Amorphous particles enhance oral exposure-a case study of a poorly soluble compound in preclinical, toxicology and early clinical studies.

OBJECTIVES: The aim of this study was to investigate whether different liquid formulations of a selected candidate drug could be utilized to improve oral absorption and subsequent in vivo exposure. METHODS: Polyethylene glycol 400 (PEG400) formulations with and without pH adjustment and hydroxypropyl-β-cyclodextrin (CD) formulations were prepared alongside amorphous and crystalline suspensions, the latter as micro- and nanocrystals. The suspensions of the compound were manufactured and evaluated for solubility, dissolution rate and in vivo exposure in rats, dogs, and humans, whereas the PEG400 and CD formulations were administered only to rats and/or dogs. KEY FINDINGS: Amorphous microsuspensions of the active pharmaceutical ingredient (API) demonstrated the most promising in vivo results. CD formulation resulted in significantly lower drug exposure than expected. When amorphous suspensions were administered, an absorption difference was observed between male and female rats and a greater than dose linear increase in exposure was noted between two doses in humans. CONCLUSION: This study demonstrated that amorphous suspensions of a newly selected candidate drug resulted in superior oral absorption compared with more commonly used liquid formulations of the API in all investigated species. However, progressing with an amorphous form always carries inherent risks regarding chemical and physical stability.