In vivo Predictive Dissolution Test Using Biorelevant Bicarbonate Buffer for High-dose Free Acid Drug

The purpose of the present study was to evaluate whether dissolution testing in biorelevant bicarbonate buffer (BCB) can predict the solubility-limited oral absorption of high-dose free acid drugs. Valsartan and naproxen were selected as model compounds exhibiting solubility-limited absorption at high doses. A biorelevant BCB solution (concentration: 10 mM, initial pH (pH_ini) = 6.5, buffer capacity (β) = 4.4 mM/pH) (BCB), a phosphate buffer solution with the same pH and β (PPB), and a USP phosphate buffer solution (β = 27 mM/pH, modified to pH_ini 6.5) were employed for dissolution tests. The dose-to-fluid volume ratio (Dose/FV) was set to reflect the clinical or compendial conditions. The fraction of a dose absorbed in humans (Fa) predicted using a simple theoretical framework was compared with the clinical Fa calculated from pharmacokinetic data in the literature. When using BCB or PPB with the same β and the clinical Dose/FV, the bulk-phase pH after 4 h (pH_bulk, _4 h) was markedly lower than pH_ini (< pH 6.0 for naproxen, < pH 5.0 for valsartan). Consequently, the dissolved drug concentration at 4 h (C_{dissolv, 4 h}) was markedly lower than the solubility at pH 6.5. Using C_{dissolv, 4 h}, the dose dependency of Fa was appropriately predicted. In contrast, when using USP or the compendial Dose/FV, the pH_bulk, _4 h and C_{dissolv, 4 h} were less reduced, leading to an overestimation of Fa. Overall, the use of BCB or PPB and a clinical Dose/FV improved the in vivo predictability for high-dose free acid drugs.