Physicochemical characterization, cyclodextrin complexation, and protonation state-dependent receptor binding of selected tyrosine kinase inhibitors

Jánoska, Ádám and Szabó, Zoltán-István and Szőcs, Levente and Fiser, Béla and Tóth, Gergő (2026) Physicochemical characterization, cyclodextrin complexation, and protonation state-dependent receptor binding of selected tyrosine kinase inhibitors. JOURNAL OF MOLECULAR STRUCTURE, 1352 (1). No. 144518. ISSN 0022-2860

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Abstract

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. 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. Our research findings contribute to a better understanding of the pharmacokinetics and receptor binding of tyrosine kinase inhibitors, while also paving the way for the development of new, modern pharmaceutical formulations.

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