Incorporating the biphasic system to GIS-α Improves In vivo prediction for low solubility drugs

The gastrointestinal simulator alpha (GIS-α) is an in vivo predictive transfer dissolution method that mimics the pH changes and peristalsis in the gastrointestinal tract, factors that are necessary in the biorelevant dissolution of drugs especially those that are under the Biopharmaceutics Classification System (BCS) class II and IV. It can be used to provide increased understanding to the dissolution, precipitation, and supersaturation of various low-solubility drugs, but lacks insights on absorption. Conducting experiments in the GIS-α with a biphasic system to add an absorptive phase in the jejunal compartment increased the observed dissolution and improved the overall in vivo prediction. In this study, the objective was to evaluate the improvement of dissolution on four representative BCS class II drugs using the biphasic format in the GIS-α. A customized double paddle was also used in the jejunal chamber to mix the aqueous buffer and organic layer simultaneously. This paddle floats in the organic layer as the aqueous volume increases and maintains the hydrodynamics in both the aqueous and organic phases. The combination of the biphasic system in the GIS-α and the moving double paddles resulted to increased dissolution profiles of fenofibrate, danazol, and celecoxib while not affecting that of ritonavir. Incorporating these dissolution profiles in a PBPK model using GastroPlus® improved the predictability of bioperformance of those oral medicines. Overall, this methodology considers both dissolution and absorption and proves to be a useful tool in predicting the in vivo performance of low-solubility drugs.