The Solubility–Permeability Interplay: Mechanistic Modeling and Predictive Application of the Impact of Micellar Solubilization on Intestinal Permeation
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.
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Acid/base nature and lipophilicity influence dissolution, absorption, and disposition, and are used as PBPK input parameters to calculate solubility and account for prandial state.
“acid/base nature, as well as lipophilicity, are thought to play important roles in dissolution, absorption, and disposition, and are often used as input parameters of the PBPK model to dynamically calculate solubility in the different segments of the GI tract and account for the influence of prandial state”
From IMI – Oral biopharmaceutics tools project – Evaluation of bottom-up PBPK prediction success part 3: Identifying gaps in system parameters by analysing In Silico performance across different compound classes (2017) · cites this paper as Miller et al., 2011
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- Authors
- Miller, J. M., Beig, A., Krieg, B. J., Carr, R. A., Borchardt, T. B., Amidon, G. E., Amidon, G. L., & Dahan, A.
- Affiliations
- Abbott (United States) (US)
- Ben-Gurion University of the Negev (IL)
- University of Michigan (US)
- Corresponding author
- Dahan, Arik
- ORCID
- Venue
- Molecular Pharmaceutics
- Publisher
- American Chemical Society (ACS)
- Published
- 2011-08-11
- Volume
- 8
- Issue
- 5
- Pages
- 1848-1856
- ISSN
- 1543-8384 (ISSN-L)
- 1543-8392
- OpenAlex
- W2036442936
- Cited by
- 204
- References
- 34
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 11 · 2023: 14 · 2022: 8 · 2021: 16 · 2020: 11 · 2019: 19 · 2018: 8 · 2017: 13 · 2016: 21 · 2015: 12 · 2014: 14 · 2013: 21 · 2012: 12
- FWCI
- 9.80
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Pharmaceutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Abbott Laboratories
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
- Physical Sciences › Chemistry › Organic Chemistry › Surfactants and Colloidal Systems
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- micellar solubilization, intestinal permeability, surfactants, solubility enhancement, sodium taurocholate, sodium dodecyl sulfate, progesterone, unstirred layer, effective permeability, critical micelle concentration, oral absorption, lipophilic drugs, jejunal perfusion
- MeSH terms
- Animals, Biological Transport, Drug Compounding, Intestinal Absorption, Jejunum, Male, Micelles, Models, Biological, Perfusion, Permeability, Pharmaceutic Aids, Progestins, Progesterone, Random Allocation, Sodium Dodecyl Sulfate, Solubility, Surface-Active Agents, Taurocholic Acid, Rats, Wistar, Rats
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