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In this work, an amorphous solid dispersion (ASD) formulation was systematically developed to simultaneously enhance bioavailability and mitigate the mechanical instability risk of the selected crystalline form of a development drug candidate, GDC-0334. The amorphous solubility advantage calculation was applied to understand the solubility enhancement potential by an amorphous formulation for GDC-0334, which showed 2.7 times theoretical amorphous solubility advantage. This agreed reasonably well with the experimental solubility ratio between amorphous GDC-0334 and its crystalline counterpart (∼2 times) in buffers of a wide pH range. Guided by the amorphous solubility advantage, ASD screening was then carried out, focusing on supersaturation maintenance and dissolution performance. It was found that although the type of polymer carrier did not impact ASD performance, the addition of 5% (w/w) sodium dodecyl sulfate (SDS) significantly improved the GDC-0334 ASD dissolution rate. After ASD composition screening, stability studies were conducted on selected ASD powders and their hypothetical tablet formulations. Excellent stability of the selected ASD prototypes with or without tablet excipients was observed. Subsequently, ASD tablets were prepared, followed by in vitro and in vivo evaluations. Similar to the effect of facilitating the dissolution of ASD powders, the added SDS improved the disintegration and dissolution of ASD tablets. Finally, a dog pharmacokinetic study confirmed 1.8 to 2.5-fold enhancement of exposure by the developed ASD tablet over the GDC-0334 crystalline form, consistent with the amorphous solubility advantage of GDC-0334. A workflow of developing an ASD formulation for actual pharmaceutical application was proposed according to the practice of this work, which could provide potential guidance for ASD formulation development in general for other new chemical entities.

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