Drug stability in liposomal suspensions: hydrolysis of indomethacin, cyclocytidine, and p-nitrophenyl acetate.
First-order rate constants (kL) for hydrolysis of p-nitrophenyl acetate, cationic cyclocytidine, and anionic indomethacin in the presence of buffered liposomal suspensions of positive, negative, and neutral charge were compared to those determined in the corresponding buffers (kB) using the ratio, Rk = kL/kB. Association between the reactants and the liposomes was evaluated by comparing assays for concentration in the filtrates (CF) with the total concentration in the liposomal suspension (CT) using RC = CF/CT. Liposomes did not influence cyclocytidine hydrolysis rates and no association was observed (Rk congruent to RC congruent to 1). In contrast, indomethacin showed approximately 80% reduction in hydrolysis rate and approximately 80% liposome association value (Rk congruent to 0.2 congruent to RC). In neutral and negatively charged liposomal suspensions, p-nitrophenyl acetate displayed approximately 30% decrease in kB (Rk congruent to 0.7) together with approximately 90% liposomal association (RC congruent to 0.1). However, hydrolysis was greatly accelerated in positively charged liposomal suspensions. Loss was described by a biexponential equation where alpha is the fast and beta is the slow pre-exponential coefficient and alpha/beta/kB = 39:6:1. The observed relationships between hydrolysis rates and reactant-liposome associations are reconciled in terms of the hydrophilicity of the reactants and the potential influence of the liposomes on the expected transition states for the hydrolysis reactions.
D003504:Ancitabine; D002021:Buffers; D003561:Cytarabine / Q000031:analogs & derivatives; D004355:Drug Stability; D006868:Hydrolysis; D007213:Indomethacin; D007700:Kinetics; D008081:Liposomes; D008956:Models, Chemical; D009596:Nitrophenols; D013535:Suspensions
D002021:Buffers; D008081:Liposomes; D009596:Nitrophenols; D013535:Suspensions; D003561:Cytarabine; C008642:4-nitrophenyl acetate; D003504:Ancitabine; D007213:Indomethacin