International Journal of Pharmaceutics 293 (2005) 101–125 Accelerated aging: Prediction of chemical stability of pharmaceuticals Kenneth C. Waterman ∗ , Roger C. Adami Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA Received 8 June 2004; received in revised form 15 December 2004; accepted 15 December 2004 Abstract Methods of rapidly and accurately assessing the chemical stability of pharmaceutical dosage forms are reviewed with re- spect to the major degradation mechanisms generally observed in pharmaceutical development. Methods are discussed, with the appropriate caveats, for accelerated aging of liquid and solid dosage forms, including small and large molecule active pharma- ceutical ingredients. In particular, this review covers general thermal methods, as well as accelerated aging methods appropriate to oxidation, hydrolysis, reaction with reactive excipient impurities, photolysis and protein denaturation. © 2005 Elsevier B.V. All rights reserved. Keywords: Drug stability; Accelerated aging; Hydrolysis; Oxidation; Shelf-life 1. Introduction In the development of pharmaceutical dosage forms, one of the persistent challenges is assuring acceptable stability. While classically stability refers to the abil- ity to withstand loss of a chemical due to decomposi- tion, in the pharmaceutical world, the term “stability” more often refers to the storage time allowed before any degradation product in the dosage form achieves a sufficient level to represent a risk to the patient. Based on this time, the expiration date (shelf-life) of a product ∗ Corresponding author. Tel.: +1 860 715 3492; fax: +1 860 715 1626. E-mail address: ken waterman@groton.pfizer.com (K.C. Waterman). is determined. The allowable level of any given impu- rity will depend on the dose and likelihood of toxicity; however, for most drugs, the allowable levels of a sin- gle impurity permissible without explicit toxicological clinical testing are generally well less than 1% based on the drug. The International Council of Harmoniza- tion (ICH) specifies the amount of impurities allowed to form during product storage (ICH, 2003). The amounts permitted are based on the total daily intake of the drug. The amount of impurity allowed is described as a reporting, identification, or qualification threshold. A reporting threshold is defined as the level that must be reported to regulatory agencies to alert them of the presence of the impurity. An identification threshold is defined as the level that requires chemical identification of the substance. Finally, the qualification 0378-5173/$ – see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.ijpharm.2004.12.013