Morphological and Compressional Mechanical Properties of Freeze-Dried Mannitol, Sucrose, and Trehalose Cakes

A novel mechanical compression test has been developed which allows cake mechanical properties to be assessed quantitatively, and can be applied to fragile and moisture-sensitive freeze-dried (FD) cakes within the vials without sample preparation. FD mannitol, sucrose, and trehalose cakes, prepared from 5% aqueous solutions, exhibited linear compressive elastic behavior for small strains with apparent moduli of 25, 148, and 207 kPa, respectively. These materials exhibited brittle cracking/crushing failure of the cells over a wide strain range, with low crushing stresses from 11 to 31 kPa for 0.15-0.25 strain. This technique is sensitive to differences in freezing conditions for sucrose formulations and the moisture content of sucrose cakes. The test highlights the rapid changes in cake mechanical properties occurring when moisture-sensitive excipients such as sucrose are briefly exposed to ambient humidity. Using established models for the compressive mechanical behavior of closed cellular solids, a method for predicting cell wall thickness is demonstrated. Three FD formulations gave predicted wall thicknesses of 1.1-1.6 μm, consistent with scanning electron microscopy (SEM) images obtained. SEM determined that unit cell dimensions for all formulations were similar and it was concluded that if all other factors were identical, excipient choice plays a minor role in determining the pore shape/morphology.