Effect of Cyclodextrin Derivation and Amorphous State Complex on Accelerated Degradation of Ziprasidone JINYANG HONG, JAYMIN C. SHAH, MAURA D. MCGONAGLE Department of Pharmaceutical Development, Pfizer Global Research and Development, Groton, Connecticut 06340 Received 3 May 2010; revised 21 December 2010; accepted 21 December 2010 Published online 31 January 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.22498 ABSTRACT: Inclusion complexes of ziprasidone with several $-cyclodextrins[$-CDs; sulfobutylether-$-cyclodextrins (SBE$CD), hydroxypropyl-$-cyclodextrins (HP$CD), methyl-$- cyclodextrins (M$CD), and carboxyethyl-$-cyclodextrins (CE$CD)] were prepared and solution stability was evaluated at elevated temperature. Solid-state stability was assessed by subject- ing various CD complexes of ziprasidone, spray-dried dispersion (SDD), partially crystalline ziprasidone–SBE$CD salts, and the physical mixture of ziprasidone–SBE$CD to (-irradiation. Degradant I was formed by oxidation of ziprasidone, which upon aldol condensation with ziprasi- done formed degradant II in both solution and solid states. In the solution state, CD complexes with electron-donating side chains, such as SBE$CD and CE$CD, produced the highest oxida- tive degradation followed by HP$CD with 6, 3, and 4 degrees of substitution. In the solid state, crystalline drug substance and physical mixture of crystalline drug–SBE$CD showed very lit- tle to no degradation. In contrast, amorphous $CD, M$CD, CE$CD, and SBE$CD 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 chemicalnature of the side chain on CD.© 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:2703–2716, 2011 Keywords: chemicalstability; cyclodextrin;complexation;kinetics; oxidation;solid-state NMR INTRODUCTION Cyclodextrin (CD) has been used in pharmaceuti- cal formulation as a solubilizer for drug molecules with low aqueous solubility. CD, with its hydrophobic cavity and hydrophilic exterior, effectively complexes with many lipophilic compoundsand thereby in- creases the aqueous solubility of these compounds. 1–4 Many chemical modifications have been made on CD’s basic structure to improve its ability to maximize solubility both in food and drug industry applica- tions. Many of these modifications involve the intro- duction of hydrophilic side chains to the exterior of CD. 3–4 Some noticeable examples of modified CDs are hydroxypropyl-$-CD (HP$CD) and sulfobutylether-$- CD (SBE$CD). 3 Correspondence to: Jinyang Hong (Telephone: 860-715-1678; E-mail: jinyang.hong@pfizer.com) Journal of Pharmaceutical Sciences, Vol. 100, 2703–2716 (2011) © 2011 Wiley-Liss, Inc. and the American Pharmacists Association In addition to solubilization, CD complexation has been claimed to stabilize drug by protecting the molecule in the CD cavity and preventing access of reactive species such as water in hydrolysis of aspirin. 5 Jarho et al. 6 reported that the deacetyla- tion of spironolactone in CD complex is pH and CD dependent, shedding light on the catalytic capability of derivatized CD on drug degradation. However, the effects of side-chain electronic and/or steric catalytic or protective effect on reaction rate of the complexed drug have not been studied systematically. Cyclodextrin complexation could affect drug moleculesin many profound ways. When a drug molecule is complexed in the CD cavity,the phys- ical environment is fundamentally different from either its native crystalline solid state or its simple solvated state in solution. In addition, complexation restricts freedom ofthe bound molecule compared with the bulk drug in solution, and with side chains in a strategic position on CD that can facilitate the JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 7, JULY 2011 2703