Membrane-water partitioning - Tackling the challenges of poorly soluble drugs using chaotropic co-solvents

Abstract

Many newly developed drugs suffer from poor water solubility and low bioavailability and hence, need special formulation vehicles like vesicular or micellar drug delivery systems. The knowledge of their membrane-water partition coefficient K becomes critical as is governs drug loading and release from the vehicle, as well as absorption into the body. The dilemma is that measuring K is particularly challenging for these very compounds. Here we establish a strategy to resolve this problem. We added DMSO to shift K and solubility into a convenient range and extrapolated these results back to zero-DMSO. Isothermal titration calorimetry revealed that logK of the kinase inhibitor Lapatinib decreased proportionally to DMSO content (2.5 - 20v%) with a slope of -1/20v% (m value = 28 kJ/mol). This implies a K of 84 mM^-1 in DMSO-free buffer. This strategy should be transferable to other poorly soluble drugs and further detection methods.

Keywords: Chaotropic co-solvents; DMSO; Hydrophobic drugs; Isothermal titration calorimetry; Membrane-water partitioning; Mole ratio partition coefficient.