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Enantiomeric Quantification of Psychoactive Substances and Beta Blockers by Gas Chromatography-Mass Spectrometry in Influents of Wastewater Treatment Plants

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Enantiomeric Quantification of Psychoactive Substances and Beta Blockers by Gas Chromatography-Mass Spectrometry in Influents of Wastewater Treatment Plants Enantiomeric quantification of psychoactive substances and beta blockers by gas chromatography-mass spectrometry in influents of wastewater treatment plants Ricardo Daniel Teixeira Gonçalves Dissertation of the 2nd Cycle of Studies Conducive to the Master’s Degree in Clinical and Forensic Analytical Toxicology, Faculty of Pharmacy, University of Porto Work performed under the orientation of: Professor Doctor Maria Elizabeth Tiritan Professor Doctor Cláudia Maria Rosa Ribeiro September 2018 IT IS NOT PERMITED TO REPRODUCE ANY PART OF THIS DISSERTATION DE ACORDO COM A LEGISLAÇÃO EM VIGOR, NÃO É PERMITIDA A REPRODUÇÃO DE QUALQUER PARTE DESTA DISSERTAÇÃO Agradecimentos Em primeiro lugar gostaria de agradecer às minhas orientadoras (ou mães da ciência), a Professora Doutora Maria Elizabeth Tiritan e a Professora Doutora Cláudia Ribeiro por me terem aceitado (adotado) para poder continuar este projeto. Obrigado por me ajudarem na iniciação de um projeto de raiz, que depois de quatro anos e muitas frustrações, vejo que não foi em vão. Por toda a ajuda, insistência, paciência, preocupação e compreensão que sempre tiveram, o maior obrigado! À Dra. Sara Cravo do laboratório de química orgânica da FFUP, que me recebeu de braços abertos, batalhou comigo durante meses e me deixou usar e abusar do seu laboratório de cromatografia gasosa. Obrigado por toda a ajuda, paciência, explicações, disponibilidade e acima de tudo, por me compreender nos momentos mais desesperantes. Estou-lhe profundamente grato por me fazer sentir “em casa” e por sempre arranjar soluções! Ao Professor Doutor Carlos Afonso do laboratório de química orgânica da FFUP por me autorizar a invadir o laboratório de química orgânica e pela preocupação constante com o progresso do trabalho. À Doutora Sara Cunha e Professor Doutor José Oliveira Fernandes, por me aceitarem nesta reta final para poder concluir com sucesso esta dissertação. Obrigado!! A todo o pessoal do laboratório de química da CESPU, que sempre me aturaram, trataram às mil maravilhas e estiveram sempre prontas a ajudar. Obrigado! Aos meus pais, pois é a eles a quem devo estar nesta etapa da minha vida. Estou-vos profundamente grato por todo o apoio e esforço que sempre fizeram para que eu conseguisse chegar até aqui. Muito obrigado, do fundo do coração! Gostaria também de agradecer às meninas que também se dizem estudantes de mestrado, Ariana Pereira e Cristiana Santos, por criarem um ambiente ótimo no laboratório. Graças a vocês o desespero foi muito menor! À Maria Miguel Coelho (que aposto que já pensava que me ia esquecer dela), porque estivemos juntos nesta batalha e com o maior orgulho posso dizer que conseguimos!! Um obrigado muito, muito especial, pela pessoa que és e pelo companheirismo durante estes 2 anos. Espero, num futuro, poder trabalhar contigo novamente. Força, foco e fé! Ao “desesperados” de toxicologia (por ordem alfabética) Eva Martins, João Alexandre, Rita Guedes e Vera Silva, por não me deixarem sofrer sozinho, pelos 10^36 cafés diários, pelo “apanhamento” de sol nos tempos mortos e principalmente, pelos incentivos à caça furtiva em ambiente académico, que me valeram umas gargalhadas valentes! Muito obrigado e que o “Erundino” nos una novamente! Agradeço também aos meus “outros amigos” João Viana, Joaquin Pereira, Leonor Ferreira, Luis Pereira, Margarida Fernandes, Marlene Pinheiro, Marta Carvalho, Pedro Cruz, Tânia i Amorim, Vanessa Barbosa e Tiago Azevedo por todos os excelentes momentos que passamos juntos, por me ajudarem a aliviar o stress e a não desanimar. Se os amigos são para as ocasiões, vocês merecem a medalha de ouro!!! Muito obrigado! À CESPU, ao Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde (Iinfacts) e ao grupo de investigação por terem cedido as instalações e todo o equipamento laboratorial. Obrigado por me ajudaram em mais uma etapa da minha vida. Até à próxima! ii This work was developed in Laboratório de Química Orgânica e Farmacêutica e Laboratório de Bromatologia e Hidrologia, Departamento de Ciências Químicas da Faculdade de Farmácia da Universidade do Porto and in Instituto de Investigação e Formação Avançada em Ciências e Tecnologias Saúde (IINFACTS)-IUCS-CESPU. This work was partially supported through national funds provided by FCT/MCTES - Foundation for Science and Technology from the Minister of Science, Technology and Higher Education (PIDDAC) and European Regional Development Fund (ERDF) through the COMPETE – Programa Operacional Factores de Competitividade (POFC) programme, under the Strategic Funding UID/Multi/04423/2013 and BIOENVIROM-CESPU-2018. Thanks to Professor Doctor Félix Carvalho and the Toxicology Laboratory of the Faculty of Pharmacy for the kind donation of the MDMA used in this dissertation. Special thanks to INFARMED for all the help and speed to the answers, as the data provided were essential for the development of this study. iii iv Some of the results presented in this dissertation were presented in the following scientific communications: Poster communications Ricardo Gonçalves, Cláudia Ribeiro, Maria Elizabeth Tiritan, Development of a gas chromatography-mass spectrometry method for quantification of chiral drugs in surface waters. 