Evolution of Supersaturation Generated from Amorphous Solid Solutions of Poorly Soluble Drugs in Glassy Hydrogels

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One major challenge in oral drug delivery has been the low bioavailability of many crystalline compounds exhibiting poor solubility characteristics. Traditional methods for solubility enhancement involving solubilizing agents (e.g. co-solvents & surfactants) and particle size reduction have not always been successful. On the other hand, the creation of solid solutions (molecular dispersions) in soluble polymers has shown potential to be effective in enhancing the dissolution and oral bioavailability due to the higher solubility of the amorphous drug (supersaturation). However, the effect of rate of supersaturation build-up on the overall time evolution of supersaturation during dissolution is not well understood and has not been fully explored. In addition, physical instability of these systems during storage such as crystallization on aging has limited their success in commercial applications. Furthermore, no criterion exists in determining the threshold drug loading level above which crystallization may occur in these soluble polymers. Despite the ongoing interest in hydrogels as biomaterials and carriers for controlled drug release, the novel application of cross-linked glassy hydrogels for stabilizing dissolved drug in an amorphous state and for enhancing the dissolution and bioavailability of poorly soluble drugs has not been fully investigated. Cross-linked hydrogels are more advantageous than soluble polymers in this regard as the three-dimensional network in the glassy state is more effective in preventing the initial nucleation and subsequent crystal growth. Preliminary evidence suggests that solid solutions based on hydrogels can also avoid peaks and valleys in the kinetic solubility profiles normally associated with solid solutions based on soluble polymers, thereby achieving a more sustained drug supersaturation than conventional systems based on soluble polymers.The long-term objective of the proposed research is to elucidate the evolution of supersaturation generation from solid solutions (molecular dispersions) based on glassy hydrophilic polymers and the underlying mechanisms governing governing the stabilization of such amorphous solid solutions in glassy hydrogels in the solid state. Our immediate objective is aimed at gaining an in-depth understanding of the kinetics of nucleation and crystallization of dissolved drug in the hydrogel phase as a function of drug loading, humidity level, and polymer characteristics, as well as the mechanism of supersaturation generation during nonsink dissolution from such diffusion-controlled glassy hydrogel systems and parameters that affect their sustained supersaturation behavior. We propose to conduct an in-depth investigation of solid solutions of poorly soluble drugs in cross-linked hydrogels, both mechanistically and experimentally, in terms of (1) effect of drug loading and its influence on the state of drug in the polymer matrix (amorphous or crystalline), and on the mechanisms of drug release; (2) the effect of polymer hydration on the drug crystallization kinetics as a function of temperature, water uptake, drug loading and polymer properties; and (3) the evolution of supersaturation generated from solid solutions of poorly soluble drugs in glassy hydrogels . We hope to establish criteria and limiting ranges of these parameters that can effectively inhibit the nucleation and crystallization of loaded drug in glassy hydrogels as well as generate an optimal supersaturation rate which maximizes the area-under-the-curve (AUC) of the kinetic solubility concentration-time profile. These aspects are of significant importance to the design of stable amorphous solid solutions/dispersions in glassy hydrogels and their ability to enhance the delivery of poorly soluble drugs.