Permeabilitysolubilitycharge State And The pH Partition Hypothesis

Fick's first law applied to a membrane [18,40-42] shows that passive diffusion of a solute is the product of the diffusivity and the concentration gradient of the solute inside the membrane. The membrane/water apparent partition coefficient relates the latter internal gradient to the external bulk water concentration difference between the two solutions separated by the membrane. For an ionizable molecule to permeate by passive diffusion most efficiently, the molecule needs to be in its uncharged form at the membrane surface. This is the essence of the pH partition hypothesis [44]. The amount of the uncharged form present at a given pH, which directly contributes to the flux, depends on several important factors, such as pH, binding to indigenous carriers (proteins and bile acids), self-binding (aggregate or micelle formation), and solubility (a solid-state form of self-binding). Low solubility enters the transport consideration as a thermodynamic "speed attenuator," as a condition that lowers the opportunity for transport. In this way, permeability and solubility are the linked kinetic and thermodynamic parts of transport across a membrane.

Consider a vessel divided into two chambers, separated by a homogeneous lipid membrane. Figure 2.1 is a cartoon of such an arrangement. The left side is the donor compartment, where the sample molecules are first introduced; the right side is the acceptor compartment, which at the start has no sample molecules.

Absorption and Drug Development: Solubility, Permeability, and Charge State. By Alex Avdeef ISBN 0-471-423653. Copyright © 2003 John Wiley & Sons, Inc.

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