ABSTRACT
Inclusion complexes of ziprasidone with several ß-cyclodextrins [ß-CDs; sulfobutylether-ß-cyclodextrins (SBEßCD), hydroxypropyl-ß-cyclodextrins (HPßCD), methyl-ß-cyclodextrins (MßCD), and carboxyethyl-ß-cyclodextrins (CEßCD)] were prepared and solution stability was evaluated at elevated temperature. Solid-state stability was assessed by subjecting various CD complexes of ziprasidone, spray-dried dispersion (SDD), partially crystalline ziprasidone-SBEßCD salts, and the physical mixture of ziprasidone-SBEßCD to γ-irradiation. Degradant I was formed by oxidation of ziprasidone, which upon aldol condensation with ziprasidone formed degradant II in both solution and solid states. In the solution state, CD complexes with electron-donating side chains, such as SBEßCD and CEßCD, produced the highest oxidative degradation followed by HPßCD with 6, 3, and 4 degrees of substitution. In the solid state, crystalline drug substance and physical mixture of crystalline drug-SBEßCD showed very little to no degradation. In contrast, amorphous ßCD, MßCD, CEßCD, and SBEßCD complexes as well as the amorphous SDD exhibited greatest extent of oxidative degradation. Results suggest that electron-donating side chains of the derivatized CD interact with transition state of the oxidation reaction and catalyze drug degradation in solution, However, higher mobility in the amorphous state of CD-drug complexes promoted chemical instability of ziprasidone under accelerated conditions irrespective of the chemical nature of the side chain on CD.
