Probing drug solubilization patterns in the gastrointestinal tract after administration of lipid‐based delivery systems: A phase diagram approach

The formation of lyotropic phases resulting from the digestion of formulation lipids has a pronounced impact on the intestinal solubilization and resultant bioavailability of poorly water‐soluble drugs. In this study, phase diagrams were produced to determine the phase behavior of the digestion products of common formulation lipids (C8:0, C12:0, and C18:1) under model physiological conditions. Pseudoternary phase diagrams were constructed using varying proportions of SEIF (Simulated Endogenous Intestinal Fluid) and fatty acid (FA) and monoglyceride (MG) (as representative exogenous lipid digestion products). A change from liquid crystal to colloidal liquid (containing mixed micelles and vesicles) was observed with decreasing FA/MG concentrations. The solubilization enhancement ratio (SER) afforded by these phases for a series of poorly water‐soluble compounds (hydrocortisone and hydrocortisone esters, clogP = 1.4 to 5.2) was measured relative to the intrinsic solubility in buffer. Large increases in SER were observed in both lamellar (10–2000 fold) and cubic (10–30,000 fold) liquid crystal phases. Positive correlations were observed between the solubilization benefit provided by each phase and drug lipophilicity (r2 ≥ 0.9). These phase/solubility trends assist in our understanding of the mechanism by which poorly water‐soluble drugs are trafficked across the intestinal colloidal species that form during the digestion of lipid‐based drug delivery systems. © 2004 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:332–348, 2004