Drug Solubilization in Simulated Intestinal Fluids vs Lipophilicity: Does Charge Matter?

Solubilization of poorly water-soluble drugs in human
intestinal
fluids influences oral absorption and is linked to food effects. Current
empirical equations for calculating intestinal solubilization via
lipophilicity are built on limited data and do not adequately account
for drug ionization. We aim to expand the data set and build a model
to clarify the link between lipophilicity and solubilization for charged
compounds. We determined the aqueous solubility, octanol–water
partition coefficient, and solubilization in fed-state simulated intestinal
fluids (FeSSIF) of 26 hydrophobic drugs. Combined with literature
data, a good correlation (R2 = 0.74, n = 198) between intestinal solubilization and LogP/D was
observed. However, data segregation showed that the solubilization
of neutral compounds correlated very well with LogP (R2 = 0.89, n = 114), whereas the correlation
with LogD was lost for the charged compounds (R2 = 0.40, n = 84). To better understand this
behavior, the pH of FeSSIF was varied to study the solubilization
of the same compounds in the neutral and charged states. While a very
good correlation between solubilization and LogD was observed in the
neutral state of the compounds (R2 = 0.92, n = 8), the correlation was again lost (R2 = 0.02, n = 4) in their charged state.
Electrostatic interactions were suggested to play a key role in the
unexpectedly low solubilization of anionic drugs and in the phase
separation observed for cationic drugs. The presented insights further
advance the understanding of the solubilization of hydrophobic drugs
in biorelevant media and provide a foundation for broader and improved
modeling approaches.