11th edition of the Youth Research Meeting of the University of Porto (IJUP18), Porto, Portugal, February 7 – 9, 2018: Ricardo Gonçalves, Ivan Langa, Cláudia Ribeiro, Maria Elizabeth Tiritan, Desenvolvimento de métodos analíticos por GC-MS para quantificação de drogas quirais. X Jornadas Científicas do Departamento de Ciências do Instituto Universitário de Ciências da Saúde / III Congresso da Associação Portuguesa de Ciências Forenses, Porto, Portugal, May 24 - 25, 2018 Ricardo Gonçalves, Cláudia Ribeiro, Sara Cravo, Carlos Afonso, Maria Elizabeth Tiritan, GC-MS analytical method to quantify chiral drugs for waste-water based epidemiology studies. 11th International Symposium on Drug Analysis & 29th International Symposium on Pharmaceutical and Biomedical Analysis, Leuven, Belgium, September 9 - 12, 2018. The abstracts are in Appendix A, B and C. v vi Abstract Currently, consumption of illicit and pharmaceuticals used as drugs of abuse has increased dramatically. After consumption, residues of these substances and their metabolites are excreted in the urine and feces being discarded into wastewater treatment plants (WWTPs), where they are ineffectively removed. In this sense, several studies have demonstrated the occurrence of residues of drugs and their metabolites in the aquatic ecosystems and particularly in high concentrations in the effluents from WWTPs. These biologically active substances are continuously released into the environment making them pseudo-persistent and potentially harmful to the health of all living organisms, including humans. Many of these drugs are chiral and can be commercially available as racemate or enantiomerically pure. In achiral environments, the enantiomers of a chiral substance behave similarly; however, in chiral environments, such as living organisms, they may exhibit different pharmacokinetic, pharmacodynamic, and toxicity activities. Regarding the forensic area, discrimination of the enantiomers as well as determination of the enantiomeric profile is useful for: distinguishing between the consumption of legally prescribed drugs and illegally synthesized drugs; distinguishing between methods and possible synthesis sites; illegal discharge of sewage or WWTP and estimation of illicit drugs and pharmaceuticals consumption by a community (sewage epidemiology). The objectives of this dissertation are the development and validation of an indirect method by gas chromatography–mass spectrometry (GC-MS) for the quantification of 11 chiral substances of forensic interest namely psychoactive drugs and β-blockers based on the formation of diastereomers using (R)-(−)-α-Methoxy-α-(trifluoromethyl)phenylacetyl chloride ((R)-MTPA-Cl) as chiral derivatization reagent; to verify the applicability of the method in influents of a WWTP and back-calculate to determine the consumption of the target chiral substances in a specific population. Validation of the method was performed for 11 substances. Linearity has showed a R2 > 0.99 for all substances. LOD was between 0.03 and 52.1 ng L-1. LOQ ranged from 0.15 and 125 ng L-1. Results showed the occurrence of amphetamine (AMP), methamphetamine (MAMP), 3,4-methylenedioxyamphetamine (MDMA), alprenolol (ALP), norfluoxetine (NFLX), fluoxetine (FLX), metoprolol (MET), propranolol (PHO) and sertraline (SER) at concentrations ranging from 19.1 ng L-1 (MAMP) to 4948.1 ng L-1 (FLX) in a influent from a WWTP. The enantiomeric fraction (EF) were determined and showed differences in the enantiomeric composition of these drugs. The presence of racemates of AMP (EF = 0.42), ALP (EF = 0.49), FLX (EF = 0.48) and PHO (EF = 0.45) and single enantiomers for MAMP (EF 1), MDMA (EF 1), NFLX (EF 0) and MET (EF 1) were observed and thus suggesting enantioseletive≅ processes.≅ ≅ ≅ vii Keywords: Chiral Derivatization Reagent, Chiral Drugs, Enantiomeric Profiling, GC-MS, Wastewater-based Epidemiology viii Resumo Atualmente, o consumo de drogas ilícitas e de medicamentos legalmente prescritos usados como droga de abuso tem aumentado de forma acentuada. Após consumo, os resíduos destas substâncias e dos seus metabolitos são excretados na urina e fezes sendo descartados para os sistemas de tratamento de águas residuais (ETAR) onde não são ineficazmente eliminados. Neste sentido, vários estudos têm demonstrado a ocorrência de drogas ilícitas
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