Physicochemical characterisation and cyclodextrin complexation of erlotinib

Abstract

Erlotinib (ERL), the anticancer drug of poor bioavailability, was quantified in terms of bio-relevant physicochemical parameters, such as acid–base properties, lipophilicity and solubility, and a comprehensive study on its inclusion complexation was carried out. The protonation constant of ERL (log K = 5.32) indicates that it exists mainly in deprotonated form at the pH of blood plasma. The high lipophilicity (log p = 2.75) explains its good permeability, while the very low solubility (S₀ = 12.46 μM) causes its low bioavailability and renders injection formulation a difficult job. This problem could be alleviated by enhancing ERL solubility through cyclodextrin (CD) inclusion complexation. Therefore, ERL–CD interactions were studied by a number of analytical techniques. The apparent stability constants of ERL with seven different CDs were determined using affinity capillary electrophoresis. Results indicated that the seven-membered β-CD and its derivatives were the most suitable hosts. Using UV Job plot titration 1:1 stoichiometry was determined, confirmed by electrospray ionisation-mass spectrometry experiments. The geometry of the inclusion complex was investigated by 2D ROESY NMR techniques, revealing that the ethynylphenyl ring enters the β-CD cavity. Phase-solubility analysis shows greatly enhanced solution concentration by CD complexation. The determined equilibrium and structural information offer molecular basis to elaborate improved drug formulation with enhanced bioavailability.

Keywords:

• Tarceva^®
• inclusion complex
• solubility
• cyclodextrin
• ROESY

Acknowledgement

This paper was published under the frame of European Social Fund, Human Resources Development Operational Programme 2007–2013, project number POSDRU/159/1.5/S/136893.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the frame of European Social Fund, Human Resources Development Operational Programme 2007–2013, [project number POSDRU/159/1.5/S/136893].