Measurement of shrinkage and cracking in lyophilized amorphous cakes. Part IV: Effects of freezing protocol

The shrinkage and cracking of pure trehalose cakes during lyophilization has been determined quantitatively using different protocols for the freezing step. The influences of shelf cooling rate and of a two-step freezing protocol with holding and annealing phases were investigated. A small change in the shelf cooling rate from 0.4°C to 0.2°C per minute produced surprisingly large increases in shrinkage and reductions in cracking over all trehalose concentrations up to 30% w/v. The two-step freezing protocol also increased shrinkage and reduced cracking in the final-product cakes, especially at trehalose concentrations ≥ 15% and with large vial fill height. A combination of two-step freezing with use of TopLyo vials produced less than 1.5% cracking even at high trehalose concentrations and large fill height. The results give further confirmation of the causal linkage of shrinkage and cracking during lyophilization, and also illustrate how cracking can be greatly reduced by manipulating the freezing protocol.