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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: K1:1 is between 37 000 and 85 000mol.l−1, whereas K1:2 is between 5.3 and 32mol.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.
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https://hal.univ-lorraine.fr/hal-01290439
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Submitted on : Friday, March 18, 2016 - 10:39:18 AM
Last modification on : Friday, November 20, 2020 - 9:46:03 AM

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R. Alfonsi, D. Attivi, A. Astier, Marie Socha, S. Morice, et al.. Characterization of mitotane (o,p′-DDD) – cyclodextrin inclusion complexes: Phase-solubility method and NMR. Annales Pharmaceutiques Françaises, Elsevier Masson, 2013, 71 (3), pp.186-92. ⟨10.1016/j.pharma.2013.02.001⟩. ⟨hal-01290439⟩

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