Applicability of a miniaturized precipitation assay as an early-stage screening tool for prototype formulation development.

Poor aqueous solubility is a frequently faced challenge in oral drug development. Therefore, the development of predictive in vitro tools for the selection of a suitable formulation is essential. For early formulation development, such an assay ideally requires minimal resources. To address this need, we evaluated the benefits of a previously published miniaturized two-compartment precipitation assay to assess formulation effects early in drug product development. The assay was originally developed for screening compounds for their absorption behavior during preclinical stage. Six poorly soluble weakly basic compounds (albendazole, ibrutinib, itraconazole, posaconazole, ritonavir, ziprasidone; two formulations each) and one poorly soluble neutral compound (fenofibrate; three formulations) were tested under simulated fasted conditions. Formulation differences found in vitro were compared to human pharmacokinetic data obtained from literature. From a qualitative perspective, the assay correctly reflected the in vivo observations for five out of the six basic compounds, as well as for fenofibrate. Quantitatively, the assay approximated the observed in vivo formulation effects for several compounds, including itraconazole, posaconazole, ritonavir, ziprasidone and fenofibrate, whereas the effect size was overestimated for albendazole and ibrutinib, likely reflecting potential assay limitations. These findings support the use of the miniaturized precipitation assay as a fit-for-purpose screening tool for early formulation development.