Guest molecular size-dependent inclusion complexation of parabens with cholic acid by cogrinding

Effects of p-hydroxybenzoate (paraben) ester chain length on the stoichiometry and structure of grinding-induced inclusion complexes with cholic acid (CA) were investigated. Physicochemical properties of the ground mixture were evaluated by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), Fourier transform infrared (FT-IR) spectroscopy, and solid-state nuclear magnetic resonance (NMR) measurements. Ethyl-, n-propyl-, and isopropyl-parabens formed equimolar inclusion complexes with CA, and the complex structures were of the β-trans bilayer type. In contrast, the stoichiometry of the CA-paraben complex was 2:1, and the structure was of the α-gauche bilayer type when isobutylparaben was used as a guest molecule. Although the stoichiometries and structures of the complexes differed, solid-state NMR showed that the molecular states of parabens in the complexes were similar and independent of the ester chain length. Complexes between CA and parabens with longer substituent groups (C >4) were not observed. Steric effects induced by increasing the guest size are likely to influence the overall structure of inclusion complexes. Mechanical forces and thermal activation by grinding were important factors in the mechanism of CA-paraben complex formation.