Understanding the Role of Water in Nonaqueous Pharmaceutical Systems

摘要

This chapter focuses initially on the dynamics and organization of water molecules and factors governing the extent of water uptake in nonaqueous pharmaceutical systems such as lipid-based drug-delivery vehicles and amorphous and crystalline solid-dosage forms. In systems that have been investigated in this laboratory, including triglyceride-monoglyceride lipid mixtures and amorphous polymers (e.g., polyvinylpyrrolidone [PVPI), water distribution is heterogeneous, with molecules tending to form strands or small clusters at relatively low moisture content (<10%) driven by hydrogen-bonding interactions with polar functional groups in the excipients and other water molecules. In lipid mixtures, water is a key contributor to the formation of organized local domains, a characteristic of microemulsions. Over short time scales, water and other solute displacements in both lipid vehicles and amorphous glasses at low water content are dominated by entrapment and jump motions, whereas the formation of water clusters at higher water content tends to alter solute diffusion such that it more closely resembles that in bulk water. The heterogeneity in water distribution, its effects of solute diffusivity and plasticization of amorphous matrices, and the higher diffusivity of water due to its relatively small molecular size become critical factors governing physical and chemical stability in solid formulations. Whereas diffusion-controlled decomposition reactions seldom need to be considered in solution, molecular mobility plays a critical role in amorphous solid-state reaction kinetics. Spatial heterogeneity in dynamic relaxation processes and their time dependence, as well as possible heterogeneity in the distribution of drug molecules, water, and other formulation components, may also be important.