Probing the Interplay between Amorphous Solid Dispersion Stability and Polymer Functionality.

Abstract

Amorphous solid dispersions containing a polymeric component often impart improved stability against crystallization for a small molecule relative to the pure amorphous form. However, the relationship between side chain functionalities on a polymer and the ability of a polymer to stabilize against crystallization is not well understood. To shed light on this relationship, a series of polymers were functionalized from a parent batch of poly(chloromethylstyrene- co-styrene) to investigate the effect of functionality on the stability in amorphous solid dispersions without altering the physical parameters of polymers, such as the average molecular weight or backbone chain chemistry. The kinetics of the crystallization of the nonsteroidal anti-inflammatory drug nabumetone from amorphous solid dispersions containing each functionalized polymer were interpreted on the basis of two interactions: hydrogen bonding between the drug and the polymer and the solubility of the polymer in the amorphous drug. It was found that hydrogen bonding between functionalized polymers and nabumetone can impart stability against crystallization, but only if the polymer shows significant solubility in amorphous nabumetone. Methylation of a protic functionality can improve the ability of a polymer to inhibit nabumetone crystallization by increasing the solubility in the drug, even when the resulting polymer lacks hydrogen bonding functionalities to interact with the pharmaceutical. Furthermore, factors, such as the glass transition temperature of pure polymers, were uncorrelated with isothermal nucleation rates. These findings inform a framework relating polymer functionality and stability deconvoluted from the polymer chain length or backbone chemistry with the potential to aid in the design of polymers to inhibit the crystallization of hydrophobic drugs from amorphous solid dispersions.