In vitro characterization of ritonavir formulations and correlation to in vivo performance in dogs.

Ritonavir (RTV) is a weakly basic drug with a pH-dependent solubility. In vitro characterization of dissolution and supersaturation behaviors of three PEG-8000 based amorphous solid dispersions (ASD) and a physical blend (PB) with crystalline drug were performed in the biomimetic media (e.g., FaSSGF, FaSSIF, FaSSIF-V2). A two-stage dissolution test and a biphasic dissolution-partition test at the small scale (referred as to biphasic test) were employed with intention to examine the in vitro and in vivo relationship (IVIVR) with retrospective PK data in dog model. The two-stage dissolution test revealed a high degree of supersaturation of RTV from these ASDs accompanied by the occurrence of liquid-liquid phase separation (LLPS) in the biomimetic media. A rapid decrease of apparent RTV concentrations of these ASDs was associated with significant precipitation upon the pH shift of the dissolution medium, revealing the important role of "the gastric stage". In comparison, the biphasic test revealed a lower degree of supersaturation of RTV that is attributed to removal of RTV through partition into octanol, acting as "the absorption compartment". These two dissolution tests provide characterization of the supersaturation state with a complex, dynamic interplay among dissolution, precipitation and partition processes. Results of both in vitro dissolution tests are in good agreement with in vivo results in dogs. In addition, three commercial generic RTV drug products were examined by the biphasic test. Agreement was also obtained between the RTV concentrations in octanol at 3 h from these generic drug products and their corresponding relative bioavailability in dogs.