Host–Guest Interactions of Risperidone with Natural and Modified Cyclodextrins: Phase Solubility, Thermodynamics and Molecular Modeling Studies |
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Authors: | M I El-Barghouthi N A Masoud J K Al-Kafawein M B Zughul A A Badwan |
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Institution: | (1) Department of Chemistry, The Hashemite University, P.O. Box 150459, Zarqa, 13115, Jordan;(2) Department of Chemistry, University of Jordan, Amman, Jordan;(3) Jordanian Pharmaceutical Manufacturing Company, Naor, Jordan |
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Abstract: | The solubility of risperidone (Risp) in aqueous buffered cyclodextrin (CD) solution was investigated for α-, β-, γ- and HP-β-CD. The effects of pH, ionic strength and temperature on complex stability were also explored. Neutral Risp tends to form
higher order complexes (1:2) with both β- and HP-β-CD, but only 1:1 type complexes with α-, and γ-CD. The tendency of Risp to complex with cyclodextrins is in the order β-CD > HP-β-CD > γ-CD > α-CD. The 1:1 complex formation constant of Risp/HP-β-CD increases with increasing ionic strength in an opposite trend to the inherent solubility (S
0) of Risp, thus indicating significant hydrophobic effect. The hydrophobic effect contributes to the extent of 72% towards
neutral Risp/HP-β-CD complex stability, while specific interactions contribute only 4.7 kJ/mol. Thermodynamic studies showed that 1:1 Risp/HP-β-CD complex formation is driven by a favorable enthalpy change (ΔH
0=−31.2 kJ/mol, ΔS
0=−7 J/mol.K) while the 1:2 complex is largely driven by entropy changes (ΔH
0=−5.0 kJ/mol, ΔS
0=42 J/mol.K). Complex stability was found to vary with pH, with a higher formation constant for neutral Risp. Molecular mechanical
computations using MM (atomic charges and bond dipole algorithms) and Amber force fields, which were carried out to explore
possible sites of interactions between Risp and CDs and to rationalize complex stoichiometry, produced similar results concerning
optimal inclusion complex geometries and stoichiometries. |
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Keywords: | binding constants complex geometries complexation thermodynamics cyclodextrins inclusion complexes molecular mechanical modeling risperidone |
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