Design-space modeling of rapid-depressurization controlled ice nucleation for pharmaceutical lyophilization

Lyophilization, also known as freeze-drying, is a process commonly used for the preservation of pharmaceutical and food products. Control over ice formation during freezing is essential for optimizing drying efficiency, leading to decreased drying times and lower production cost. Rapid-depressurization controlled ice nucleation (RD-CIN) is a method by which uniform freezing can be induced across large batches of product, thus providing control over the stochastic nature of ice nucleation. In this work, a Computational Fluid Dynamics (CFD) model based on isentropic approximation of rapid-depressurization is implemented to determine the critical process parameters that lead to complete nucleation of product across large batches of pharmaceutical vials. Inputs for the model such as initial discharge pressure, shelf temperature, gas-type, chamber size, and vial size are varied across common laboratory and production scale processes. Response surface maps that predict nucleation are generated from numerical data. The study is validated against experimental results using pure water in standard 2R and 6R vials. Results show that critical process parameters for RD-CIN can be effectively tuned to achieve consistent nucleation, reducing product variability and enabling faster freeze-drying cycles.