Cucurbit[7,8]urils binding to gefitinib and the effect of complex formation on the solubility and dissolution rate of the drug

Abstract

The host–guest interactions of macrocyclic hosts cucurbit[7,8]urils (Q[7,8]) with prototropic forms of the drug gefitinib (diprotonated: GH²⁺ and neutral: G) were investigated by electronic absorption spectroscopy. The two hosts Q[7,8] showed strong binding to the diprotonated form due to the ion–dipole interaction between the polar carbonyl oxygens of the hosts and the cationic GH²⁺. Q[7] and Q[8] showed similar binding to the neutral gefitinib, shifting its pK_a by about 1.4 units and 0.7 units downward, respectively. Determination of the thermodynamic parameters of complex formation showed that the formation of inclusion complexes between gefitinib and Q[7,8] was enthalpy controlled, suggesting that hydrophobic and van der Waals interactions were the main driving forces. Moreover, the formation of inclusion complexes between Q[7] and Q[8] and gefitinib was confirmed by ¹H NMR, which showed that the phenyl moiety of gefitinib was entrapped in the Q[7] cavity or likely located on the outside of the Q[7] cavity. The two models showed a fast dynamic equilibrium. Our results indicate that the complexation of gefitinib with Q[7] could enhance the solubility and dissolution rate of gefitinib in aqueous solution.