LAUSR

The characterization of intestinal dissolution of poorly soluble drugs represents a key task during development of both new drug candidates and drug products. The bicarbonate buffer is considered as the most biorelevant buffer for simulating intestinal conditions. However, due to its complex nature, being the volatility of CO2, it has only been rarely used in the past. The aim of this study was to investigate the effect of a biorelevant bicarbonate buffer on intestinal supersaturation and precipitation of poorly soluble drugs using a GI transfer model. Therefore, results of ketoconazole, pazopanib, and lapatinib transfer model experiments using FaSSIFbicarbonate were compared to results obtained using standard FaSSIFphosphate. Additionally, the effect of HPMCAS as precipitation inhibitor was investigated in both buffer systems and compared to rat PK studies with and without co-administration of HPMCAS as precipitation inhibitor. While HPMCAS was found to be an effective precipitation inhibitor for all drugs in FaSSIFphosphate, the effect in FaSSIFbicarbonate was much less pronounced. The PK studies revealed that HPMCAS did not increase the exposure of any of the model compounds significantly, indicating that the transfer model employing bicarbonate-buffered FaSSIF has a better predictive power compared to the model using phosphate-buffered FaSSIF. Hence, the application of a bicarbonate buffer in a transfer model set-up represents a promising approach to increase the predictive power of this in vitro tool and to contribute to the development of drug substances and drug products in a more biorelevant way.