Vial breakage during freeze‐drying: Crystallization of sodium chloride in sodium chloride‐sucrose frozen aqueous solutions

The purpose of this study was to evaluate sodium chloride‐sucrose frozen solutions with regard to sodium chloride crystallization and vial strain. Sodium chloride‐sucrose solutions were studied using Differential Scanning Calorimetry (DSC) and a strain gauge instrumented vial. The sodium chloride concentration was varied with a fixed concentration of sucrose to identify a composition where crystallization was observed during heating and this composition was examined using the strain‐gauged vials. DSC heating thermograms of a 1:1 (w/w) ratio of sodium chloride–sucrose solution show a sodium chloride crystallization exotherm at approximately −45°C. Examination of this composition in a strain‐gauged vial shows an increase in strain, which corresponds to the temperature of the exotherm. Vial breakage is a phenomenon reported for mannitol containing solutions, which is associated with crystallization of mannitol in frozen solution. These data also suggest that vial strain and breakage is associated with the crystallization of solutes and the crystallization of water, which is released from the amorphous phase to form ice, and volume expansion. The results demonstrate the importance of understanding effect of excipient ratios, specifically in systems containing crystallizing and non‐crystallizing excipients, and thermal history when developing freeze‐dried formulations. © 2007 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 1848–1853, 2007