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DE OLIVEIRA, A. R. M. Microextraction techniques applied to the stereoselective analysis of ibuprofen, hydroxychloroquine and their metabolites in human urine. 2007. 126 p. Thesis (Doctoral Degree). Faculdade de Ciências Farmacêuticas de Ribeirão Preto – Universidade de São Paulo, Ribeirão Preto, 2007. The stereoselective analysis has been standing out in several areas, and it is mainly present in the pharmaceutical industry, since many drugs are marketed as racemic mixtures. The stereoselective analysis employing high-performance liquid chromatography (HPLC) and capillary electrophoresis (CE) is very useful for the determination of enantiomers at very low concentrations, as the ones found in biological matrices, for instance, in pharmacokinetic studies. The first step in the analysis of drugs in biological fluids is the extraction procedure. The most common extraction procedures employed are liquid-liquid extraction and solidphase extraction. These techniques show several drawbacks, such as the high amount of organic solvent consumed. So, based on this fact, techniques that consume small amounts of organic solvents are desirable. Among these techniques, solid-phase microextraction (SPME) and liquid-phase microextraction (LPME) have been stood out. The main advantages of these techniques are the small amount of organic solvent consumed and its high capacity in drug concentration. In this work, our purpose was to employ the SPME and the LPME as sample preparation techniques to develop stereoselective methods to be further applied in pharmacokinetic studies. SPME was employed for the stereoselective analysis of ibuprofen, hydroxychloroquine and their major metabolites. On the other hand, LPME was employed only for the enantioselective analysis of hydroxychloroquine and its metabolites. The first step was the separation optimization of the drugs and their metabolites by HPLC using several chiral columns, and the separation optimization of hydroxychloroquine and its metabolites by CE. Next, the extraction optimizations and method validations were performed. The enantioselective analysis of ibuprofen in human urine was carried out in the Chiralpak AD-RH column, using methanol-pH 3.0 phosphoric acid solution (75 : 25 v/v) as mobile phase. The method was linear over the 0.5 – 25 μg mL concentration range for both enantiomers. The fiber used in this method was PDMS-DVB 60 μm. The analysis of 2-hydroxyibuprofen and carboxyibuprofen was performed on a Chiralpak AS column using hexane:isopropanol (95 : 5 v/v) plus 0.05% trifluoroacetic acid as the mobile phase. The method was linear over the 5 – 50 μg mL concentration range. To perform the extractions, a CW-TPR 50 μm coated fiber was employed. The analysis of hydroxychloroquine and its major metabolites (DCQ and DHCQ) was done on a Chiralcel OD-H column using hexane-methanol-ethanol (96 : 2 : 2, v/v/v) plus 0.2% diethylamine as mobile phase. The extraction was performed using a PDMS-DVB 60 μm coated fiber. The method was linear over the range of 50 – 1000 ng mL for HCQ enantiomers and over the range of 42 416 ng mL for DCQ and DHCQ enantiomers. LPME and CE were applied for the chiral determination of hydroxychloroquine and its metabolites (DCQ, DHCQ, BDCQ) in human urine. The electrophoretic separations were carried out in 100 mmol L tris(hydroxymethyl)aminomethane buffer (pH adjusted to 9.0 with phosphoric acid) containing 1% (w/v) S-β-CD and 30 mg mL HP-β-CD, with a constant voltage of +18 kV. The method was linear over the concentration range of 10-1000 ng mL -1 for each HCQ stereoisomer and 21-333 ng mL –1 for each metabolite stereoisomer. Within-day and between-day assay precision and accuracy for all described methods were lower than 15%. The developed methods were applied for the determination of the cumulative urinary excretion of ibuprofen metabolites and hydroxychloroquine and its metabolites after oral administration of racibuprofen and rac-hydroxychloroquine to health volunteers. Comparing the techniques, both SPME and LPME were efficient to extract the drugs and their metabolites from human urine.

Técnicas de microextração aplicadas à análise estereosseletiva do ibuprofeno, da hidroxicloroquina e de seus metabólitos em urina