Understanding Polymer Properties Important for Crystal Growth Inhibition—Impact of Chemically Diverse Polymers on Solution Crystal Growth of Ritonavir

Abstract

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.