Effect of polymeric excipients on nucleation and crystal growth kinetics of amorphous fluconazole

Amorphous solids have been widely used to improve the solubility and oral bioavailability of poorly water-soluble drugs. Biocompatible polymeric materials are usually incorporated into formulations to inhibit the crystallization of high-energy amorphous drugs. Crystallization typically consists of two steps, nucleation and crystal growth. The impacts of polymeric excipients on the crystal growth of amorphous drugs have been intensively studied. However, the nucleation behaviors of amorphous drugs in the presence of polymers remain largely unexplored. Herein, we report that three chemically distinct polymers show significantly different effects on nucleation kinetics of amorphous fluconazole (FCZ), a classical antifungal drug. The addition of 10% w/w HPMCAS shows the largest inhibitory effect on the nucleation rates of FCZ, while the same amount of PVP has only a minor effect. Conversely, the nucleation rates for both polymorphs of FCZ are significantly increased in the presence of PEO. In addition, the polymeric additives are found to influence the kinetics of nucleation and crystal growth to a similar extent, suggesting that the two processes may share a similar kinetic barrier. The present study is helpful in the optimization of formulations of amorphous solid dispersions and understanding the nucleation behavior of polymorphic drugs.

Automated summary

Amorphous solids are commonly used to enhance the solubility and oral bioavailability of poorly water-soluble drugs. Biocompatible polymeric materials are added to formulations to inhibit the crystallization of high-energy amorphous drugs. The impact of polymeric excipients on the nucleation behaviors of amorphous drugs remains largely unexplored.