RESUMO
A rapid approach for estimating the pK(a) value of small organic molecules was developed using vacuum-assisted multiplexed capillary electrophoresis (VAMCE) with ultraviolet detection. The VAMCE method employed a 96-capillary array, arranged in a standard 8 x 12 microtiter plate configuration, with each row of capillaries filled with 12 individual running buffers of equal ionic strength (I = 50 mM) covering a pH range from 2.2 to 10.7. A separate compound was injected hydrodynamically into each row of capillaries allowing the estimation of pK(a) values for eight compounds in a single run. The application of a vacuum during the separation generated a bulk fluid flow and allowed the electrophoretic separation to be completed within 5 min. The complete VAMCE method, conditioning, and electrophoretic separation was optimized to allow the pK(a) estimation for between 128 to 168 compounds in an 8-h period. The VAMCE method provided a reliable approach for estimating pK(a) values both within- and between-day. The pK(a) values for a series of 96 compounds estimated by VAMCE agreed well with some of literature pK(a) values with an average absolute difference of 0.22 log units.
Assuntos
Preparações Farmacêuticas/análise , Preparações Farmacêuticas/química , Eletroforese Capilar/métodos , Concentração de Íons de Hidrogênio , Espectrofotometria Ultravioleta/métodos , Termodinâmica , VácuoRESUMO
To fully realize the potential of combinatorial synthesis and high-throughput screening for increasing the efficiency of the drug discovery and development process, issues related to compound purity must be addressed. Impurities, often present after synthesis, can lead to ambiguous screening results and inhibit the development of quality structure-activity relationships. The demand for high-throughput analytical characterization of combinatorial libraries has prompted the development of more rapid methods to keep pace with compound production. Recent progress has focused upon the development of parallel separation methods, multiplexed detector interfaces, and synergistic combinations of different detectors possessing complementary selectivities.
Assuntos
Técnicas de Química Combinatória/normas , Avaliação Pré-Clínica de Medicamentos/normas , Técnicas de Química Combinatória/métodos , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Espectroscopia de Ressonância Magnética/métodos , Espectrometria de Massas/métodos , Peso Molecular , Controle de Qualidade , Relação Estrutura-Atividade , Fatores de TempoRESUMO
Combinatorial processes have been widely applied to many disciplines in chemistry and biology. The vast numbers of unique entities generated by combinatorial synthesis have led to the development of high-throughput methods for characterizing samples, to avoid bottlenecks created by the application of conventional, serial-based analytical techniques. In recent years, high-throughput and novel methods utilizing mass spectrometry, multiplexed capillary electrophoresis, various forms of optical detection, and even sound waves have been investigated for a variety of applications.
