Influence of hydroxypropyl β-cyclodextrin on the stability of benzylpenicillin in chloroacetate buffer

Abstract

Hydroxypropyl β-cyclodextrin (HPβCyD) has been shown to stabilize a wide variety of chemically distinct pharmaceutical entities through inclusion-complex formation between drug and cyclodextrin. The effect of HPβCyD on the acid-catalysed hydrolysis of benzylpenicillin (penicillin G) was evaluated in chloroacetate buffer at pH 2.20. At penicillin G:cyclodextrin molar concentration ratios from 1:1 to 1:10, HPβCyD effected stabilization of penicillin G by 1.56- to 5.21-fold. At all temperatures, the observed first-order rate constant (k(obs)) values assumed a non-linear, Michaelis-Menten type decrease as a function of increasing HPβCyD concentration. Degradation of penicillin G complexed with HPβCyD (penicillin G-HPβCyD), was approximately ninefold slower than uncomplexed penicillin G. The proportion of penicillin G degrading in either of these forms was, in turn, determined by the equilibrium constant for the complexation. The apparent thermodynamic and activation parameters for the complexation between penicillin G and HPβCyD have also been evaluated. The negative standard enthalpy change (ΔH°) for the complexation implied that the penicillin G-HPβCyD complex would be predisposed towards enhanced stability, and thus the k(obs) value for the hydrolysis of penicillin G decreased with reduction of temperature in these systems. The lack of difference between the enthalpies of activation (ΔH@?) for the hydrolysis of uncomplexed and complexed penicillin G seemed to be compensated by the significant difference between the entropies of activation (ΔS@?) for these hydrolytic reactions. The results indicate that HPβCyD represents a viable means of stabilization of penicillin G solutions at the pH employed in this study.