A duloxetina é um potente inibidor duplo da recaptação de serotonina e norepinefrina, disponível como enantiômero puro, sob a forma S-duloxetina e comercializado como pellets em cápsulas. O R enantiômero da duloxetina é também um inibidor da recaptação, no entanto, este é menos potente que seu isômero, sendo considerado como impureza enantiomérica. Este trabalho teve como objetivos o desenvolvimento e a validação de métodos analíticos para o controle de qualidade da duloxetina e de sua respectiva impureza enantiomérica por cromatografia líquida de alta eficiência (CLAE), e por eletroforese capilar (EC). A resolução dos enantiômeros da duloxetina foi realizada a partir da utilização de fase estacionária quiral, baseada celulose, por CLAE. A separação por EC foi desenvolvida a partir da utilização de hidroxipropil-β-ciclodextrina (HPβCD) como seletor quiral. A validação dos métodos foi efetuada de acordo com os guias de validação disponíveis na literatura e os métodos propostos foram considerados específicos, lineares, precisos, exatos e robustos. A análise comparativa entre os métodos desenvolvidos demonstrou não haver diferença estatisticamente significativa na quantificação do enantiômero S-duloxetina. / Duloxetine is a double potent inhibitor of serotonin and norepinephrine reuptake, available as a pure enantiomer, in the S-duloxetine form and marketed as pellets into capsules. The R enantiomer of duloxetine is also an inhibitor of reuptake, however, less potent and being considered enantiomeric impurity. This work aimed the development and validation of analytical methods for quality control of duloxetine and its respective enantiomeric impurity by high performance liquid chromatography (HPLC) and capillary electrophoresis (CE). The resolution of the enantiomers of duloxetine was performed with the use of chiral stationary phase, based on cellulose, by HPLC. The separation by CE was developed with the use of hydroxypropyl-β-cyclodextrin (HPβCD) as chiral selector. The method validation was performed according to the guides available in the literature and the proposed methods were considered specific, linear, precise, accurate and robust. The comparative analysis between the methods developed showed no statistically significant difference in the quantification of S-duloxetine enantiomer.

Doctor of Philosophy / Department of Chemistry / Christopher J. Levy / This work examines the synthesis of novel chiral Schiff-base complexes derived from (1R,2R)-cyclohexanediamine and (R)-[1,1’-binaphthalene]-2-2’-diamine structural backbones with quinoline, isopropyl-quinoline, and benzoquinoline structural side-arms. We incorporated some degree of flexibility in the ligands and complexes so they can accommodate the sterics of different substrates during a catalytic reaction. We successfully achieved this by reducing the imine bond in the ligands to the corresponding amine bond. Therefore, the successful reduction and metallation of some of these ligands to give structures of different symmetries is reported. We had difficulty reducing ligands with the binaphthalene backbone but were able to partially reduce the ligand through a one-pot reaction with a zinc(II) salt and NaBH4. The complete 1H NMR assignments of the complexes reported in this thesis serve as a valuable tool for use in the characterization of future complexes. The complete NMR characterization of compounds reported is a complex process because they are polycyclic aromatic systems and the coupling network similarity in different parts of the molecule usually results in severe overlap of their 1H resonances. To overcome this impediment, we took advantage of various 2D-NMR techniques (COSY, NOESY, ROSEY, HSQC, and HMBC) along with other 1D-NMR experiments (1H HOMODEC, 1H, and 13C) to completely assign the desired complexes. Subsequently we also studied the coordination chemistry of several meal cations with our ligand system with the goal of obtaining single stranded monhelices. The potential use of some of the complexes in the area of NMR discrimination and kinetic resolution of racemic mixtures was examined and shown to be promising. Several NMR experiments were conducted using the racemic olefins 3-buten-2-ol and 1-penten-3-ol to demonstrate the discriminating power of our silver(I) complexes. We discovered that sterics play an important role in this resolution experiment and the bulky nature of our complexes affect the overall efficiency of the NMR discriminatory process as it diminishes the contact between the reactive metal center and the olefins involved. Temperature also plays a vital role in the chiral recognition of racemic olefins as we examined the ideal temperature needed to reduce the various dynamic processes that take place in solution at room temperature.

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