The effect of the keratolytic, drug salicylic acid (SA) on the thermotropic properties and fluidity of the mixed lipid membrane dipalmitoyl phosphatidylcholine (DPPC)-dipalmitoyl phosphatidylethanolamine (DPPE) had been studied using DSC, (H-1 and P-31) NMR, SAXS, and dynamic light scattering. The membrane was in multilamellar vesicular (MLV) and unilamellar vesicular (ULV) form with SA/(DPPC + DPPE) molar ratios, R-m, in the range from 0 to 0.5. It was found that the mechanism of interaction of SA with the lipid mixture exhibited similar patterns in both ULV and MLV. Both the NMR and DSC studies indicated that the drug molecules were probably localized in the lipid-water interfacial region neighboring the lipid headgroups or the glycerol moiety. The presence of the drug increased the fluidity of the membrane and the acyl chain order. However, studies on MLV showed that the presence of the drug in high concentration (R-m >= 0.2), caused destabilization of the DPPC-DPPE mixture, as indicated by the appearance of two endothermic transitions. DSC studies indicated that prolonged equilibration of the membrane led to reduced interaction between the lipid headgroups and the SA molecules. This reduced interaction could be due to the sequestering of the drug molecules into the lipid-water interfacial region, out of proximity to the polar headgroup or glycerol moiety. Effect of inclusion of cholesterol in the membrane systems was also studied. (c) 2005 Elsevier Inc. All rights reserved.