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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/207541
High throughput determination of relevant physicochemical parameters in the drug discovery and HPLC processes. Microfluidic devices
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[eng] Determining the acidity (pKa) and lipophilicity (log Po/w) of organic compounds is fundamental in analytical chemistry fields, with potential relevance in drug development, material science, analytical separation, and environmental research. In the first part of the thesis, a high-throughput internal standard capillary electrophoresis (IS- CE) method was established to determine the pKa of ISs at different concentrations of methanol and acetonitrile from 0 to 90% (v/v). The acid and base scales of methanol-water mixtures and acetonitrile-water mixtures were properly anchored to the potentiometrically obtained pKa values of reference compounds to get absolute pKa scales. As a consequence, a set of 46 acid- base compounds with changing structures were proposed as internal standards for consistent pKa measurements in methanol-water and acetonitrile-water mixtures buffers using capillary electrophoresis. The determined ISs reference set facilitates the determination of analytes pKa and measurement of buffer pH in the range 4-11.5 (in water) for any methanol-water and acetonitrile-water composition. Secondly, to prove its feasibility, the IS-CE approach was successfully used to determine the aqueous pKa in methanol-aqueous buffer compositions up to 40% of methanol in volume. The Yasuda-Shedlovsky extrapolation method was utilized to determine seven drugs of different chemical nature with intrinsic water solubilities lower than 10−6 M. The results were successfully compared to literature ones obtained by other approaches. It is concluded then that the IS-CE methodolgy permits the measurement of aqueous pKa values using lower ratios of methanol than the classical method, becoming then more accurate in the extrapolation procedure than other reference methods. Finally, since methanol-water and acetonitrile-water mixtures are solvents of interest in liquid chromatographic separations because of their use as the mobile phase, the IS-CE method was also applied to measure the pKa of eight organic bases in methanol-water and acetonitrile-water mixtures (0-90%,v/v), which are usually used as test compounds in HPLC column evaluation. In the second part of the thesis, a new approach based on microfluidics was developed to determine the octanol-water partition. As a first step, a design with a perpendicular configuration of the channels was developed using direct 3D printed microfluidics. A gravitational perfusion system was implemented to create a spontaneous flow within the octanol and water channels without need for external pump. The movement of octanol and water phases was successfully validated using fluorescent dyes. After that, the intensity of the fluorescent dye was used to evaluate the partition dynamics in static and dynamic conditions. The results prove that the proposed design with this microfluidic methodology allows the evaluation of molecule partition, achieving high efficiency partition and reaching the equilibrium of O/W partition faster than conventional techniques. Later, the design was adapted to a parallel configuration of the channels to be compatible with up-scalable manufacturing techniques and parallelize it for up to 56 simultaneous determinations in a single platform. Finally, both the perpendicular and parallel designs were validated using several drugs with well standardize log Po/w values that cover a wide range of lipophilicity. The microfluidic device was coupled with HPLC to determine their partition coefficients from the peak areas of the compounds in octanol and in water after partition. Good agreement with the literature values was achieved, showing the capability of microfluidic chips for precise and accurate prediction of the partition coefficient. Finally, the progress of a cost-effective and consistent method for predicting partition coefficient via microfluidic chips demonstrated a great advancement in the field of analytical chemistry, with powerful applications in drug discovery and other related fields. The results gotten from this investigation offer an establishment for additional research and advance of this approach.
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ALBISHRI, Abdulkarim khalaf. High throughput determination of relevant physicochemical parameters in the drug discovery and HPLC processes. Microfluidic devices. [consulta: 5 de desembre de 2025]. [Disponible a: https://hdl.handle.net/2445/207541]