The unstirrable water layer is unstirrable because it does not exist

A number of membrane-permeation models require the incorporation of an unstirred or unstirrable water layer (UWL). An example occurs in PAMPA models when the effective permeation rate of lipophilic acids and bases, P(e), falls behind the expected permeation rate, P(m), at pH values providing a high concentration of unionized species in the donor phase. In such cases, the compound has an apparent pKa of a weaker acid or base. The explanation is that an UWL adjacent to the membrane provides a rate-limiting diffusion barrier for such compounds. The thickness of the UWL is correlated with the difference between the aqueous pKa and the apparent pK(a) (pK(a)(flux)). Here, we provide an explanation for the pK(a)(flux) term that requires no UWL. It comes from the fact that, in the process of passing into a membrane, an ionizable compound undergoes a change in pKa. At some point along its path into the membrane, the compound attains a maximum free energy, at which point it is as likely to continue into the membrane, as it is to return to the donor phase. This is the transition state for absorption. The pK(a)(flux) is the pKa of the compound at the transition state. This is a testable hypothesis (see text). The relevance of absorption to permeation depends on the rate-limiting step of permeation.