The impact of endogenous gastrointestinal molecules on the dissolution and precipitation of orally delivered hydrophobic APIs

Introduction: Given that hydrophobic active pharmaceutical ingredients (APIs) intended for oral delivery comprised about 68% of US FDA approvals in 2019 alone, the impact of endogenous gastrointestinal (GI) molecules on their inherently unstable solution behavior needs to be elucidated. Areas covered: The interactions between hydrophobic API’s and GI phospholipids, bile acids/salts and digestive proteins are explored. The impact of the complex relationship between the GI molecules and hydrophobic APIs on solubilization by micelle formation, complexation or by inhibiting the nucleation of high energy forms of hydrophobic APIs, so called supersaturating drug delivery systems is complex. The ability of these endogenous GI molecules to manipulate the solution behavior of hydrophobic APIs has been demonstrated both at their native concentrations and when included as exogenous formulation additives. Specific studies of the impact of proteins and mixed micelles on solubilization and crystallization are reported. Expert opinion: Elucidation of the complex molecular interactions between orally administered hydrophobic APIs and endogenous GI molecules will enable better in vivo/in vitro correlation and potentially lead to formulation strategies that avoid the stochastic nature of hydrophobic API precipitation in the GI tract.