Astemizole/Cyclodextrin Inclusion Complexes: Phase Solubility, Physicochemical Characterization and Molecular Modeling Studies

• Published in: Journal of solution chemistry 2008-06, Vol.37 (6), p.875-893
• Main Authors: Al Omari, Mahmoud M., Zughul, Mohammad B., Davies, J. Eric D., Badwan, Adnan A.
• Format: Article
• Language: English
• Subjects: Chemistry; Chemistry and Materials Science; Condensed Matter Physics; Exact sciences and technology; General and physical chemistry; Geochemistry; Industrial Chemistry/Chemical Engineering; Inorganic Chemistry; Oceanography; Physical Chemistry; Solutions
• ISSN: 0095-9782; 1572-8927
• DOI: 10.1007/s10953-008-9277-z

Guest–host interaction of astemizole (Astm) with cyclodextrins (CDs) has been investigated using phase solubility diagrams (PSD), differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), proton nuclear magnetic resonance ( 1 H-NMR) and molecular mechanical modeling (MM + ). Estimates of the complex formation constant, K 11 , show that the tendency of Astm to complex with CDs follows the order: β -CD>HP- β -CD> γ -CD, α -CD. 1:1 Astm/ β -CD complex formation at pH=5.0 was largely driven by the hydrophobic effect (desolvation), which was quantitatively estimated at −16.5 kJ⋅mol −1 , whereas specific interactions contribute only −5.3 kJ⋅mol −1 to 1:1 complex stability (Δ G 11 o =−22.7 kJ⋅mol −1 ). The percentage contributions of the hydrophobic effect and specific interactions were therefore 73 and 27%, respectively. Both enthalpic and entropic factors contribute equally well (−11 kJ⋅mol −1 each) to 1:1 Astm/ β -CD complex stability. 1 H-NMR and MM + molecular modeling studies indicate the formation of different isomeric 1:1 and 1:2 complexes. The dominant driving force for complexation is evidently van der Waals with very little electrostatic contribution. PSD, 1 H-NMR, DSC, XRPD and MM + studies proved the formation of inclusion complexes in solution and the solid state.