Intestinal solubility is higher in fed state compared to fasted state. However, the dissolution rate does not increase to the same extent. Dog seems to be a good model for man with respect to dissolution in the small intestine after intake of a meal, whereas FeSSIF is a poorer means of determining intestinal saturation solubility in the fed state.

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This study indicated that simple in vitro methods of in vivo precipitation of orally administered bases overpredict the intestinal crystalline precipitation in vivo in humans. Hydrodynamic conditions were identified as one important factor that needs to be better addressed in future in vivo predictive methods.

PurposeTo develop predictive models of apparent solubility (Sapp) of lipophilic drugs in fasted state simulated intestinal fluid (FaSSIF) and aspirated human intestinal fluid (HIF).MethodsMeasured Sapp values in FaSSIF, HIF and phosphate buffer pH 6.5 (PhBpH6.5) for 86 lipophilic drugs were compiled and divided into training (Tr) and test (Te) sets. Projection to latent structure (PLS) models were developed through variable selection of calculated molecular descriptors. Experimentally determined properties were included to investigate their contribution to the predictions.ResultsModest relationships between Sapp in PhBpH6.5 and FaSSIF (R2 = 0.61) or HIF (R2 = 0.62) were found. As expected, there was a stronger correlation obtained between FaSSIF and HIF (R2 = 0.78). Computational models were developed using calculated descriptors alone (FaSSIF, R2 = 0.69 and RMSEte of 0.77; HIF, R2 = 0.84 and RMSEte of 0.81). Accuracy improved when solubility in PhBpH6.5 was added as a descriptor (FaSSIF, R2 = 0.76 and RMSETe of 0.65; HIF, R2 = 0.86 and RMSETe of 0.69), whereas no improvement was seen when melting point (Tm) or logDpH 6.5 were included in the models.ConclusionComputational models were developed, that reliably predicted Sapp of lipophilic compounds in intestinal fluid, from molecular structures alone. If experimentally determined pH-dependent solubility values were available, this further improved the accuracy of the predictions.

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