Freeze-drying has always been considered an extremely expensive procedure to dehydrate food or pharmaceutical products, and for this reason, it has been employed only if strictly necessary or when the high added value of the final product could justify the costs. However, little effort has been made to analyze the factors that make this technology so unaffordable. In this work, a model was proposed to calculate in detail the operational (OC) and capital costs (CC) of a freeze-drying cycle and an evaluation of the process bottlenecks was made. The main result is that the process itself, contrary to the classic belief, is not the most expensive part of freeze-drying, while the initial investment is the real limiting factor. Under this consideration, the optimization of a freeze-drying cycle should be formulated in order to fit more cycles in the lifespan of the apparatus, instead of merely reducing the power consumption of the machine.

The freezing phenomenon has a dramatic impact on the quality of freeze-dried products. Several freezing models applied to solutions in vials have been proposed to predict the resulting product morphology and describe heat transfer mechanisms. However, there is a lack of detailed experimental observations of the freezing phenomenon in vials in the literature. Thus, the present work offers new experimental observations of the freezing phenomenon in vials by infrared (IR) thermography. IR imaging allowed each vial’s whole axial temperature profile to be collected during freezing, providing significant insights into the process. Spontaneous nucleation and vacuum-induced surface freezing (VISF), as a controlled nucleation technique, are investigated. Batches having vials in direct contact with the shelf (exchanging heat mainly through conduction) as well as suspended (exchanging heat mainly through natural convection and radiation) were tested. The study used three solutions: sucrose 5%, mannitol 5%, and dextran 10%. SEM images coupled with an automated image segmentation technique were also performed to examine possible correlations between the freezing observations and the resulting pore size distributions. IR thermography was found to be a promising tool for experimentally predicting the resulting product morphology in-line.

Infrared-based (IR) thermal imaging data was combined here with mathematical modeling to describe the freezing process of a pharmaceutical formulation being lyophilized using two different loading configurations; (i) vials in direct contact with the shelf and (ii) vials suspended over it. In all the experiments, the nucleation event was trigged at a specific time instant using the vacuum induced surface freezing (VISF) method. The IR thermal data was given as input to three different mathematical models for freezing and used to estimate the resulting cake’s pore size (d p ) distribution. The resulting d p values were then compared to experimental data obtained through SEM images coupled with an image segmentation tool. The supersaturation model showed the best agreement between the estimated d p and experimental values, while minor discrepancies were shown by the other two models. Nonetheless, the outcomes of these last two models, given as inputs to a mathematical model for the primary drying phase, resulted in satisfactory predictions of the product temperature at the moving front, the product resistance to vapor flow, and the primary drying end point. It follows that the combination of the IR thermocamera and freezing modeling is a promising tool for the in-line monitoring and optimization of a freeze-drying cycle.

The nucleation behavior of water is crucial in many fields, spanning meteorology, glaciology, biology, and astrophysics. We here report observations suggesting an effect of diffusion kinetics in water on the nucleation temperature distribution of ice. We performed differential scanning calorimetry analyses of repeated freeze/thaw cycles and investigated the effect of several variables on the regularity of the distributions obtained. We intriguingly observed that the thawing temperature and residence time above 0°C affect the width of the measured distributions. Specifically, conditions of enhanced diffusion translated into broader, more scattered distributions, while conditions of limited diffusion translated into narrower, more regular distributions. We propose a theoretical explanation centered on the temperature dependence of diffusion kinetics in water based on our experimental findings.

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