The solubility–permeability interplay in using cyclodextrins as pharmaceutical solubilizers: mechanistic modeling and application to progesterone
Open accessAbstract
A quasi-equilibrium mass transport analysis has been developed to quantitatively explain the solubility-permeability interplay that exists when using cyclodextrins as pharmaceutical solubilizers. The model considers the effects of cyclodextrins on the membrane permeability (P(m)) as well as the unstirred water layer (UWL) permeability (P(aq)), to predict the overall effective permeability (P(eff)) dependence on cyclodextrin concentration (C(CD)). The analysis reveals that: (1) UWL permeability markedly increases with increasing C(CD) since the effective UWL thickness quickly decreases with increasing C(CD); (2) membrane permeability decreases with increasing C(CD), as a result of the decrease in the free fraction of drug; and (3) since P(aq) increases and P(m) decreases with increasing C(CD), the UWL is effectively eliminated and the overall P(eff) tends toward membrane control, that is, P(eff) approximately P(m) above a critical C(CD). Application of this transport model enabled excellent quantitative prediction of progesterone P(eff) as a function of HP beta CD concentrations in PAMPA assay, Caco-2 transepithelial studies, and in situ rat jejunal-perfusion model. This work demonstrates that when using cyclodextrins as pharmaceutical solubilizers, a trade-off exists between solubility increase and permeability decrease that must not be overlooked; the transport model presented here can aid in striking the appropriate solubility-permeability balance in order to achieve optimal overall absorption.
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The concentration of molecularly dissolved drug provides the driving force for absorption.
“Several studies have shown that the concentration of molecularly dissolved drug provides the driving force for absorption while using different solubilising agents: non-ionic surfactants (Fischer et al., 2011a; Fischer et al., 2011b), cyclodextrins (Dahan et al., 2010) or bile-salt micelles in simulated intestinal fluid (Frank et al., 2012).”
From Exploring impact of supersaturated lipid-based drug delivery systems of celecoxib on in vitro permeation across PermeapadⓇ membrane and in vivo absorption (2020) · cites this paper as Dahan et al., 2010
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- Authors
- Dahan, A., Miller, J. M., Hoffman, A., Amidon, G. E., & Amidon, G. L.
- Affiliations
- University of Michigan (US)
- Hebrew University of Jerusalem (IL)
- Corresponding author
- Amidon, Gordon L.
- Venue
- Journal of Pharmaceutical Sciences
- Publisher
- Elsevier BV
- Published
- 2010-06
- Volume
- 99
- Issue
- 6
- Pages
- 2739-2749
- ISSN
- 0022-3549 (ISSN-L)
- OpenAlex
- W2159728014
- Semantic Scholar
- 2c6db6a5b1a4b1bef5ef23c7ebd1c945b56ed3f8
- Cited by
- 224
- References
- 39
- Citations by year
- 2026: 10 · 2025: 9 · 2024: 11 · 2023: 20 · 2022: 13 · 2021: 15 · 2020: 12 · 2019: 13 · 2018: 11 · 2017: 17 · 2016: 21 · 2015: 16 · 2014: 8 · 2013: 24 · 2012: 13
- FWCI
- 5.21
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Locations
- Journal of Pharmaceutical Sciences (publishedVersion)
- PubMed (publishedVersion)
- Deep Blue (University of Michigan) (submittedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Keywords
- cyclodextrins, membrane permeability, unstirred layer, effective permeability, progesterone, hydroxypropyl-β-cyclodextrin, drug absorption, Pampas, Caco-2 cells
- MeSH terms
- Absorption, 2-Hydroxypropyl-beta-cyclodextrin, Animals, Cell Membrane Permeability, Cyclodextrins, Dosage Forms, Pharmaceutical Preparations, Excipients, Humans, Male, Permeability, Progesterone, Random Allocation, Solubility, Water, Rats, Wistar, beta-Cyclodextrins, Rats
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