O d

pH 12

--> 2

pH 12

--> 2


pH 2 -

> 12

pH 12

-- > 2

between pH 5.5 and 8.0 with concentrations in excess of 1 p.M. For pH > 8, phosphatidic and possibly free fatty acids start to ionize, approximately to the extent of 1% of the total soy content by pH 9.

7.7.6 Intrinsic Permeability, Permeability-pH Profiles, Unstirred Water Layers (UWL), and the pH Partition Hypothesis

Up to now we have focused on measurement of permeability and membrane retention at pH 7.4. Since the GIT covers a range of pH values, with pH 5-8 characterizing the small intestine, it is necessary to address the pH dependence of the transport of drug molecules. Even nonionizable molecules may be affected by pH dependence, since several biological membrane components themselves are ionizable (pKa values listed in Fig. 7.4). For example, with PS, PA, and DA (free fatty acid) undergoing changes in charge state in the pH 5-8 interval. In this section, we examine the consequences of pH dependence. Unstirred Water Layer Effect (Transport across Barriers in Series and in Parallel)

Passive transport across a membrane barrier is a combination of diffusion through the membrane and also diffusion through the stagnant water layers at the two sides of the membrane. Stirring the bulk aqueous solution does not appreciably disturb the water layers in contact with the membrane. When the solute is introduced into the bulk aqueous phase, convective mixing resulting from applied stirring, quickly positions the drug molecule next to the so-called unstirred water layer (UWL). At that point, the passage through the UWL is governed by the laws of diffusion, and is independent of stirring. In simple hydrodynamic models [534-538] the UWL is postulated to have a distinct boundary with the rest of the bulk water. The UWL can be made thinner with more vigorous stirring, but it cannot be made to vanish. Extensions of the simple UWL models have been discussed in the literature [539,540], but such models are not often used in practice.

The actual thickness of the unstirred water layer depends somewhat on the transport model system. The in vivo UWL is significantly different from the in vitro assay measuring cell UWL. Because of the efficient mixing near the surface of the epithelium, the in vivo UWL is estimated to be 30-100 mm thick. The UWL in the endothelial microcapillaries of the brain is nil, given that the diameter of the capillaries is ^7 mm and the efficiency of the mixing due to the passage of erythrocytes [612]. However, in unstirred in vitro permeation cells, the UWL values can be 1500-2500 mm thick, depending on cell geometry and dimensions.

It may be assumed that the total resistance to passive transport across the trilamellar (UWL-membrane-UWL) barrier is the sum of the resistances of the membrane and the UWL on each side of it. Resistance is the inverse of permeability. So

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