Guest-host interactions of haloperidol (Halo) with β-cyclodextrin (β-CD) have been investigated 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 an analysis of the PSDs, both protonated and neutral Halo (pK a=8.5) form soluble 1:1 and 1:2 Halo/β-CD complexes, while the insoluble complex has 1:2 (Halo:β-CD) stoichiometry (BS-type PSD). Ionization of Halo reduces its tendency to complex with β-CD, where the protonated species at pH=4.6 and 6.0 have K 11 values of 100 L⋅mol−1 and 298 L⋅mol−1, respectively, compared with 2000 L⋅mol−1 for neutral species at pH=10.6. The hydrophobic character of Halo was found to provide 32% of the driving force for complex stability, whereas other factors including specific interactions contribute −15 kJ⋅mol−1.
1H-NMR and MM+ studies indicate the formation of isomeric 1:1 and 1:2 complexes, where the chlorophenyl, flurophenyl, piperidine and butanone moieties become included into separate β-CD cavities. The dominant driving force for complexation is evidently van der Waals with very little electrostatic contribution. PSD, 1H-NMR, XRPD, DSC and SEM studies indicate the formation of inclusion complexes in solution and in the solid state.