17-β-Estradiol—β-Cyclodextrin complex as an aqueous solution: Structural and physicochemical characterization supported by MM and QM calculations

• Published in: Journal of molecular structure Vol. 1313; p. 138710
• Main Authors: Mazurek, Anna Helena, Szeleszczuk, Łukasz, Bethanis, Kostas, Christoforides, Elias, Dudek, Marta Katarzyna, Wielgus, Ewelina, Pisklak, Dariusz Maciej
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 05.10.2024
• Subjects: Complex stability constant; Cyclodextrin; DFT calculations; Estradiol; Cyclodextrin; Complex stability constant; Estradiol; DFT calculations
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2024.138710

•HRMS studies confirm estradiol:β-cyclodextrin complex molar ratio to be 1:2.•Estradiol:β-cyclodextrin complex stability constant has been determined.•MD-MMGBSA simulations predict molar ratio and stability constant of the complex.•Quantum Chemical calculations of complex structures are assessed. 17-β-estradiol (EST) is an Active Pharmaceutical Ingredient characterized by a low water solubility. Complexation with β-cyclodextrin (βCD) enhances its bioavailability, hence such complex is an interesting research object from pharmaceutical point of view. However, basic facts like description of complex's structure and definition of its molar ratio, were debatable already for decades. This work for the first time justifies the EST:βCD molar ratio as 1:2 using the HRMS (high-resolution mass spectrometry) and phase solubility studies. The latter are used to define complex stability constant, as well. The structure and stability is analyzed using a variety of computational approaches: Quantum Mechanics (QM) based methods (DFT, semiempirical approaches) and MD/MMGBSA approach. In case of the QM, for the first time in the computational analysis of cyclodextrin complexes, a thorough benchmarking test is presented. Different computational parameters (solvent model, presence/absence of dispersion correction etc.) are used. Obtained results are compared with the experimental data. [Display omitted]