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612814 
Journal Article 
Application of a two-state kinetic model to the heterogeneous kinetics of reaction between cysteine and hydrogen peroxide in amorphous lyophiles 
Luo, D; Anderson, BD 
2008 
Yes 
Journal of Pharmaceutical Sciences
ISSN: 0022-3549
EISSN: 1520-6017 
97 
9 
3907-3926 
The bimolecular reaction between cysteine (CSH) and hydrogen peroxide (H2O2) in amorphous PVP and trehalose lyophiles has been examined at different reactant and excipient concentrations and at varying pH and temperature. Initial rates of product formation and complete reactant and product concentration-time profiles were generated by HPLC analyses of reconstituted solutions of lyophiles stored for various periods of time. While only cystine (CSSC) forms in aqueous solutions, cysteine sulfinic (CSO2H) and sulfonic (CSO3H) acids are significant degradants in amorphous solids. The formation of alternative degradants was consistent with the solution reaction mechanism, which involves a reactive sulfenic acid (CSOH) intermediate, coupled with the restricted mobility in the amorphous solid-state, which favors reaction of CSOH with the smaller, mobility-advantaged H2O2 over its reaction with cysteine. Complex rate laws (i.e., deviations from 1st order for each reactant) observed in initial rate studies and biphasic concentration-time profiles in PVP were successfully fitted by a two-state kinetic model assuming two reactant populations with different reactivities. The highly reactive population forms CSSC preferentially while the less reactive population generates primarily sulfinic and sulfonic acids. Reactions in trehalose could be described by a simple one-state model. In contrast to the reaction in aqueous solutions, the ‘pH’ effect was minimal in amorphous solids, suggesting a change in the rate-determining step to diffusion control for the model reaction occurring in amorphous lyophiles. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:3907–3926, 2008 [ABSTRACT FROM AUTHOR] Copyright of Journal of Pharmaceutical Sciences is the property of Wiley-Liss, Inc., A Wiley Company and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts) 
CHEMICAL kinetics; REACTIVITY (Chemistry); HYDROGEN peroxide; CYSTEINE proteinases; FREEZE-drying; ACIDS; amorphous solids; cysteine; heterogeneous kinetics; lyophilization; poly(vinylpyrrolidone); solid-state kinetics; thiol oxidation; trehalose