title: Characterization of mitotane (o,p'-DDD)--cyclodextrin inclusion complexes: phase-solubility method and NMR.
abstract: Mitotane (o,p'-dichlorodimethyl dichloroethane [o,p'-DDD]) is used for the treatment of adrenocortical cancer and occasionally Cushing's syndrome. This drug is very poorly soluble in water, and following oral administration, approximately 60% of the dose is recovered in the feces unaltered. The preparation of a soluble formulation (i.e. by complexation with cyclodextrins) with improved bioavailability is the aim of this work. The inclusion of mitotane in methyl-ß-cyclodextrins was studied using both phase-solubility methods and NMR experiments. To elucidate the inclusion mechanism, o,p'-DDD was compared to its regioisomer (i.e. p,p'-DDD). It was demonstrated that two dimethyl-ß-cyclodextrins (DMßCD) can complex with the aromatic rings. From the phase-solubility diagrams, we observe that both cases are very different: K(1:1) is between 37 000 and 85 000 mol.l(-1), whereas K(1:2) is between 5.3 and 32 mol.l(-1). The NMR experiments confirmed the inclusion but it also gave an insight into the kinetics of the dissociation: the ortho-chloro moiety is in slow exchange on the NMR time scale, whereas the para-chloro moiety is in fast exchange rate.
authors.affiliation: Équipe CITHEFOR (EA3452), université de Lorraine, 5, rue Albert-Lebrun, 54000 Nancy, France.
authors.forename: R
authors.initials: R
authors.lastname: Alfonsi
authors.forename: D
authors.initials: D
authors.lastname: Attivi
authors.forename: A
authors.initials: A
authors.lastname: Astier
authors.forename: M
authors.initials: M
authors.lastname: Socha
authors.forename: S
authors.initials: S
authors.lastname: Morice
authors.forename: S
authors.initials: S
authors.lastname: Gibaud
mesh_terms: D000465:Algorithms; D000970:Antineoplastic Agents / Q000737:chemistry*; D003505:Cyclodextrins / Q000737:chemistry*; D005612:Freeze Drying; D009682:Magnetic Resonance Spectroscopy; D008939:Mitotane / Q000737:chemistry*; D012995:Solubility
chemical_list: D000970:Antineoplastic Agents; D003505:Cyclodextrins; D008939:Mitotane