Industry focus on freeze-drying bottled technology

During the freeze-drying of the drug, the freezing step serves as a critical step to determine the morphology of the frozen material and the final morphology of the freeze-dried material. At the same time, the freezing step is also the most difficult step to control due to the random nature of the nucleation activity during the freezing process. In addition, the freezing step is also a destructive step, resulting in a loss of biological activity of the medicinal protein. The author analyzed some experimental data and mastered the data of ice crystal morphology and sublimation rate obtained when using the standard formulation to stabilize the pharmaceutical protein in the freeze-drying process.
First of all, for different bottle configurations and freezing parameters (ie bottle type <molded bottle or tubular bottle> fill height, bottle size, temperature of the freeze-drying rack), the author analyzed the direct observation with a light microscope in the freezer compartment. The data on the size of ice crystals. It is demonstrated that the ice crystal size distribution depends not only on the freezing rate but also on the size and type of the bottle and the fill height of the bottle. This behavior can be explained by the reduction of the overcooling effect. In general, the undercooling effect can result in a large and heterogeneous ice crystal size distribution, and it has been demonstrated that an appropriate annealing treatment can significantly homogenize and increase the average size of the ice crystals.
Secondly, the authors studied and designed an ultrasound system to control the ice nucleation of standard formulations (mannitol, bovine serum albumin, sucrose) loaded in various bottles. It is demonstrated that the nucleation temperature of the sample can be controlled at a selected predetermined value during supercooling. It was confirmed that ultrasonically controlled nucleation significantly homogenized the ice crystal morphology, thereby accelerating a drying rate during the freeze-drying process.
The analysis shows that in the freeze-drying of drugs, the key factor in optimizing the morphological characteristics of freeze-dried matrices is to control the freezing step, especially to control the nucleation phenomenon. It has been demonstrated that in the freezer compartment, the optical microscope can easily and conveniently exhibit the ice-phase morphology of the frozen substrate by reflection. The morphology of the ice phase is directly related to the rate of sublimation and the final structure of the freeze-dried substrate.
It has been experimentally observed that ultrasonically controlled nucleation can effectively trigger the nucleation process of glass bottles (different sizes and types) equipped with over-cooled standard formulations. The over-cooled standard formulation of this glass bottle is used industrially for freeze-drying of pharmaceutical proteins. Triggering the nucleation temperature of the sample at a set value allows for different overcooling states and different ice crystal growth rates. Moreover, the large number of frozen samples proved that this ultrasonic control can make the ice crystal structure of the frozen samples more uniform, obtaining a more permeable freeze-dried matrix, and ultimately reducing the sublimation time.
The author hopes to develop this system and be able to conduct pilot and industrial applications to improve the freeze-drying cycle quality of drugs.

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