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, (HNMR)-H-1 and molecular dynamics (MD) simulations to investigate complex formation of OLN with Heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DM-,beta-CD) and beta-CD and its effect on OLN solubility. pK(a1) and pK(a2) of OLN were found to be 4.79 and 7.72, respectively, both of which underwent a shift by similar to 0.4-0.5 upon complexation with beta-CD, while only pK(a1) exhibited a shift by-0.5 in complex with DM-beta-CD. FT-IR and (HNMR)-H-1 spectra demonstrated the formation of the OLN/DM-beta-CD inclusion complex, with PSDs indicating 1:1 stoichiometry and a complex formation constant for DM-beta-CD greater than for beta-CD. MD simulations and the computed free energies showed that the neutral OLN complexes are more stable than the protonated complexes and the preference of both hosts to include the benzodiazepine moiety. Furthermore, the more favorable AG for DM-beta-CD is in accord with experiment. (c) 2022 Elsevier B.V. All rights reserved.