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Biopharmaceutic Classification System Class II drugs pervasively overwhelm product pipelines since they suffer from dissolution-rate limited bioavailability. Although amorphization can impart a significant ‘solubility advantage’ to these compounds, solution-mediated phase transformation (SMPT) (i.e., recrystallization to the poorly soluble form) has limited its commercial application. Recently, controlled release amorphous solid dispersions (CRASD) have been introduced to circumvent excessive precipitation, while boasting precise, predictable sustained release. Hence, expanded research in this field may ultimately lead to greater industrial success rates and a wider breadth of available therapies. In this thesis, CRASD membrane-reservoir coated beads prepared by fluid-bed coating were investigated as a potential solid oral delivery system for poorly soluble model drug, celecoxib (CEL). By analyzing dissolution and recrystallization behaviors, the effects of: (1) pore-former (polyvinylpyrrolidone (PVP)) content and coating level, (2) novel terpolymer nanoparticle (TPN) versus conventional pore former (PVP), and (3) dose configuration by ASD reservoir loading level and bead quantity were evaluated. In the first study, the combination of high pore former content (PVP) and high coating level of a polyvinyl acetate-based CR membrane provided a moderately fast initial CEL release rate followed by sustained release, yielding the highest overall extent of release. The thicker, porous coating structure was proposed to serve as a transient drug reservoir, relieving supersaturation at both the interior and exterior sides of the membrane. In the second part, incorporation of TPN as an advanced pore former in ethylcellulose-based CR membranes produced smoother coatings resistant to surface precipitation and higher extent of release compared to those of PVP. The non-leachability and swelling mechanism of TPN advantageously enhanced molecular separation and steric hindrance of CEL crystal formation within the membrane. In the final study, excess ASD reservoir loading in CRASD with ethylcellulose-TPN membranes was disadvantageous, as release profiles were significantly supressed compared to lower reservoir loadings with lower doses, which was attributed to a higher propensity for internal SMPT. To conclude, truly maximizing the benefit of solubility enhancement requires the CRASD strategy to focus on all system features capable of enhancing and balancing the preservation of amorphous drug both within and external to the dosage form.
