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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.

The use of supersaturating dosage forms, such amorphous dispersions, is an increasingly common approach for improving delivery of poorly water-soluble drugs. Crystallization must be prevented to maintain supersaturation, and so, the presence of an effective crystal growth inhibitor in solution is desirable to prolong supersaturation. In this study, the effectiveness of a group of chemically diverse polymers, including a number of novel cellulose derivatives, at inhibiting the crystal growth of ritonavir from solution was quantified, enabling key polymer properties important for crystal growth inhibition of ritonavir to be elucidated. In general, the greater effectiveness of the cellulose derivatives relative to the synthetic polymers was ascribed to a moderate level of hydrophobicity, the semirigid structure of the cellulose polymers, and their amphiphilicity. Interestingly, some of the novel cellulose polymers were found to be more effective crystal growth inhibitors than commercially available cellulose derivatives. Orthogonal partial least-squares analysis further pointed to the importance of polymer hydrophobicity. These properties of the cellulose-based polymers are likely to promote adsorption onto the crystallizing drug surface. Given the diversity of impact of polymers on crystal growth inhibition, it is clearly important to consider this factor when choosing a polymer for a supersaturating dosage form.