Product temperature during the primary drying step of freeze-drying is controlled by a set point chamber pressure and shelf temperature. However, recent computational modeling suggests a possible variation in local chamber pressure. The current work presents an experimental verification of the local chamber pressure gradients in a lab-scale freeze-dryer. Pressure differences between the center and the edges of a lab-scale freeze-dryer shelf were measured as a function of sublimation flux and clearance between the sublimation front and the shelf above. A modest 3-mTorr difference in pressure was observed as the sublimation flux was doubled from 0.5 to 1.0 kg·h·m at a clearance of 2.6 cm. Further, at a constant sublimation flux of 1.0 kg·h·m, an 8-fold increase in the pressure drop was observed across the shelf as the clearance was decreased from 4 to 1.6 cm. Scale-up of the pressure variation from lab- to a manufacturing-scale freeze-dryer predicted an increased uniformity in drying rates across the batch for two frequently used pharmaceutical excipients (mannitol and sucrose at 5% w/w). However, at an atypical condition of shelf temperature of +10°C and chamber pressure of 50 mTorr, the product temperature in the center vials was calculated to be a degree higher than the edge vial for a low resistance product, thus reversing the typical edge and center vial behavior. Thus, the effect of local pressure variation is more significant at the manufacturing-scale than at a lab-scale and accounting for the contribution of variations in the local chamber pressures can improve success in scale-up.
The flow physics in the product chamber of a freeze dryer involves coupled heat and mass transfer at different length and time scales. The low-pressure environment and the relatively small flow velocities make it difficult to quantify the flow structure experimentally. The current work presents the three-dimensional computational fluid dynamics (CFD) modeling for vapor flow in a laboratory scale freeze dryer validated with experimental data and theory. The model accounts for the presence of a non-condensable gas such as nitrogen or air using a continuum multi-species model. The flow structure at different sublimation rates, chamber pressures, and shelf-gaps are systematically investigated. Emphasis has been placed on accurately predicting the pressure variation across the subliming front. At a chamber set pressure of 115 mtorr and a sublimation rate of 1.3 kg/h/m, the pressure variation reaches about 9 mtorr. The pressure variation increased linearly with sublimation rate in the range of 0.5 to 1.3 kg/h/m. The dependence of pressure variation on the shelf-gap was also studied both computationally and experimentally. The CFD modeling results are found to agree within 10% with the experimental measurements. The computational model was also compared to analytical solution valid for small shelf-gaps. Thus, the current work presents validation study motivating broader use of CFD in optimizing freeze-drying process and equipment design.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.