1. Collapse
Cause: This is a phenomenon that occurs in amorphous solids when the product reaches a temperature above the collapse temperature Tc (close to the glass transition temperature Tg). The amorphous phase of the solid undergoes internal movement without reaching the melting point, resulting in the breakage or collapse of the freeze-dried cake.
Solution: Keep the product temperature below the collapse temperature during the primary drying stage (when there is still ice in the product). Avoid forming on the top of the surface.
2. Melt-back
Cause: This happens when the primary drying stage ends, but there is still ice at the bottom of some vials. During the secondary drying process, the remaining ice cannot be removed. When the process ends, this ice that has not been properly removed will melt and wet the dried product, forming some voids.
Solution: Set a longer primary drying time. Increase the safety time between primary and secondary drying.
3. Wall climbing
Cause: When the primary drying starts, parts of the unfrozen product boil, burst and stick to the inner sidewalls of the vials from the top layer, and the temperature of the sidewalls is lower than that of the product.
Solution: Add an annealing step for heat treatment. Use components that prevent the product from migrating to the top layer.
4. Separation
Cause: When the solid concentration in the product solution is low, a reduction in the lyophilized mass may occur, as a result of which the lyophilized cake falls off the inner wall of the vial and some cracking may occur.
Solution: Increase the concentration of the components, the concentration of the solids, to obtain a more consistent lyophilized product.
5. Inhomogeneity
Cause: This occurs when the product concentration is too low or the product undergoes a very fast freezing step and the product contains a low concentration of a substance such as mannitol.
The concentration of the substance can also be increased.
6. Cracked bottom of the vial
Cause: Recrystallization occurs during freezing, mainly in amorphous products, and the volume of the lyophilized cake increases. In addition, in concentrated solutions, if too much energy is applied to the product at the beginning of primary drying, the air pressure acting on the bottom of the vial may also increase.
Solution: Cool the product and prefreeze slowly to promote the formation of larger and dendritic ice crystals, or add an annealing step of heat treatment, and finally cool slowly before starting the primary drying, applying heat smoothly to facilitate the flow of water vapor from the bottle. Use thicker vials or higher quality vials.
7. Shrinkage
Cause: If the freeze-drying cycle ends but the product still has a high percentage of residual moisture, or if the bottle is filled with humid air, the freeze-dried cake may shrink due to the absorption of moisture from the atmosphere in the bottle.
Solution: Make sure that the drying phase of the entire freeze-drying cycle has been completed correctly. Pre-degassing before corking with dry nitrogen.
8. Puffing (full boiling)
Cause: Overheating causes natural melting of the product. The product may flow to the outside of the vial. This may also be because the bottle has been closed with an incorrect cork at the beginning of the cycle.
Solution: Reduce heat input in the first stage of primary drying and increase the time of the step. At the same time, control the vacuum level.
9. Top crust
Cause: When micro-boiling occurs on the top layer, an impermeable surface layer is formed, which blocks the path of the sublimation vapor flow. The root cause is insufficient freezing, and the product spontaneously concentrates on the top layer due to the influence of freezing concentration or slow evacuation of the freeze-drying chamber during the vacuum stage.
Solution: Apply high freezing rates appropriately. Evacuate the freeze-drying chamber as quickly as possible. Perform primary drying at low temperatures and sublimation rates so that water vapor can be discharged through the formed surface layer.