Maintaining Supersaturation in Aqueous Drug Solutions: Impact of Different Polymers on Induction Times

Abstract

The use of polymeric additives is an increasingly common approach for inhibiting crystallization from the supersaturated solutions used to enhance the delivery of poorly water-soluble drugs. Maintaining supersaturation by employing polymeric additives depends on their ability to inhibit nucleation and crystal growth. In solution crystallization, nucleation initiates the process of crystallization, and therefore adequate control over crystallization from supersaturated solutions cannot be achieved without understanding the mechanism of nucleation inhibition by polymers. In this study, the effectiveness of a group of chemically diverse polymers, including several recently synthesized cellulose derivatives, on induction times in aqueous solutions was quantified. Nucleation was quantified by measuring the induction time for the appearance of particulates from unseeded desupersaturation experiments for three model pharmaceutical compounds: celecoxib, efavirenz, and ritonavir. Induction times in the absence of the polymers varied from approximately 2 min for celecoxib to 2 h for ritonavir. Some polymers were found to extend induction times by up to a factor of 5–6 at the highest supersaturations tested. The effectiveness of the various polymers appeared to depend on the hydrophobicity of the polymer relative to that of the drug. The hydrophobicity of the polymer most likely influences the ability of the polymer to form polymer–solute interactions relative to polymer–solvent and polymer–polymer interactions. Polymer–solute interactions would be expected to hinder the reorganization of a cluster of solute molecules into an ordered crystal structure.