Posted by The comprehensive physicochemical characterization and cyclodextrin complexation of four tyrosine kinase inhibitors — erlotinib, gefitinib, vandetanib, and lapatinib — were studied using a suite of advanced analytical techniques. Determination of the acid-base properties, lipophilicity, and solubility of the four drugs highlighted that low solubility is a key factor limiting the bioavailability of these drugs. Protonation of the quinazoline ring was identified as essential for receptor binding, as demonstrated by molecular docking studies of protonation state-dependent interactions. Cyclodextrin complexation presents a promising approach to enhance the solubility of tyrosine kinase inhibitors.
Phase solubility studies indicated that the cavity size of β-cyclodextrin (β-CD) is particularly well-suited for the incorporation of these molecules. Among the modified β-CDs tested — randomly methylated, hydroxypropylated, and sulfobutylated β-CD — sulfobutylated β-CD conferred the greatest solubility enhancement, increasing solubility for each compound, providing an opportunity to develop a novel injection-based formulation. The inclusion complexes exhibit a 1:1 stoichiometry in all cases, confirmed by NMR Job plot titration. Additionally, 2D ROESY NMR spectroscopy and molecular modeling provided atomic-level structural insights into the structures of the complexes.
Ádám Jánoska, Zoltán-István Szabó, Levente Szőcs, Béla Fiser, Gergő Tóth (2026) Physicochemical characterization, cyclodextrin complexation, and protonation state-dependent receptor binding of selected tyrosine kinase inhibitors. Journal of Molecular Structure 1352, 144518.
https://doi.org/10.1016/j.molstruc.2025.144518.