An experimental technique is presented to determine independently shrinkage and cracking in lyophilized amorphous cakes based on photographic imaging of their top surface. An inverse correlation between cake shrinkage and cracking during freeze-drying is seen. Shrinkage relaxes the drying tension and gives little cracking, whereas if shrinkage is restrained then more cracking occurs. A lower shrinkage and greater cracking with higher disaccharide concentration correlates with change in cake hardness and brittleness. Adhesion of the cake to the inside vial wall could not be identified as a determining factor for shrinkage. Shrinkage is non-uniform across the cake's surface and is manifested largely in the peripheral region. A correlation between shrinkage and w_g′ for different disaccharides suggests that drying tension develops as non-frozen water is lost from the porous solid after sublimation of the ice phase has exposed the solid/gas interface. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:155–164, 2015

The importance of cake adhesion to the inside vial wall during lyophilization of amorphous trehalose cakes was determined by using hydrophobized vials. The degrees of cake shrinkage and cracking were determined independently by photographic imaging of the cake top surface in a dark cell. Additionally, measurements with microcomputed tomography were performed. Adhesion is found to be a determining factor in both cake shrinkage and cracking. The correlation between cake detachment from the vial inner wall and trehalose concentration indicates that adhesion of the frozen solute phase is a determining factor in shrinkage. The hydrophobized vials give reduced cracking at trehalose concentrations of up to 15%. The reduced wetting of the hydrophobized inside vial wall gives a planar cake topography with a uniform distribution of cracks within the cake. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:2040–2046, 2015

An F(ab’)₂ fragment of an IgG has been spray-dried on a bench-top machine to examine the presence of insoluble particulates in the redissolved powder product. Preliminary experiments showed that treatment of the F(ab’)₂ in aqueous solution in a water bath at 65°C for 1 h produced fragmentation and also insoluble particulates, but no alteration in soluble aggregates. On spray drying, there was, however, no fragmentation but rather formation of soluble aggregates and insoluble particulates. There is therefore a strong difference between isothermal heat-induced damage in solution and during spray drying. The insoluble particulates were detected using a particle counter as a number distribution that was converted to a weight distribution. Addition of trehalose to the liquid feed strongly reduced the formation of the insoluble particulates, indicating that these are insoluble aggregates of the protein and not particulate contamination from the spray dryer. Trehalose (100 mM) was required to suppress formation of the insoluble aggregates, whereas 10 mM was sufficient to prevent formation of soluble aggregates. The particle counter and also isoelectric focusing gave consistent detection of the insoluble particles, whereas photon correlation spectroscopy gave inconsistent results. Spray-drying of small volumes of liquid feed on the bench-top scale can be performed without introducing nonproteinaceous insoluble particulates. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1021–1031, 2014

A single-droplet acoustic levitator was used to determine the drying rate and the kinetics of inactivation of glutamate dehydrogenase in the presence of added trehalose or sorbitol. The solution was also spray dried under the same process condition of drying gas temperature on a bench-top machine. Both trehalose and sorbitol delay the point of onset of enzyme inactivation which lies after the critical point of drying. Both carbohydrates also reduce the apparent rate constant of inactivation calculated during the subsequent inactivation phase. The carbohydrates stabilise, therefore, the enzyme during droplet drying and particle formation mainly during the falling rate drying period. There is no difference between the stabilising effects of the two carbohydrates when examined as levitated single droplets. This suggests the importance of water replacement as a stabilising mechanism in the levitated droplets/particles. On spray drying, the trehalose stabilises the enzyme better than does the sorbitol at a drying gas (outlet) temperature of 60°C. This suggests glass formation with the trehalose but not the sorbitol during the very rapid drying process of small-atomised droplets in the spray dryer. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:4268–4273, 2013