Study of the degradation of 5-azacytidine as a model of unstable drugs using a stopped-flow method and further data analysis with multivariate curve resolution

摘要

A general strategy for the study of degradation processes of drugs based on stopped-flow monitoring in a flow system is proposed. The flow system consists of a two-channel manifold for pumping sample and buffer solutions, which join and mix in a PTFE coil (57 cm x 0.7 mm i.d). The flow is stopped when the sample reaches the detection cell and, then, the corresponding kinetic processes are monitored in the spectral range 200-300 nm using a UV-vis diode array spectrophotometer. 5-Azacytidine has been chosen as a model of unstable drugs to illustrate the possibilities of the procedure. Kinetic runs have been developed at temperatures in the range 25-80 degrees C and pH values from 2 to I I in order to investigate the influence of these factors on the degradation of the pharmaceutical agent. Multivariate curve resolution based on alternating least squares has been used for the data treatment in order to obtain the kinetic and spectral profiles of species involved in the degradation as well as to calculate the kinetic constants. Results indicate that 5-azacytidine is moderately stable in acid solutions while quickly decomposes in alkaline media. In addition, the degradation is dramatically accelerated with increasing temperature. (c) 2007 Elsevier B.V. All rights reserved.