Primary Drying Step Research Articles

Use of soft sensors to monitor a pharmaceuticals freeze-drying process in vials

Purpose: This paper presents a soft sensor that can be effectively used for in-line monitoring of the primary drying step of a pharmaceuticals freeze-drying process in vials.Methods: Process modeling and product temperature measurements are used to estimate the residual amount of ice in the vial and the heat transfer coefficient from the shelf to the product in the vial. The resistance of the dried cake to vapor flow is determined through the heat balance equation at the interface of sublimation. Mathematical simulation and experimental tests have been carried out to validate the estimations provided by the soft sensor.Results: Accurate estimations of the dynamics of the product until the end of primary drying are obtained, as well as of the heat and mass transfer coefficients, even in the case of a highly non-uniform batch. The reduction in the number of variables directly estimated by the soft sensor allows increasing the robustness of the tool with respect to other sensors presented in the literature.Conclusions: The proposed soft sensor is thus effective for process monitoring and it allows using model-based tools for cycle development in lab-scale units, where thermocouples are usually available, and for process monitoring in industrial-scale freeze-dryers, in case wireless sensors are used.

In Situ Monitoring of Proteins during Lyophilization using Micro-Raman Spectroscopy: A Description of Structural Changes induced by Dehydration

Raman investigations were carried out in situ in real time during the lyophilization of three proteins (β-lactoglobulin, bovine serum albumin, and chymotrypsinogen) characterized by different structural properties. Structural changes in the proteins were only and systematically detected after the primary drying step of the lyophilization, through a frequency shift and a general broadening of amide I and III bands. These spectral changes have been interpreted in terms of local disordering related to the distortion of the structural elements induced by ice desorption. Structural changes of the secondary structure were found almost reversible upon rehydration, whereas changes in the solvent accessibility to protein residues are detected and related to the alteration of the tertiary and/or quaternary structures. The influence of the lyophilization parameters, corresponding to different stress conditions, on the degree of protein denaturation has been analyzed.

Freeze-Drying Cycle Optimization Using Model Predictive Control Techniques

The problem of process control in the field of pharmaceutical freeze drying is discussed, and a model predictive control (MPC) system is proposed to control, and optimize, in-line the primary drying step, beside preserving product quality. The controller can provide the optimal recipe for a given product, taking into account process constraints and modeling errors. Two control algorithms are proposed: the former manipulates both the chamber pressure and the temperature of the technical fluid, while the latter manipulates only the temperature of the fluid. The optimal formulation of the algorithms and the tuning of controller parameters are discussed by means of mathematical simulations.

Modeling of freezing step during vial freeze‐drying of pharmaceuticals—influence of nucleation temperature on primary drying rate

AbstractTo optimize the primary drying step of freeze‐drying processes, it is very important to control morphological parameters of the frozen matrix. A mathematical model that simulates temperature profiles during freezing process of standard pharmaceutical formulations was set up and the ice crystal mean sizes were semi‐empirically estimated from the simulated thermal profiles. Then, water vapor mass transfer kinetics during sublimation step was estimated from ice phase morphological parameters. All these numerical data were compared with experimental data and a quite good agreement was observed, which confirmed the adequacy of the present model calculations. It was confirmed that, for a given formulation, the mass transfer parameters during freeze‐drying were strongly dependent on morphological textural parameters, and consequently, on the nucleation temperatures that fix the ice phase morphology. The influence of freezing rates was also predicted from the simulations, proving that an increase of cooling rates led to slower primary drying rates. Copyright © 2010 Curtin University of Technology and John Wiley & Sons, Ltd.