INFLUENCE OF HYDROXYPROPYL-BETA-CYCLODEXTRIN ON THE STABILITY OF BENZYLPENICILLIN IN CHLOROACETATE BUFFER

Hydroxypropyl beta-cyclodextrin (HP beta CyD) has been shown to stabil ize a wide variety of chemically distinct pharmaceutical entities thro ugh inclusion-complex formation between drug and cyclodextrin. The eff ect of HP beta CyD on the acid-catalysed hydrolysis of benzylpenicilli n (penicillin G) was evaluated in chloroacetate buffer at pH 2.20. At penicillin G:cyclodextrin molar concentration ratios from 1:1 to 1:10, HP beta CyD effected stabilization of penicillin G by 1.56- to 5.21-f old. At all temperatures, the observed first-order rate constant (k(ob s)) values assumed a non-linear, Michaelis-Menten type decrease as a f unction of increasing HP beta CyD concentration. Degradation of penici llin G complexed with HP beta CyD (penicillin G-HP beta CyD), was appr oximately ninefold slower than uncomplexed penicillin G. The proportio n of penicillin G degrading in either of these forms was, in turn, det ermined by the equilibrium constant for the complexation. The apparent thermodynamic and activation parameters for the complexation between penicillin G and HP beta CyD have also been evaluated. The negative st andard enthalpy change (Delta H degrees) for the complexation implied that the penicillin G-HP beta CyD complex would be predisposed towards enhanced stability, and thus the k(obs) value for the hydrolysis of p enicillin G decreased with reduction of temperature in these systems. The lack of difference between the enthalpies of activation (Delta H-d ouble dagger) for the hydrolysis of uncomplexed and complexed penicill in G seemed to be compensated by the significant difference between th e entropies of activation (Delta S-double dagger) for these hydrolytic reactions. The results indicate that HP beta CyD represents a viable means of stabilization of penicillin G solutions at the pH employed in this study.