, 1976). The release rate of Mz from the formulation depends on the chemical potential (activity) of the model drug in the formulation, which is strongly related to the formulation composition. We aim at an experimental set-up where the chemical potential of Mz is the same in all formulations. As we cannot get direct experimental data on the chemical potential of Mz, we use an approximate condition by adjusting the concentration in relation to the total solubility in each formulation. Navitoclax molecular weight The solubility of Mz

was determined for all formulations in three replicates following the procedures in (Björklund et al., 2010). The solubility data are summarized in Table 1. The drug concentration in each formulation was then adjusted by multiplying the total Mz solubility with an arbitrary factor so that the concentration in neat PBS solution was 0.75 wt% (7.5 mg ml−1), which

is the concentration used in several commercial topical formulations containing Mz (e.g. Rosex cream and Rosex gel, Galderma Nordic AB). This procedure, i.e. to adjust the Mz concentration to achieve similar chemical potential of Mz, is supported by diffusion measurements with silicone membranes showing that the release rate from all formulations is the same (see Fig. 1 and Fig. 2). In the steady state flux experiments, the water activity gradient is defined by the boundary conditions given by water activity in the donor formulation and the receptor solution. The water gradient can be expressed in terms of the water activity, aw, or the chemical potential

of water, Δμw, XAV-939 by the relation aw = exp(Δμw/RT). The water activity (ranging from zero to unity) is defined as the ratio between the vapor pressure of water above a solution, p, and the vapor pressure above pure water, p0, and related to the relative humidity, RH, by aw = p/p0 = RH/100. The water activity in the formulations used in this study was determined the with an isothermal calorimetric method, developed in house, that allows for high precision measurements in the high range of water activities ( Björklund and Wadsö, 2011). Measured values for the water activities for all formulations studied are compiled in Table 1. The experimental method to determine the steady state flux (Jss) of Mz was the same used as in previous studies ( Björklund et al., 2010). In brief, the system consists of 15 flow-through cells (receptor phase flow-rate was 1.5 ml h−1) with mixing from magnetic stirrers placed in both the donor and the receptor phase. The temperature in the diffusion cells was 32 ± 0.3 °C. To enable studies of steady state flux and constant boundary conditions in Mz, glycerol, urea, and water, we used large donor formulation volumes of 2 ml. In average, the decrease in Mz concentration in the donor phase after 24 h was less than 1%, taking all formulations into account.