigão (Ceinture pyriteuse ibérique, Portugal), et le gisement à Zn–Cu de Kipushi (R.D. Congo). Les porteurs de Ge les plus importants sont respectivement la sphalérite (jusqu’à 2580 ppm), la chalcopyrite (jusqu’à 5750 ppm) et la réniérite (5,0–9,1 %). Les résultats montrent qu’il existe une relation de premier ordre entre la concentration en Ge dans la sphalérite et le type de gisement. La spectroscopie XANES par rayonnement synchrotron met en évidence la présence de Ge4+ en site tétraédrique dans les sulfures analysés. Les corrélations élémentaires observées dans la sphalérite et la chalcopyrite suggèrent une incorporation du Ge par co-substitutions, e.g., 3Zn2+ ↔ Ge4+ + 2(Cu,Ag)+ et 3Fe3+ ↔ 2Ge4+ + Cu+, ou via la création de lacunes cristallographiques, e.g., 2Zn2+ ↔ Ge4+ + ?. La corrélation positive δ74Ge–[Ge]ZnS des sphalérites de Saint-Salvy indiquerait que coefficient de partage (KdGe) augmenterai avec T. Les compositions isotopiques δ74Ge des sulfures étudiés varient de –5,72‰ à +3,67‰. Les compositions légères mesurées dans les gisements de Saint-Salvy et Barrigão semblent liées à des variations de température des fluides (basse à moyennes T) lors de l’incorporation de Ge en système ouvert, alors que la tendance marquée vers les compositions isotopiques lourdes à Kipushi indiquerait un fractionnement de Rayleigh. / Germanium is a critical metalloid in many high-tech industries, especially for the energy transition and the communication sector. Being distinctly siderophile, lithophile, chalcophile and organophile, Ge can be a particularly useful geochemical tracer. This thesis aims at understanding the Ge geochemistry and the factors controlling its concentration in Ge-bearing minerals and ore deposits. Three contrasted Ge-bearing deposits were studied, the Saint-Salvy Zn vein-type deposit, French Massif Central, the Barrigão Cu vein-type deposit, Iberian pyrite belt, Portugal, and the Kipushi Zn–Cu carbonate-hosted deposit, Central African copper-belt, D.R. Congo. The most important Ge-bearing minerals are sphalerite (up to 2580 ppm Ge), chalcopyrite (up to 5750 ppm Ge), and renierite (5.0–9.1 wt.% Ge). The results show a first order relation between the Ge content and the deposition temperature. Synchrotron-based XANES spectroscopy showed that Ge4+ occur in tetrahedral sites in the studied sulphides. Element correlations suggest that Ge is chiefly incorporated in sphalerite and chalcopyrite through coupled substitutions, e.g., 3Zn2+ ↔ Ge4+ + 2(Cu,Ag)+ and 3Fe3+ ↔ 2Ge4+ + Cu+, respectively, or via the creation of lattice vacancies, e.g., 2Zn2+ ↔ Ge4+ + ?. The positive δ74Ge–Ge content correlation observed in sphalerite from Saint-Salvy could indicate that Ge partition coefficient (KdGe) increases with temperature. Ge isotopes in sulphides yield δ74Ge values spanning from –5.72‰ to +3.67‰. The light δ74Ge compositions of Saint-Salvy and Barrigão ores appear to be related to variations in low to moderate fluid temperatures during Ge uptake in open system (e.g., fluid cooling), while the trend towards heavy δ74Ge compositions observed at Kipushi likely translates a Rayleigh fractionation effect during ore formation in closed system, associated with significant fluid modification.

La surveillance radiologique de l’environnement est un enjeu majeur pour étudier l Impact des activités industrielles et humaines mettant en œuvre des substances radioactives. Umalyse de l:tImet Pu présents à l’échelle des ultra-traces dans les sols et les sédiments (- mBq.kg-1) est souvent menée par spectrométrie (après séparation chimique. Ces méthodes souffrent de plusieurs inconvénients. Les objectifs de cette thèse sont par conséquent de simplifier la méthode de séparation et d'obtenir une limite de détection basse et un temps d’analyse relativement court en utilisant lICPMS-HR couplé au système d’introduction Apex-Q/ACM. Sur la base des données de la littérature, une méthode chimique utilisant une seule résine d’extraction chromatographique (DGA) est proposée pour isoler les concentrations ultra-traces d’Am et de Pu des différents types d'éléments interférents. La méthodologie proposée a été évaluée avec des solutions synthétiques avant l'utilisation de solutions de lixiviation d’échantillons préalablement analysés par spectrométrie alpha. La méthode retenue demande plusieurs procédure d’élution pour pouvoir séparer les majeurs, les interférents isobariques, les lanthanides, l’uranium et le thorium. Des rendements de chimie supérieurs à 90% pour Am et 60% pour Pu ont pu être mesurés. La robustesse de la méthode d’analyse a été validée avec un standard de référence certifié (AIEA-38S) .Enfin, le protocole analytique d’isolation et de dosage des ultra-traces d241Am et de 239Pu par ICP-MS-HR solution a été appliqué à des échantillons de sédiments échantillonnés dans l’estuaire de la Loire pour caractériser L’état radiologique du fleuve. / Radiological monitoring of the environment is a key issue for studying the impact of industrial and human activities using radioactive substances. The analysis of Am and Pu present at ultra-trace concentrations in soils and sediments (-mBq.kg-l) is often carried out by spectrometry after chemical separation. This procedure suffers from several drawbacks (multi-step separation process and long coun.tingtime). The objectives of this PhD are consequently simplify separation process and to achieve a low limit of detection with a relatively short analysis time using a high-resolution plasma source mass spectrometer HR-ICP-MScoupled to the introduction system Apex-Q/ACM. Base on literature data, a chemical methodology using a single column extraction chromatography resin (DGA) is proposed for isolating ultra-trace concentrations of Am and Pu from different types of interfering elements. The proposed methodology is assessed with synthetic solutions prior to the use of real leaching solutions previously analyzed by alpha spectrometry. The chosen method requires several elution procedures in order to separate the majors element, isobaric interferes, lanthanides, uranium and thorium. Recovery yields greater than 90% for Am and 60% for Pu were determined. The robustness of the analytical method was validated with a certified reference standard sample (IAEA-385). Finally, the analytical process for isolation and analysis of 241Am and 239Pu at ultra-trace concentration by ICP-MS-HRsolution was applied to samples of sediment taken from Loire estuary to characterize the radiological status of this river.

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