Complexation of Fluorofenidone by Cucurbit[7]uril and β‑Cyclodextrin: Keto–Enol Tautomerization to Enhance the Solubility

This study is designed to compare drug encapsulation
by cucurbit[7]uril
and β-cyclodextrin, using fluorofenidone as a model drug. Single-crystal
X-ray diffraction analysis was employed to successfully determine
the crystal structures of fluorofenidone·H+@cucurbit[7]uril
Form, fluorofenidone@cucurbit[7]uril Form, and fluorofenidone@β-cyclodextrin
Form. Keto–enol tautomerization of fluorofenidone mediated
by cucurbit[7]uril in acid solution is confirmed by crystal structures,
pH titration, and nuclear magnetic resonance experiments. However,
β-cyclodextrin cannot cause the keto–enol tautomerization
of fluorofenidone under similar conditions. The phase solubility study
demonstrates that cucurbit[7]uril has a much higher solubilization
capacity for fluorofenidone than β-cyclodextrin in 0.1 M HCl
since the Kc values of fluorofenidone
with cucurbit[7]uril and β-cyclodextrin were 1223.97 ±
452.68 and 78.49 ± 10.56 M–1, respectively.
Excellent solubility can be attributed to the keto–enol tautomerization
of fluorofenidone under the conditions of cucurbit[7]uril in acid
solution. The enol form of fluorofenidone is encapsulated by cucurbit[7]uril
by hydrogen bonding interaction and hydrophobic interaction to increase
binding affinity. Rat pharmacokinetic studies demonstrate that the
area under the plasma concentration–time curve from time 0
to 7 h value of fluorofenidone@cucurbit[7]uril complex is 1.70-fold
greater than that of free fluorofenidone, and the mean residence time
from time 0 to 7 h is slightly prolonged from 1.29 to 1.76 h (P < 0.01) after oral administration. However, no significant
difference is found between fluorofenidone and fluorofenidone@β-cyclodextrin
complex. This work indicates that the induction of keto–enol
tautomerization of drugs using macrocyclic molecules has the potential
to be an effective method to improve their solubility and bioavailability,
providing valuable insights for the application of macrocyclic molecules
in the biomedical field.