Supersaturating formulations have become a popular approach for enhancing the oral bioavailability of poorly water-soluble drugs. These formulation strategies can increase the intraluminal concentration by generating and maintaining supersaturation, which provides an enhanced driving force for <i>in vivo</i> absorption. Due to their inherent metastability however, crystallization in these systems can occur, negatively impacting their bioperformance. Therefore, it is critical to characterize the phase behavior and crystallization tendency of supersaturated solutions under biorelevant conditions in order to assess their potential for maximized oral absorption. Biorelevant media are commonly employed to simulate the presence of bile salts and phospholipids found in the human intestinal fluids. Currently, there is little knowledge of how simulated and aspirated intestinal media can impact the complex phase behavior of supersaturated solutions. More importantly, commonly-used simulated media rely on oversimplified recipes in terms of bile salt composition. As a result, comprehensive understanding of how well simulated media correlate with aspirated media with respect to supersaturation stability and phase transition outcomes, is still lacking. The work presented within this thesis aims to address the knowledge gap by assessing the phase behavior of supersaturated solutions using complementary analytical approaches. Depending on the type of medium used to evaluate supersaturation, variations in solubility, supersaturation thermodynamics and crystallization kinetics can be observed. This understanding can aid future efforts to optimize simulated media, design supersaturating formulations and predict their <i>in vivo</i> performance.

Dissolution testing and physiological based pharmacokinetic modeling are the essential methods during drug development. However, there is a lack of a sound approach and understanding of the parameter that controls dissolution and absorption of amorphous formulations. Robust dissolution conditions and setup and PBPK models that have a predictability of in vivo results will expedite and facilitate the drug development process. In this project, cefuroxime axetil, CA (Zinnat® as the amorphous formulations); itraconazole, ITR (Sporanox® as the amorphous formulation) and a compound undergoing clinical trial, Compound X, CX (CX tablet as the amorphous formulation) were chosen. The design of experiments for the in vitro dissolution studies using different apparatus, media and setup which closely simulate the physiological condition of humans (CA and ITR) and dogs (CX) were implemented. The dissolution of CA, ITR and CX formulations was successfully characterised using different dissolution apparatus, setting and media (compendial, biorelevant and modified media) to simulate the changes of pH, contents, hydrodynamic conditions (flow rate and rotation speed) in human gastrointestinal tract (fasted and fed state). The change of hydrodynamics combined with media change that corresponded to the physiological conditions created with USP apparatus 4 and biorelevant dissolution media were able to mimic the in vivo performance of the tested formulations. Furthermore, surface UV dissolution imaging methodology that could be used to understand the mechanism of CA and ITR (Active compounds and their amorphous formulations) dissolution were developed in this project. The UV images developed using surface UV imaging apparatus provided a visual representation and a means for the qualitative as well as quantitative assessment of the differences in dissolution rates and concentration for the model compounds used. In this project, validated PBPK models for fasted state (CA, ITR) and fed state (CA, ITR and CX) were developed. These models incorporated in vitro degradation, particle size distribution, in vitro solubility and dissolution data as well as in vivo human/ dog pharmacokinetics data. Similarly, the results showed that level A IVIVCs for all three model compounds were successfully established. Dissolution profiles with USP apparatus 4 combined with biorelevant media showed close correlation with the in vivo absorption profiles. Overall, this project successfully provides a comprehensive biorelevant methodology to develop PBPK models and IVIVCs for orally administered amorphous formulations.