The solubility-permeability interplay: Mechanistic modeling and predictive application of the impact of micellar solubilization on intestinal permeation

Jonathan M. Miller, Avital Beig, Brian J. Krieg, Robert A. Carr, Thomas B. Borchardt, Gregory E. Amidon, Gordon L. Amidon, Arik Dahan

    Research output: Contribution to journalArticlepeer-review

    148 Scopus citations

    Abstract

    Surfactants are routinely employed to increase the apparent aqueous solubility of poorly soluble drugs. Yet the impact of micellar solubilization on the intestinal membrane permeability of a lipophilic drug is often overlooked and poorly understood. In this work, the interplay between the apparent solubility increase and intestinal membrane permeability decrease that exists when surfactants are used as drug solubility enhancers is described. A quasi-equilibrium mechanistic mass transport analysis was developed and employed to describe the effect of micellar solubilization by sodium taurocholate (STC) and sodium lauryl sulfate (SLS) on the intestinal membrane permeability of the lipophilic drug progesterone. The model considers the effects of micellar solubilization on both the membrane permeability (P m) and the unstirred water layer (UWL) permeability (P aq), to predict the overall effective permeability (P eff) dependence on surfactant concentration (C S). The analysis reveals that (1) the effective UWL thickness (h aq) quickly decreases with increasing C S above the critical micelle concentration (CMC), such that P aq markedly increases with increasing C S; (2) the free fraction of drug available for membrane permeation decreases with increasing C S above CMC, such that P m decreases with increasing C S; and (3) P aq increases and P m decreases with increasing C S above CMC, consequently the UWL is effectively shorted out and the overall P eff tends toward membrane control with increasing C S. The model enabled excellent quantitative prediction of the progesterone P eff as a function of C S in the rat jejunal perfusion model. This work demonstrates that a trade-off exists between micellar apparent solubility increase and permeability decrease that must be taken into account to strike the optimal solubility-permeability balance. The model presented in this work offers the formulation scientist a simple method for a priori prediction of this interplay, in order to maximize the overall oral absorption.

    Original languageEnglish
    Pages (from-to)1848-1856
    Number of pages9
    JournalMolecular Pharmaceutics
    Volume8
    Issue number5
    DOIs
    StatePublished - 3 Oct 2011

    Keywords

    • drug solubility
    • drug transport analysis
    • intestinal membrane permeability
    • intestinal permeation
    • low-solubility drugs
    • oral drug absorption
    • progesterone
    • sodium lauryl sulfate
    • sodiumtaurocholate
    • solubility-permeability trade-off
    • surface active agents
    • surfactants

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