Enhancement of Drug Solubility in Supramolecular and Colloidal Systems

Statins, as efficient HMG‐CoA (3‐hydroxy‐3‐methylglutaryl‐coenzyme‐A) reductase inhibitors are widely used in the management of cardiovascular diseases. Interactions in aqueous solutions between highly lipophilic statins and cyclodextrins (CDs) in the absence and the presence of a dissolved polymer or its monomeric compound, respectively, were studied. The solubility of lovastatin and simvastatin at various temperatures and pHs were investigated by phase‐solubility measurements. Surface activity of solutes in binary (CD-statin) and ternary (CD-statin-polymer) systems was studied by determining the surface tension of the solutions. For the characterization of the CD-statin inclusion complexes, stability constants for associates of different molar ratios have been calculated. It was shown that complexation may lead to improvement of the aqueous solubilities of both statins by 1-2 orders of magnitude. Especially, randomly methylated β‐cyclodextrin (RAMEB) showed outstanding solubilizing effects. In binary systems dominantly CD-statin associates of 1:1 molar ratios form, which exhibit considerable surface activity. RAMEB forms more stable complexes with these drugs than the native β‐CD, and also the surface activity of the former solutes is higher. In polymer‐containing ternary systems the solubility of both statins could be further improved. The enhanced drug solubilities can be ascribed to the formation of CD-statin-polymer associates with supramolecular structure. A portion of the surface active CD-statin complexes are very likely anchored at the macromolecular chains. In these solutions, the total amounts of solutes are composed of the sum of the “free” binary and the supramolecular ternary associates. © 2008 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:484-494, 2009