Industry focus on freeze-drying bottled technology
During the freeze-drying process of pharmaceuticals, the freezing step plays a crucial role in determining both the morphology of the frozen material and the final structure of the lyophilized product. However, this step is also one of the most challenging to control due to the unpredictable nature of nucleation during freezing. Additionally, the freezing process can be damaging to biological molecules, such as proteins, potentially reducing their activity. The author has analyzed various experimental data, including ice crystal morphology and sublimation rates, obtained when using standard formulations to stabilize pharmaceutical proteins during freeze-drying.
First, the study examined different bottle configurations and freezing parameters—such as bottle type (molded or tubular), fill height, and bottle size—as well as the temperature of the freeze-drying rack. Using a light microscope, direct observations were made within the freezer compartment to analyze ice crystal size. The results showed that ice crystal size distribution depends not only on the freezing rate but also on the bottle's geometry and fill level. This behavior can be attributed to the reduction of the overcooling effect. Typically, undercooling leads to uneven ice crystal growth, but controlled annealing has been shown to improve homogeneity and increase average crystal size.
Secondly, the authors developed an ultrasound system to regulate ice nucleation in standard formulations, including mannitol, bovine serum albumin, and sucrose, placed in various types of bottles. The experiments demonstrated that the nucleation temperature could be precisely controlled during supercooling. It was found that ultrasonically induced nucleation significantly improved the uniformity of ice crystal formation, which in turn accelerated the drying process during lyophilization.
The analysis highlights that controlling the freezing step—particularly the nucleation process—is essential for optimizing the morphological properties of the freeze-dried matrix. In the freezer compartment, optical microscopes provide a convenient way to observe ice-phase morphology through reflection. The structure of the ice phase directly affects the sublimation rate and the final texture of the dried product.
Experiments have shown that ultrasonically controlled nucleation effectively initiates ice formation in glass bottles with overcooled standard formulations, which are commonly used in industrial freeze-drying of protein-based drugs. By setting a specific nucleation temperature, different levels of supercooling and ice growth rates can be achieved. A large number of frozen samples confirmed that this technique produces more uniform ice structures, resulting in a more permeable lyophilized matrix and ultimately reducing sublimation time.
The author aims to further develop this system for pilot and industrial applications, with the goal of enhancing the quality and efficiency of the freeze-drying cycle for pharmaceutical products.
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