Studies on the Instability of Chlorhexidine, Part I: Kinetics and Mechanisms

The objectives of the studies presented herein were to determine the pH-dependent chlorhexidine (CHD) degradation scheme, to determine the rate laws, and to propose reasonable mechanisms for CHD hydrolysis in aqueous solutions. A series of degradation kinetic studies was conducted at 90.0°C using reaction mixtures containing 0.10 mM CHD prepared in the pH range of 0.5-9.0 using hydrochloric acid, sodium hydroxide, acetate, phosphate, or 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid buffers at a constant ionic strength of 0.500 M. Concentration-time profiles for all degradation products, intermediates, and substrates were determined by high-performance liquid chromatography (HPLC). Degradation products and intermediates were identified using a combination of liquid chromatography-mass spectrometry, kinetic analysis, and HPLC comparison with authentic compounds. pH-dependent degradation scheme and rate laws were parameterized using nonlinear regression. The direct formation of p-chloroaniline (PCA) from CHD is the major pathway in acidic conditions, whereas the indirect formation of PCA via the formation of p-chlorophenylurea is the main pathway in alkaline conditions. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association.