A new mathematical model for monitoring the temporal evolution of the ice crystal size distribution during freezing in pharmaceutical solutions.

The freezing step plays a key role in the overall economy of the vacuum freeze-drying of pharmaceuticals, since the nucleation and crystal growth kinetics determine the number and size distribution of the crystals formed. In this work, a new mathematical model of the freezing step of a (bio)pharmaceutical solution is developed and validated. Both nucleation and crystal growth kinetics are modeled and included in a one-dimensional population balance (1D-PBM) that describes, given the product temperature measurement, the evolution of the pore size distribution during freezing. The developed model is coupled with the real-time measurements obtained from an infrared video camera. The ending time of the primary drying stage, and the maximum temperature inside the material, simulated through a simplified model of the process and the pore distribution forecast, resulted in good agreement with experimental values. The resulting Process Analytical Technology (PAT) has the potential to boost the development and optimization of a freeze-drying cycle and the implementation of a physically grounded Quality-by-Design approach in the manufacturing of pharmaceuticals. A more general mathematical model, including the aforementioned population balance, of a vial filled with a solution of sucrose was also developed and used to further validate the approach.

Monitoring of the freezing stage in a freeze-drying process using IR thermography.

This paper presents a new Process Analytical Technology based on the use of an infrared camera and a mathematical model to estimate the ice crystal size distribution obtained at the end of the freezing stage of a vial freeze-drying process. Both empirical laws and first-principle based equations, already presented in the Literature, may be used to this purpose, if the temperature gradient in the frozen product and the freezing front rate are obtained from the analysis of the thermal images. The resistance of the dried product to vapor flux may be then calculated from the distribution of the ice crystal diameters, thus enabling the use of a one-dimensional model for process simulation and optimization. Freeze-drying of 5% and 10% w/w aqueous sucrose solutions, and of 5% w/w aqueous mannitol solutions, were considered as case study. The results were validated comparing the calculated diameters of the pores of the dried cake, corresponding to the ice crystal diameters, with the results experimentally obtained from the analysis of the SEM images, and comparing the values of drying duration and maximum product temperature calculated with the mathematical model with those measured experimentally. Results evidences the effectiveness of the proposed system for process monitoring.

On the Use of Infrared Thermography for Monitoring a Vial Freeze-Drying Process.

Monitoring a vial freeze-drying process without interfering with product dynamics is a challenging issue. This article presents a novel device constituted by an infrared camera designed to be placed inside the drying chamber, able to monitor the temperature of the vials, very close to that of the product inside. By this way it is possible to estimate the ending point of the primary drying, the heat transfer coefficient to the product (Kv), and the resistance of the dried product to vapor flux (Rp). Experiments were carried out in a pilot-scale freeze-dryer, processing 5% and 10% sucrose solutions at different values of shelf temperature and chamber pressure, using both thermocouples and the IR camera to track product dynamics. Results evidence that the measurements (of temperature) and the estimates (of the ending point of the main drying and of Kv and Rp) obtained using the 2 systems are very close, thus validating the IR camera as an effective process analytical technologies for the freeze-drying process. Besides, it was shown that the presence of the IR camera in the chamber is not responsible for any additional heating to the product and that monitored vials are representative of the majority of the vials of the batch.

On the effect of ultrasound-assisted atmospheric freeze-drying on the antioxidant properties of eggplant.

The low operating temperatures employed in atmospheric freeze-drying permits an effective drying of heat sensitive products, without any impairment of their quality attributes. When using power ultrasound, the drying rate can be increased, thus reducing the process duration. However, ultrasound can also affect the product quality. The aim of this study was to evaluate the effect of various drying process variables, namely air temperature and velocity, ultrasound power and sample size, on the antioxidant properties of eggplant (Solanum melongena L.) samples. For this reason, drying experiments were carried out at different drying temperatures (-5, -7.5, -10 °C), power ultrasound levels (0, 25, 50 W; 21.9 kHz) and air velocities (2, 5 m s-1) using different sample sizes (8.8 mm and 17.6 mm cube side). The ascorbic acid content (Jagota and Dani method), total phenolic content (Folin-Ciocalteau method), and the antioxidant capacity (FRAP method) of the dried products were considered as quality indicators of the dried samples. The increase in air velocity and temperature, as well as the sample size, significantly reduced the antioxidant potential of the dried samples (p-value < .05). For a given sample size, the application of ultrasound, at the acoustic power levels tested, did not produce significant effects on the antioxidant indicators considered. Temperature measurements inside the drying sample showed a non-negligible temperature rise when acoustic power was applied.