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. Erlotinib is used against non-small cell lung cancer and pancreatic cancer, gefitinib against certain breast and lung cancer, lapatinib against breast cancer, while vandetanib is applied for the treatment of certain tumors of the thyroid gland. 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. Thus, in-depth characterization of cyclodextrin complexation of these anticancer drugs using state-of-the-art analytical methods is crucial. 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 Volume 1352, 144518. https://doi.org/10.1016/j.molstruc.2025.144518