Biopredictive in vitro testing methods to assess intestinal drug absorption from supersaturating dosage forms

The discovery pipelines in pharmaceutical companies are highly populated with poorly soluble compounds, demanding for an appropriate solution to overcome this problem. Generating supersaturated concentrations for these drugs in the gastrointestinal (GI) tract has been put forward as a promising strategy to assure sufficient systemic exposure after oral intake of the drug. Numerous publications have shown to which extent supersaturating dosage forms can create supersaturated concentrations by testing these formulations in in vitro dissolution models. The obtained dissolution profiles can serve as a valuable input for computational software programs to simulate the systemic outcome of the drug. To improve our fundamental knowledge and understanding of the impact of supersaturation/precipitation on oral absorption, attempts have been made to develop biopredictive in vitro dissolution systems such as the Gastrointestinal Simulator (GIS), the dissolution/permeation system, and the biphasic test system. Moreover, aspiration studies in humans have been performed throughout the years to measure simultaneously GI and systemic concentrations of the drug in order to directly envisage the impact of supersaturation on systemic exposure. This manuscript aims to provide a comprehensive review with respect to the predictive power of in vitro tools towards the in vivo performance of supersaturating dosage forms. Different case studies will be thoroughly presented where a plethora of supersaturating formulations was tested applying a biopredictive setting. Recent investigations on liquid-liquid phase separation of supersaturated solutions, which makes comprehension of the dissolution process of supersaturating dosage forms extremely challenging, are also discussed.