PhD Scientific Days 2018

Budapest, April 19–20, 2018

Physicochemical characterization and cyclodextrin complexation of tyrosine kinase inhibitors

Tóth, Gergő

Gergő Tóth1, Mohammadhassan Foroughbakhshfasaei, Ádám Jánoska1, Gergely Völgyi1, Zoltán-István Szabó2, Béla Noszál1

1Department of Pharmaceutical Chemistry, Semmelweis University, Budapest , Hungary
Department of Drugs Industry and Pharmaceutical Management, University of Medicine and Pharmacy, Tîrgu Mureș, Romania

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Introduction: Tyrosine kinase inhibitors (TKI) are the drugs of hope in various types of cancer. Being a selective signal transduction therapy, TKIs have a more attractive side effect profile than cytotoxic drugs. In our research four TKIs (erlotinib, lapatinib, gefitinib and vandetanib) were investigated.

Aims: The aims of our study were to determine the physicochemical properties of the investigated TKI, which is crucial to understand the pharmacokinetic behavior at the molecular level, and in order to enhance solubility and bioavailability, inclusion complex formation with cyclodextrins (CDs) were also studied by a number of analytical techniques.

Method: Protonation constants, octanol/water partitions and the intrinsic solubilities of TKIs were determined using various literature methods. TKI–CD interactions were studied by a number of analytical techniques such as 1D and 2D NMR, UV spectroscopy, ESI-MS and phase-solubility.

Results: The highly lipophilic nature of the drugs (logP = 2.75 – 5.65) and extremely low water solubility (S0 = 0.82 nM – 192.3 µM) limit the development of a parenteral formulation. Native α-, β- és γ- and their substituted derivatives were used to determine equilibrial and structural properties of the inclusion complexes. Continuous variation method (Job’s plot) showed a 1:1 stoichiometry for all complexes. The stability constants with native identified that the seven membered β-CD is the most suitable host. The largest binding constants were observed in the case of sulfobutylether-β-CD. The geometry of the complexes was elucidated by 2D ROESY NMR measurements, indicating that the partial molecular encapsulation includes the substituted phenyl ring of TKIs. Phase-solubility analyses show greatly enhanced solution concentration by CD complexation.

Conclusion: The determined equilibrium and structural information offer molecular basis to elaborate improved drug formulation with enhanced bioavailability.

Acknowledgement: This work was supported by the ÚNKP-17-4 New National Excellence Program of The Ministry of Human Capacities (G.T.).

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