Figure 7.11 Intrinsic permeabilities versus alkane-water partition coefficients for drugs: PAMPA filters soaked with alkane [509].

7.3.4 Hydrophilic Filter Membrane PAMPA Model (Aventis Model)

Zhu et al. [563] found the use of hydrophilic filters (low-protein-binding PVDF) as an advantage in lowering the permeation time to 2 h. Egg lecithin, 1% wt/vol in dodecane, was used as the membrane medium. Over 90 compounds were characterized at pH 5.5 and 7.4. For each molecule, the greater Pe value of the two measured at different pH [509,554] was used to compare to Caco-2 permeabilities reported in the literature. It is noteworthy that many ionizable molecules did not follow the permeability-pH dependency expected from the pH partition hypothesis. It may be that water channels were contributing to the unexpected permeability-pH trends. Solute retention by the membrane was not considered. They tried using the Chugai five-component model, but found difficulties in depositing the lipid mixture on hydrophilic filters. Human intestinal absorption (HIA) values were compared to PAMPA measurements, Caco-2 permeabilities, partition coefficients (log Kp / log Kd), polar surface area (PSA) and quantitative structure-property relations (QSPRs) developed by Winiwarter et al. [56] It was concluded that PAMPA and Caco-2 measurements best predicted HIA values.

7.3.5 Permeability-Retention-Gradient-Sink PAMPA Models (pION Models)

The system reported by Avdeef and co-workers [25-28,556-560] is an extension of the Roche approach, with several novel features described, including a way to assess membrane retention [25-28,556,557] and a way to quantify the effects of iso-pH [558] and gradient pH [559] conditions applied to ionizable molecules. A highly pure synthetic phospholipid, dioleoylphosphatidylcholine (DOPC), was initially used to coat the filters (2% wt/vol DOPC in dodecane). Other lipid mixtures were subsequently developed, and are described in detail in this chapter.

7.3.6 Structure of Phospholipid Membranes

The structure of the filter-immobilized artificial membranes is not known with certainty. Thompson et al. [543] hypothesized that polycarbonate filters had a single bilayer per pore, based largely on the behavior of amphotericin B in the pore-forming oligomerization reaction. Hennesthal and Steinem [568], using scanning force microscopy, estimated that a single bilayer spans exterior pores of porous alumina. These observations may be incomplete, as there is considerable complexity to the spontaneous process of the formation of BLMs (Section 7.2.1). When 2% phosphatidylcholine (PC)-dodecane solution is suspended in water, where the water exceeds 40 wt%, the lipid solution takes on the inverted hexagonal (HII) structure, where the polar head groups of the PC face water channels in a cylindrical structure [569]. Such structures can alter transport properties, compared to those of normal phases [570]. (It may be possible to model the paracellular transport mechanism, should the presence of aqueous pores be established.) Suspensions of 2% PC-dodecane have been titrated potentiometrically from pH 10 down to pH 3. Along the way, at about pH 4, the pH electrode stopped functioning and appeared to be choked by a clear gelatinous coating, suggesting that some sort of phase transition had taken place then [Avdeef, unpublished].

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