Viscosity Study on the Self-Association of Doxorubicin in Aqueous Solution

Abstract

The viscosity of doxorubicin aqueous solution as a function of pH, ionic strength, and temperature was studied in detail. The viscosity increased in the presence of NaCl and maximum viscosity was observed at pH 5 to 7 in the pH profiles. When NaCl was added to various concentrations of doxorubicin aqueous solution, the viscosity suddenly increased when the NaCl concentration exceeded a certain level. This concentration for critical gel formation was found to be inversely correlated with the logarithmic doxorubicin concentration. The viscosity of doxorubicin aqueous solution was decreased with rising temperature. The analysis of viscosity on temperature-dependence revealed two gel structures at 20 to 30 °C. Activation energy of the viscous flow at lower temperatures was about 15 kcal/mol and that at higher temperatures was about 60 kcal/mol. The viscosity of doxorubicin aqueous solution also increased in the presence of various cations or anions. This increase in the viscosity caused by monovalent cations or anions was in almost inverse correlation with the lyotropic series, which showed that those ions having a weaker dehydration ability induce a higher viscosity of doxorubicin aqueous solution and promote gel formation. In the viscosity increase caused by monovalent cations or anions, a mechanism involving hydration and self-association owing to n-n stacking of doxorubicin molecules was strongly suggested. In the case of bivalent or trivalent cations, those cations having a stronger chelation ability caused a larger increase in the viscosity of doxorubicin aqueous solution, which indicated that self-association due to intermolecular chelation could be the mechanism of gel formation. © 1991, The Pharmaceutical Society of Japan. All rights reserved.