Kinetics of hydrolysis and stabilization of acetylsalicylic acid in liposome formulations

Abstract

The stability of acetylsalicylic acid (ASA) has been determined in liposome systems under various conditions of liposome composition, pH, ionic strength, temperature, liposome and ASA concentrations. ASA was preferentially stabilized in its anionic form, although a larger fraction of ASA was associated with the lipid phase ( f l ) of the liposomes at low pH. Liposomes possessing increased bilayer rigidity resulted in a lower f l and an increased pseudo-first-order hydrolysis rate constant ( k obs) of ASA. Increasing the ionic strength decreased R k ( = k obs k B , where k B is the rate constant in aqueous buffer solution) only under hypertonic conditions. R k was lowest in the vicinity of the phase transition temperature ( T c) of the phospholipid. Significant stabilization of ASA was observed only if the drug was incorporated into liposomes via the organic phase. The addition of stearylamine to liposomes resulted in a substantially greater degree of stabilization of anionic ASA whereas adding an excess of salicylic acid increased k obs to values near k B. It is concluded that the binding of anionic ASA to positive centers of charge located below the surfaces of the bilayers protects ASA from base-catalyzed hydrolysis. The degree of stabilization of ASA is, in most cases, proportional to f l . Thus, methods used to increase f l or maintain a fairly constant f l for longer periods of time should result in useful stabilized preparations of ASA.