Figure 7.40 Permeability-pH profiles for ketoprofen under iso-pH conditions for two different PAMPA models: unfilled circles = 2% DOPC/dodecane, filled circles = 20% soy lecithin/dodecane. [Reprinted from Avdeef, A., in van de Waterbeemd, H.; Lennernas, H.; Artursson, P. (Eds.). Drug Bioavailability. Estimation of Solubility, Permeability, Absorption and Bioavailability. Wiley-VCH: Weinheim, 2003 (in press), with permission from Wiley-VCH Verlag GmbH.] Gradient pH Effects

The gradient pH soy lecithin, acceptor sink systems (models 26.1-30.1 in Table 7.3) were explored in the search for the best GIT PAMPA model [559]. Figures 41a-c show examples of three bases: verapamil, propranolol, and metoprolol (in order of decreasing lipophilicities; see Table 7.4). In each case, the acceptor pH was 7.4, but the donor pH values ranged from 3 to 10. Figures 42a-c show examples of three acids: naproxen, ketoprofen, and piroxicam (decreasing lipophilicity order). In all of the examples above, the diffusion-controlled zone spans a much wider pH range, compared to the DOPC system (Figs. 7.34 and 7.35). This is the consequence of increased intrinsic permeabilities in the soy-based system. Figure 7.43 shows examples of two neutral molecules: carbamazepine and antipyrine. It was possible to approximate the membrane permeability curve for carbamazepine (dashed line in Fig. 7.43), based on the analysis of the UWL permeabilities of the ionizable molecules. Antipyrine is hydrophilic and has equivalent Pm and Pe curves.

Table 7.17 summarizes the analysis of the gradient pH experiments. The range of intrinsic permeabilities spans 11 orders of magnitude! The UWL permeabilities ranged from 16 to 52 x 10~6 cm/s. Those molecules that appeared to bind strongly to the sink-forming acceptor surfactant showed UWL Pu values that were about twice those calculated from the iso-pH nonsink assays (Table 7.15). The strong binding between the solute and the surfactant in the acceptor wells drives the unbound fraction of the solute molecules to near zero. According to the pH partition hypothesis, it is the unbound neutral species which crosses the membrane. Since its

(a) DOUBLE-SINK (Soy Lecithin 20% wt/vol in Dodecane, SINK in Acceptor) 2

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