Effect of Polymer Hydrophobicity on the Stability of Amorphous Solid Dispersions and Supersaturated Solutions of a Hydrophobic Pharmaceutical

Amorphous solid dispersions of pharmaceuticals often show improved solubility over crystalline forms. However, the crystallization of amorphous solid dispersions during storage, or from elevated supersaturation once dissolved, compromise the solubility advantage of delivery in the amorphous phase. To combat this phenomenon, polymer additives are often included in solid dispersions to inhibit crystallization; however, the optimal properties for polymer to stabilize against crystallization are not fully understood, and furthermore, it is not known how inhibition of precipitation from solution is related to the propensity of a polymer to inhibit crystallization from the amorphous phase. Here, polymers of varied hydrophobicity are employed as crystallization inhibitors in supersaturated solutions and amorphous solid dispersions of the BCS Class II pharmaceutical ethenzamide to investigate the chemical features of polymer that lead to long-term stability for a hydrophobic pharmaceutical. A postpolymerization functionalization strategy was employed to alter the hydrophobicity of poly(N-hydroxyethyl acrylamide) without changing physical properties such as number-average chain length. It was found that supersaturation maintenance for ethenzamide is improved by increasing the hydrophobicity of dissolved polymer in aqueous solution. Furthermore, amorphous solid dispersions of ethenzamide containing a more hydrophobic polymer showed superior stability compared to those containing a less hydrophobic polymer. This trend of increasing polymer hydrophobicity leading to improved amorphous stability is interpreted by parsing the effects of water absorption in amorphous solid dispersions using intermolecular interaction strengths derived from global structural analysis. By comparing the structure function relationships, which dictate stability in solution and amorphous solid dispersions, the effect of hydrophobicity can be broadly understood for the design of polymers to impart stability throughout the application of amorphous solid dispersions.