Inclusion complexes of pyrimethamine in 2-hydroxypropyl-β-cyclodextrin: Characterization, phase solubility and molecular modelling

A 1:1 inclusion complex of pyrimethamine with hydroxypropyl β-cyclodextrin was prepared, characterized and modelled by AM1 method. Phase solubility and stoichiometry of the system were carried out by standard methods. The inclusion complexation of pyrimethamine in 2-hydroxypropyl-β-cyclodextrin has been investigated by 2D 1H NMR, FTIR and UV/visible spectroscopy and also by molecular modelling methods (AM1, PM3, MM3). From the phase-solubility diagram a linear increase was observed in pyrimethamine aqueous solubility in the presence of 2-hydroxypropyl-β-cyclodextrin, evidencing the formation of a soluble inclusion complex. According to the continuous variation method (Job’s plot) applied to fluorescence measurements, a 1:1 stoichiometry has been proposed for the complex. Concerning the structure of the complex, a Cl-in orientation of pyrimethamine in the 2-hydroxypropyl-β-cyclodextrin cavity has been proposed from the theoretical calculations, being confirmed by two-dimensional 1H NMR spectroscopy (ROESY). The thermal behaviour has also been studied, providing complementary evidences of complex formation.