title: Effect of cyclodextrin derivation and amorphous state of complex on accelerated degradation of ziprasidone.
abstract: Inclusion complexes of ziprasidone with several β-cyclodextrins [β-CDs; sulfobutylether-β-cyclodextrins (SBEβCD), hydroxypropyl-β-cyclodextrins (HPβCD), methyl-β-cyclodextrins (MβCD), and carboxyethyl-β-cyclodextrins (CEβCD)] 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-SBEβCD salts, and the physical mixture of ziprasidone-SBEβCD 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 SBEβCD and CEβCD, produced the highest oxidative degradation followed by HPβCD with 6, 3, and 4 degrees of substitution. In the solid state, crystalline drug substance and physical mixture of crystalline drug-SBEβCD showed very little to no degradation. In contrast, amorphous βCD, MβCD, CEβCD, and SBEβCD 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.
authors.affiliation: Department of Pharmaceutical Development, Pfizer Global Research and Development, Groton, Connecticut 06340, USA. jinyang.hong@pfizer.com
authors.forename: Jinyang
authors.initials: J
authors.lastname: Hong
authors.forename: Jaymin C
authors.initials: JC
authors.lastname: Shah
authors.forename: Maura D
authors.initials: MD
authors.lastname: Mcgonagle
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D014150:Antipsychotic Agents / Q000737:chemistry* / Q000528:radiation effects; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D003460:Crystallization; D018360:Crystallography, X-Ray; D004339:Drug Compounding; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry*; D005720:Gamma Rays; D006358:Hot Temperature; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D010084:Oxidation-Reduction; D010879:Piperazines / Q000737:chemistry* / Q000528:radiation effects; D033362:Powder Diffraction; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods; D013844:Thiazoles / Q000737:chemistry* / Q000528:radiation effects; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D014150:Antipsychotic Agents; D005079:Excipients; D010879:Piperazines; D013844:Thiazoles; D047392:beta-Cyclodextrins; C517669:carboxyethyl-beta-cyclodextrin; C108732:methyl-beta-cyclodextrin; D000073738:2-Hydroxypropyl-beta-cyclodextrin; C092292:ziprasidone