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.

Applying Biopharmaceutical Classification System (BCS) Criteria to Predict Oral Absorption of Drugs in Dogs: Challenges and Pitfalls

“…If the bile salt-drug interactions result in micelle formation, the resulting encapsulation can lead to a decrease in drug transport, limiting the ability of free drug to move across a biological membrane (88). The formation of micelles can either increase or decrease drug absorption, depending upon the magnitude of its impact on solubility versus permeability (89). A micellar-induced increase in the solubility of lipophilic compounds (due to endogenous, food-associated, or formulation-associated surfactants) can increase or decrease drug intestinal permeability (90) by reducing the partition coefficient between the intraluminal fluid and the biological membrane (91).…”

Dissolution behavior of co-amorphous amino acid-indomethacin mixtures: The ability of amino acids to stabilize the supersaturated state of indomethacin

“…Converting a crystalline material into an amorphous form is one of the most promising ways to improve apparent solubility, since the maximum concentrations in solution achieved with the amorphous form may be significantly higher due to its higher internal energy than with its crystalline counterpart [9][10][11][12]. Furthermore, the increased apparent solubility does not decrease the drug's permeability through intestinal wall [13][14][15]. Unfortunately, the greater internal energy and molecular movement of the amorphous form may also cause the material to convert spontaneously back to its crystalline form during processing, storage or dissolution.…”

Biomimetic PVPA in vitro model for estimation of the intestinal drug permeability using fasted and fed state simulated intestinal fluids

“…Due to the high bile salt concentration, FeSSIF is reported to often lead to decreased apparent permeability of drugs (Dahan and Miller, 2012;Jantratid et al, 2008;Miller et al, 2011). Another factor that may influence the apparent permeability of the drug compounds is the relation between the drugs pKa values and the pH of the different media.…”