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Background
Phosphate buffer is often used as a replacement for the physiological bicarbonate buffer in pharmaceutical dissolution testing, although there are some discrepancies in their properties making it complicated to extrapolate dissolution results in phosphate to the
in vivo
situation. This study aims to characterize these discrepancies regarding solubility and dissolution behavior of ionizable compounds.
Methods
The dissolution of an ibuprofen powder with a known particle size distribution was simulated
in silico
and verified experimentally
in vitro
at two different doses and in two different buffers (5 mM pH 6.8 bicarbonate and phosphate).
Results
The results showed that there is a solubility
vs
. dissolution mismatch in the two buffers. This was accurately predicted by the in-house simulations based on the reversible non-equilibrium (RNE) and the Mooney models.
Conclusions
The results can be explained by the existence of a relatively large gap between the initial surface pH of the drug and the bulk pH at saturation in bicarbonate but not in phosphate, which is caused by not all the interfacial reactions reaching equilibrium in bicarbonate prior to bulk saturation. This means that slurry pH measurements, while providing surface pH estimates for buffers like phosphate, are poor indicators of surface pH in the intestinal bicarbonate buffer. In addition, it showcases the importance of accounting for the H
2
CO
3
-
CO
2
interconversion kinetics to achieve good predictions of intestinal drug dissolution.