Molecular mobility, physical stability, and transformation kinetics of amorphous and hydrated pharmaceutical solids.

摘要

Amorphous forms have been shown to improve the bioavailability of poorly water-soluble drugs. However, its intrinsic tendency to undergo crystallization imposes great challenges in the formulation of amorphous drugs. This study aims to provide a fundamental understanding of the physical instability, that is the crystallization, of amorphous pharmaceuticals in terms of configurational thermodynamic quantities and molecular mobility, as well as solid-state kinetics.; Using five model compounds that form amorphous phases with distinct crystallization tendencies, we have shown that configurational entropy and molecular mobility are equally important in determining the crystallization tendencies of amorphous phases in the rubbery state. For spontaneous crystallization to occur, amorphous phases with high configurational entropy require high molecular mobility. As a result, greater effort is required to stability amorphous forms of small, rigid molecules than those of large, flexible molecules.; Molecular mobility in glasses is greatly influenced by annealing and decreases with annealing time. However, for both fresh and annealed glasses, the temperature dependence of molecular mobility conforms approximately to the Arrhenius equation. Ritonavir and nifedipine glasses have different annealing behavior, which explains the differences in their stability.; Amorphous griseofulvin readily crystallizes above and below T_g. Our results suggest that molecular diffusion plays an important, but not exclusive, role in determining the rate of crystallization. However, the correlation between the rate of crystallization and molecular mobility is reduced in the glassy state. This observation is explained by the higher molecular mobility in real glasses than in the ideal glasses.; Crystallization kinetics of amorphous nifedipine was treated by model-fitting and model-free approaches. Model-free analysis provides a more realistic picture of the actual process of crystallization and gives improved predictions. The model-free treatment has also been successfully applied to the analysis of the dehydration kinetics of nedocromil sodium trihydrate. Finally, we explain the model-independent activation energy derived from isothermal kinetic data and the model-dependent activation energy derived from nonisothermal kinetic data.; The knowledge gained from this thesis should provide a fundamental understanding of the physical stability of amorphous phases and their solid-state kinetics and should assist in improving the stability of pharmaceutical products.