Dynamic modeling of the secondary drying stage of freeze drying reveals distinct desorption kinetics for bound water

The pharmaceutical industry is progressing toward the development of more continuous manufacturing techniques. At the same time, the industry is striving toward more process understanding and improved process control, which requires the implementation of process analytical technology tools (PAT). For the purpose of drying biopharmaceuticals, a continuous spin freeze-drying technology for unit doses was developed, which is based on creating thin layers of product by spinning the solution during the freezing step. Drying is performed under vacuum using infrared heaters to provide energy for the sublimation process. This approach reduces drying times by more than 90% compared to conventional batch freeze-drying. In this work, a new methodology is presented using near-infrared (NIR) spectroscopy to study the desorption kinetics during the secondary drying step of the continuous spin freeze-drying process. An inline PLS-based NIR calibration model to predict the residual moisture content of a standard formulation (i.e., 10% sucrose) was constructed and validated. This model was then used to evaluate the effect of different process parameters on the desorption rate. Product temperature, which was controlled by a PID feedback mechanism of the IR heaters, had the highest positive impact on the drying rate during secondary drying. Using a higher cooling rate during spin freezing was found to significantly increase the desorption rate as well. A higher filling volume had a smaller negative effect on the drying rate while the chamber pressure during drying was found to have no significant effect in the range between 10 and 30 Pa.

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Understanding and optimization of the secondary drying step of a freeze-drying process: a case study

Drying Technology ◽

10.1080/07373937.2020.1739065 ◽

2020 ◽

pp. 1-15 ◽

Cited By ~ 1

Author(s):

Getachew Assegehegn ◽

Edmundo Brito-de la Fuente ◽

José M. Franco ◽

Críspulo Gallegos

Keyword(s):

Freeze Drying ◽

Drying Process ◽

Secondary Drying

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Effect of Bound Water in the Freeze-Drying Process

Transactions of the ASAE ◽

10.13031/2013.37480 ◽

1973 ◽

Vol 16 (1) ◽

pp. 0183-0188 ◽

Cited By ~ 3

Author(s):

G. L. Gentzler ◽

F. W. Schmidt

Keyword(s):

Freeze Drying ◽

Bound Water ◽

Drying Process

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Monitoring of the Secondary Drying in Freeze-Drying of Pharmaceuticals

Journal of Pharmaceutical Sciences ◽

10.1002/jps.22311 ◽

2011 ◽

Vol 100 (2) ◽

pp. 732-742 ◽

Cited By ~ 24

Author(s):

Davide Fissore ◽

Roberto Pisano ◽

Antonello A. Barresi

Keyword(s):

Freeze Drying ◽

Secondary Drying

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Mathematical Modelling of the Primary and Secondary Drying Stages of Bulk Solution Freeze-Drying in Trays: Parameter Estimation and Model Discrimination by Comparison of Theoretical Results With Experimental Data

Drying Technology ◽

10.1080/07373939708917262 ◽

1997 ◽

Vol 15 (3-4) ◽

pp. 791-810 ◽

Cited By ~ 102

Author(s):

H. Sadikoglu ◽

A. I. Liapis

Keyword(s):

Experimental Data ◽

Parameter Estimation ◽

Mathematical Modelling ◽

Freeze Drying ◽

Bulk Solution ◽

Model Discrimination ◽

Secondary Drying ◽

Theoretical Results

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FEATURES OF THE DEVELOPMENT OF A LYOPHILIZED INJECTABLE DOSAGE FORM OF THE ORIGINAL ANTICANCER DRUG LCS-1208

International Journal of Applied Pharmaceutics ◽

10.22159/ijap.2021v13i4.41371 ◽

2021 ◽

pp. 102-105

Author(s):

ILYA GULYAKIN ◽

ANNA LANTSOVA ◽

LYUDMILA NIKOLAEVA ◽

MARIA DMITRIEVA ◽

NATALIYA OBOROTOVA ◽

...

Keyword(s):

Freeze Drying ◽

Dosage Form ◽

Freezing Temperature ◽

Antitumor Drug ◽

Secondary Drying ◽

Filter Unit ◽

Series Of Experiments ◽

Drying Chamber ