Impact of Storage Conditions on the Physical Stability of Amorphous Solid Dispersions Containing Two Structurally...

The physical stability of two structurally similar drugs, indomethacin (IND) and indomethacin methyl ester (INDME), was investigated by comparison of thermodynamic, kinetic, and structural factors affecting crystallization. The impact of drug loading, storage temperature relative to the glass transition temperature (T_g), and hydrogen bonding ability has been explored for their relative importance as the cause for crystallization in amorphous solid dispersions (ASDs). IND or INDME and polyvinylpyrrolidone (PVP) K12 ASDs were formulated at varying drug loadings via cryomilling and melt-quenching. Differential scanning calorimetry was used to assign storage temperatures in the supercooled liquid and glassy states based on the T_g of each dispersion. The crystallization onset time (t_c) was monitored using powder X-ray diffraction while Fourier-transform infrared spectroscopy monitored changes in hydrogen bonding. IND formed strong homogeneous and IND-PVP hydrogen bonds while there was scarce evidence of INDME hydrogen bonding. The t_c of IND and INDME ASDs was inversely related to drug loading and storage temperature. However, systems with 80% IND or greater exhibited a deviation from the exponential relationship in t_c as T_g was approached. At high drug loadings, IND crystallized faster at temperatures near and slightly below T_g than at temperatures above T_g. IND has a greater thermodynamic driving force for crystallization relative to INDME at all temperatures above T_g. However, this is offset by a reduction in molecular mobility due to extensive hydrogen bonding with PVP. Near T_g, IND still has extensive translational mobility driven by the formation of IND-IND dimers during nucleation and crystallization and is proposed as a possible cause of the increased IND crystallization kinetics. Increased drug loading and temperature provide a larger thermodynamic driving force for crystallization and reduce the crystallization onset time. However, their relative contributions may change with decreasing temperature to the point where crystallization onset time above T_g may not be extrapolated below T_g. For the first time, diffusionless crystallization is observed in systems above 2% polymer to which a difference in thermodynamics, driven by hydrogen bond formation, is thought to be the cause. A better understanding of the causes of destabilization and their relative significance toward causing crystallization will help to make better informed decisions during formulation and storage.