Sweta Modi1, Bradley D Anderson. 1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, A323A ASTeCC Bldg., Lexington, Kentucky, 40506, USA.
Abstract
PURPOSE: Models to predict membrane-water partition coefficients (Kp) as a function of drug structure, membrane composition, and solution properties would be useful. This study explores the partitioning of dexamethasone (Dex) and its ionizable 21-phosphate (Dex-P) in liposomes varying in acyl chain length, physical state, and pH. METHODS: DMPC:mPEG DMPE, DPPC:mPEG DPPE, and DSPC:mPEG DSPE (95:5 mol%) liposomes were prepared by thin film hydration. Kp values for Dex and Dex-P were determined from pH 1.5-8 by equilibrium dialysis and equilibrium solubility (Dex). RESULTS: Dex Kp values at 25°C were 705 ± 24, 106 ± 11, and 58 ± 9 in DMPC, DPPC, and DSPC, increasing to 478 ± 20 in DPPC liposomes at 45°C. Both neutral and anionic species contributed to the Kp of Dex-P versus solution pH (1.5-8). A linear correlation was found between the natural logarithm of Kp and the inverse of bilayer free surface area (1/afree) where afree is a parameter reflecting chain ordering that depends on bilayer composition and temperature. CONCLUSIONS: Models of the pH dependence of partitioning of ionizable compounds must include contributions of both neutral and ionized species. Bilayer free surface area may be an important variable to predict Kp of drug molecules versus lipid composition and temperature.
PURPOSE: Models to predict membrane-water partition coefficients (Kp) as a function of drug structure, membrane composition, and solution properties would be useful. This study explores the partitioning of dexamethasone (Dex) and its ionizable 21-phosphate (Dex-P) in liposomes varying in acyl chain length, physical state, and pH. METHODS:DMPC:mPEGDMPE, DPPC:mPEGDPPE, and DSPC:mPEG DSPE (95:5 mol%) liposomes were prepared by thin film hydration. Kp values for Dex and Dex-P were determined from pH 1.5-8 by equilibrium dialysis and equilibrium solubility (Dex). RESULTS:Dex Kp values at 25°C were 705 ± 24, 106 ± 11, and 58 ± 9 in DMPC, DPPC, and DSPC, increasing to 478 ± 20 in DPPC liposomes at 45°C. Both neutral and anionic species contributed to the Kp of Dex-P versus solution pH (1.5-8). A linear correlation was found between the natural logarithm of Kp and the inverse of bilayer free surface area (1/afree) where afree is a parameter reflecting chain ordering that depends on bilayer composition and temperature. CONCLUSIONS: Models of the pH dependence of partitioning of ionizable compounds must include contributions of both neutral and ionized species. Bilayer free surface area may be an important variable to predict Kp of drug molecules versus lipid composition and temperature.