Improving Heat Transfer at the Bottom of Vials for Consistent Freeze Drying with Unidirectional Structured Ice

The quality of lyophilized products is dependent of the ice structure formed during the freezing step. Herein, we evaluate the importance of the air gap at the bottom of lyophilization vials for consistent nucleation, ice structure, and cake appearance. The bottom of lyophilization vials was modified by attaching a rectified aluminum disc with an adhesive material. Freezing was studied for normal and converted vials, with different volumes of solution, varying initial solution temperature (from 5°C to 20°C) and shelf temperature (from -20°C to -40°C). The impact of the air gap on the overall heat transfer was interpreted with the assistance of a computational fluid dynamics model. Converted vials caused nucleation at the bottom and decreased the nucleation time up to one order of magnitude. The formation of ice crystals unidirectionally structured from bottom to top lead to a honeycomb-structured cake after lyophilization of a solution with 4% mannitol. The primary drying time was reduced by approximately 35%. Converted vials that were frozen radially instead of bottom-up showed similar improvements compared with normal vials but very poor cake quality. Overall, the curvature of the bottom of glass vials presents a considerable threat to consistency by delaying nucleation and causing radial ice growth. Rectifying the vials bottom with an adhesive material revealed to be a relatively simple alternative to overcome this inconsistency.