Heptakis (2, 6-di-O-methyl)-?-CD as a host of olanzapine: Experimental and computational study

Olanzapine (OLN) is an atypical antipsychotic drug used for the treatment of schizophrenia and bipolar depression which suffers from low aqueous solubility. We employ phase solubility diagrams (PSDs), pH-dependent UV absorption profiles, FT-IR, 1HNMR and molecular dynamics (MD) simulations to investigate complex formation of OLN with Heptakis(2,6-di-O-methyl)-?-cyclodextrin (DM-?-CD) and ?-CD and its effect on OLN solubility. pKa1 and pKa2 of OLN were found to be 4.79 and 7.72, respectively, both of which underwent a shift by ?0.4?0.5 upon complexation with ?-CD, while only pKa1 exhibited a shift by -0.5 in complex with DM-?-CD. FT-IR and 1HNMR spectra demonstrated the formation of the OLN/DM-?-CD inclusion complex, with PSDs indicating 1:1 stoichiometry and a complex formation constant for DM-?-CD greater than for ?-CD. MD simulations and the computed free energies showed that the ?