Structure Of Octanol

Given the complexities of the phospholipid bilayer barriers separating the luminal contents from the serosal side, it is remarkable that a simple 'isotropic' solvent system like octanol has served so robustly as a model system for predicting transport properties [98]. However, most recent investigations of the structure of water-saturated octanol suggest considerable complexity, as depicted in Fig. 2.8 [99,100]. The 25 mol% water dissolved in octanol is not uniformly dispersed. Water clusters form, surrounded by about 16 octanols, with the polar hydroxyl groups pointing to the clusters and intertwined in a hydrogen-bonded network.

The aliphatic tails form a hydrocarbon region with properties not too different from the hydrocarbon core of bilayers. The clusters have an interfacial zone

Figure 2.8 Modern structure of wet octanol, based on a low-angle X-ray diffraction study [100]. The four black circles at the center of each cluster represent water molecules. The four hydrogen-bonded water molecules are in turn surrounded by about 16 octanol molecules (only 12 are shown), H-bonded mutually and to the water molecules. The aliphatic tails of the octanol molecules form a hydrocarbon region largely free of water molecules. It is thought that ion-paired drug molecules are located in the water-octanol clusters, and thus can readily diffuse through the ''isotropic'' medium. For example, filters impregnated with octanol show substantial permeability of charged drug species. However, permeabilities of charged drugs in filters impregnated with phospholipid-alkane solutions are extremely low. [Avdeef, A., Curr. Topics Med. Chem., 1, 277-351 (2001). Reproduced with permission from Bentham Science Publishers, Ltd.]

between the water interior and the octanol hydroxyl groups. Since water can enter octanol, charged drug molecules need not shed their solvation shells upon entry into the octanol phase. Charged drugs, paired up with counterions (to maintain charge neutrality in the low dielectric medium of octanol, e = 8), can readily diffuse in octanol. Phospholipid bilayers may not have a comparable mechanism accorded to charged lipophilic species, and free diffusion may not be realizable.

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