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.
Purpose
Present (i) an infrared (IR)-based Process Analytical Technology (PAT) installed in a lab-scale freeze-dryer and (ii) a micro freeze-dryer (MicroFD®) as effective tools for freeze-drying design space calculation of the primary drying stage.
Methods
The case studies investigated are the freeze-drying of a crystalline (5% mannitol) and of an amorphous (5% sucrose) solution processed in 6R vials. The heat (Kv) and the mass (Rp) transfer coefficients were estimated: tests at 8, 13 and 26 Pa were carried out to assess the chamber pressure effect on Kv. The design space of the primary drying stage was calculated using these parameters and a well-established model-based approach. The results obtained using the proposed tools were compared to the ones in case Kv and Rp were estimated in a lab-scale unit through gravimetric tests and a thermocouple-based method, respectively.
Results
The IR-based method allows a non-gravimetric estimation of the Kv values while with the micro freeze-dryer gravimetric tests require a very small number of vials. In both cases, the obtained values of Kv and Rp, as well as the resulting design spaces, were all in very good agreement with those obtained in a lab-scale unit through the gravimetric tests (Kv) and the thermocouple-based method (Rp).
Conclusions
The proposed tools can be effectively used for design space calculation in substitution of other well-spread methods. Their advantages are mainly the less laborious Kv estimation process and, as far as the MicroFD® is concerned, the possibility of saving time and formulation material when evaluating Rp.
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.
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