Inclusion Complexation of Loratadine with Natural and Modified Cyclodextrins: Phase Solubility and Thermodynamic Studies

Abstract The extent and mode of solubility enhancement exerted by the cyclodextrins (α-, β-, γ-, and HP-β-CDs) on loratadine (Lort) have been experimentally measured under controlled conditions in buffered aqueous solutions. Rigorous nonlinear regression analysis of the phase solubility diagrams obtained in 0.1 mol⋅L−1 phosphate buffer at pH=7.0 and 25 °C revealed the following: neutral Lort (pKa=4.6) tends to form soluble 1:1 and 1:2 Lort/CD complexes with all four of the examined CDs, where complex stability follows the decreasing order β-CD>HP-β-CD>γ-CD>α-CD. The hydrophobic character of Lort constitutes about 66% of the driving force for complex formation whereas specific interactions contribute 11.2 kJ⋅mol−1 towards the stability of the complexes. Thermodynamic studies showed that Lort/CD complex formation was favored by large enthalpic contributions but was impeded by negative entropic changes. Dissolution studies indicate that the dissolution rate of Lort from the freeze-dried Lort/β-CD complex is significantly higher than that of the corresponding physical mixture. Both DSC studies and molecular mechanical modeling of Lort/β-CD interactions were carried out to explore the possible formation of inclusion complexes.

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