Development of an Amorphous Solid Dispersion Formulation for Mitigating Mechanical Instability of Crystalline Form and Improving Bioavailability for Early Phase Clinical Studies

Abstract

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.

Generality of Enhancing the Dissolution Rates of Free Acid Amorphous Solid Dispersions by the Incorporation of Sodium Hydroxide

“…It was found that drugs with lower amorphous solubilities would benefit more from the incorporation of NaOH in terms of improving its release from ASDs. With the increasing complexity and lipophilicity of drug candidates arising from the drug discovery pipeline, it is not uncommon that new chemical entities may have low solubilities even in their amorphous states. , Our results thus suggest a promising path to develop solubility-enabling formulations of these types of molecules to further improve their dissolution rates if they have ionizable functional groups.…”

Comparative Evaluation of Particle Size Reduction, Salt Formation, and Amorphous Formulation on the Biopharmaceutical Performance of a Weak Base Drug Candidate

“…For particle size reduction, mechanical stress-induced form instability was not observed for GDC-3280. However, for other new chemical entities, if solid form instability or transformation was observed upon mechanical stress, risks for downstream development would be significantly increased due to the difficulty of controlling solid form and the stability of the disordered/transformed phases. , In such a case, careful evaluation of particle size reduction technologies, process parameters, and other approaches of improving bioavailability would be needed. For salt formation, the low p K a of 2.5 for GDC-3280 requires a strong acidic counterion to form a stable salt.…”

“…, surfactant, pH modifier). − Among all of these approaches, the selection of a solubility-enabling solid form or engineering of particles (usually particle size reduction) is usually the most considered option to overcome the low-solubility challenge. Numerous studies have reported their success in improving solubility, dissolution rate, and bioavailability for poorly water-soluble drugs. − ,− However, reports of comparatively assessing different approaches on the biopharmaceutical performance using the same molecule are sparse. , …”