Dipyridamole/β-cyclodextrin complexation: effect of buffer species, thermodynamics, and guest–host interactions probed by 1H-NMR and molecular modeling studies

Abstract

The complexation parameters of dipyridamole (Dipy) with β-cyclodextrin (β-CD) were investigated by using several techniques including phase solubility diagrams (PSD), proton nuclear magnetic resonance (1H-NMR), x-ray powder diffractometry (XRPD), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and molecular mechanical modeling (MM+). From the pH-solubility profiles, two basic pKas at 6.4 and 2.7 were estimated. The linear correlation of the free energy of Dipy/β-CD complex formation (ΔG11) with the corresponding free energy of inherent Dipy aqueous solubility (ΔGSo), obtained from the linear variation of ln K11 with that of the inherent Dipy solubility (ln So) at different pHs and ionic strengths, was used to measure the contribution of the hydrophobic character of Dipy to include into the hydrophobic β-CD cavity. Complex formation of Dipy was driven by favorable enthalpy (ΔH° = −14.8 kJ/mol) and entropy (ΔS° = 31.9 J/mol K) factors. 1H-NMR and molecular mechanical modeling studies indicate the formation of different isomeric 1:1 and 1:2 complexes, where both the piperidine and diethanolamine moieties get separately included into the β-CD cavity. Molecular mechanical modeling computations indicate that the dominant driving force for complexation is Van der Waals with lower contribution from electrostatic interactions. 1H-NMR and XRPD, DSC, SEM studies of isolated solid complexes indicate the formation of inclusion complexes in aqueous solution.