Characterization of mitotane (o,p'-DDD)--cyclodextrin inclusion complexes: phase-solubility method and NMR.

Area of Science:

• Pharmaceutical Chemistry
• Drug Delivery Systems
• Medicinal Chemistry

Background:

• Mitotane (o,p'-DDD) is a crucial drug for adrenocortical cancer and Cushing's syndrome.
• Poor aqueous solubility of mitotane leads to low bioavailability, with ~60% excreted unchanged orally.
• Developing soluble formulations is key to enhancing mitotane's therapeutic efficacy.

Purpose of the Study:

• To prepare a soluble mitotane formulation using cyclodextrin complexation.
• To investigate the inclusion mechanism and kinetics of mitotane within methyl-ß-cyclodextrins (DMßCD).
• To assess the potential for improved bioavailability of complexed mitotane.

Main Methods:

• Phase-solubility studies were conducted to quantify mitotane-DMßCD complexation.
• Nuclear Magnetic Resonance (NMR) spectroscopy was employed to confirm inclusion and study dissociation kinetics.
• Comparative analysis with the regioisomer (p,p'-DDD) elucidated the inclusion mechanism.

Main Results:

• Mitotane forms stable 1:1 and 1:2 inclusion complexes with DMßCD, with high association constants (K(1:1) 37,000–85,000 M⁻¹, K(1:2) 5.3–32 M⁻¹).
• NMR confirmed mitotane inclusion within DMßCD, revealing differential dissociation kinetics for ortho- and para-chloro moieties.
• The ortho-chloro group exhibits slow exchange, while the para-chloro group shows fast exchange on the NMR timescale.

Conclusions:

• Methyl-ß-cyclodextrins effectively complex mitotane, forming stable inclusion complexes.
• The complexation significantly enhances mitotane's aqueous solubility, paving the way for improved oral bioavailability.
• Understanding the inclusion mechanism and kinetics provides a basis for optimizing mitotane drug formulations.