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

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 in DMSO-free buffer. This strategy should be transferable to other poorly soluble drugs and further detection methods.