International Journal of Pharmaceutics 269 (2004) 149–156 The improvement of aqueous chemical stability of a model basic drug by ion pairing with acid groups of polyelectrolytes A.F. Jimenez-Kairuz, D.A. Allemandi, R.H. Manzo ∗ Departamento de Farmacia, Facultad de Ciencias Qu´ ımicas, Universidad Nacional de Córdoba, Edificio Ciencias 2, Ciudad Universitaria, 5000 Córdoba, Argentina Received 29 August 2002; received in revised form 11 July 2003; accepted 5 September 2003 Abstract Carbomer (C) and procaine (P) were selected respectively as models of polyelectrolyte (PE) and basic drug (B) of low stability in aqueous solution. The purpose of this investigation was to test if a (C–P) aqueous system provides a microenvironment in which P is less exposed to hydroxyl ion catalyzed degradation, its main degradation pathway over a wide pH range. It was determined that in (C–P) a high fraction of P was present in the form of ion pairs [RCOO - PH + ] with the carboxylate groups of C. The [RCOO - PH + ] fraction was above 97% for compositions containing higher than 50 mol% of P. The chemical stability of C–P was assayed at two selected pHs (7.5 and 8.5) in comparison with conventional reference solutions (RS) without C. Procaine in (C–P) was 4.2 and 6.2 times more stable than in its respective RS at the two conditions assayed. The stabilizing factor was calculated as the ratio of the rate constants k RS obs /k C–P obs . Since C–B systems exhibit negative electrokinetic potential that attracts positive ions such as (H + ) and repels negative ones such as (OH - ), the stabilizing effect would be associated with the higher acidity of (C–P) environment, in which PH + molecules attached to the PE should also have lower kinetic energy than those in the bulk medium. © 2003 Elsevier B.V. All rights reserved. Keywords: Carbomer hydrogels; Polyelectrolyte–drug interaction; Chemical stability improvement; Polyelectrolyte stabilizing effect; Procaine stability improvement 1. Introduction In the field of chemical stability of drugs, kinetics and mechanisms of specific acid and base catalyzed reactions are among the best described (Carstensen and Rhodes, 2000; Guillory and Poust, 1996; Connors et al., 1986; Kostenbauder and Bogardus, 1999). For many valuable drugs, these degradation pathways are the limiting factor that prevents the design of liquid ∗ Corresponding author. Tel.: +54-351-4334163; fax: +54-351-4334127. E-mail addresses: alfejika@yahoo.com.ar (A.F. Jimenez-Kairuz), rubmanzo@dqo.fcq.unc.edu.ar (R.H. Manzo). pharmaceutical dosage forms. It is also well known that the pH of maximum stability of many drugs is <7(Connors et al., 1986); in such cases the reactiv- ity of the drug towards HO - -catalysis is higher than the reactivity towards H + -catalysis. Consequently, the HO - -catalyzed pathway is of prime relevance in drug stability and will be addressed here. In connection with this point, in previous works (Jimenez-Kairuz, 2002; Vilchez, 2002; Jimenez- Kairuz, 2003) we have reported equilibrium and re- leasing properties of aqueous systems consisting of an acid polyelectrolyte (PE), i.e. carbomer (C), loaded with a basic drug (B). In these transparent or quasi transparent hydrogels a high fraction of loaded B is 0378-5173/$ – see front matter © 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.ijpharm.2003.09.008