Phase behavior of supersaturated solutions of poorly soluble small molecules

Solid oral formulations such as amorphous solid dispersions that give rise to supersaturated solutions are collectively termed as enabling formulations. These formulations have had tremendous success in enhancing in vivo drug uptake and bioavailability of poorly soluble molecules. For a successful amorphous solid dispersion strategy it is important to address stability in the solid as well as the solution state. Amorphous solids tend to crystallize over time and although polymers have been used to impede precipitation from solution there is a gap in our mechanistic understanding of how polymers impact dissolution, stabilize supersaturated solutions and affect polymorphic transitions. There is a need to characterize solution-state crystallization tendency particularly in the presence of polymers and ascertain their impact on phase behavior of supersaturated solutions. Phase behavior of supersaturated solutions is extremely complex, poorly understood and plagued with numerous phase transitions viz. solid-liquid phase transitions such as crystallization and amorphous-amorphous phase precipitation and as our research efforts have recently uncovered, liquid-liquid phase separation (LLPS). LLPS is a novel phenomenon that occurs in highly supersaturated solutions once a certain threshold concentration is exceeded. According to data presented in the forthcoming pages, this threshold concentration corroborates to amorphous solubility and is a startling discovery. LLPS is known to occur in polymer blends, proteins and peptides, in industrial crystallization when recrystallizing small molecules from a mixture of aqueous and organic solvent and has even been documented as promiscuous aggregation on the pharmaceutical discovery end. However, this is the first such report of LLPS in a binary system comprising of drug and water. The focus of this thesis work is to understand the underlying theromdynamics of LLPS and its relationship with amorphous solubility and stabilizing such systems using pharmaceutical excipients such as polymers, lipids and surfactants. A consequence of this work is the development of ultraviolet (UV) and fluorescence spectroscopic techniques to detect LLPS onset as well as a simple diffusion cell approach to predict thermodynamic activity and passive drug uptake of LLPS systems in the absence and presence of additives. Understanding phase behavior of supersaturated solutions and the impact of excipients will enable us to exploit enabling formulation strategy, stabilize such systems against crystallization and drive drug exposure in vivo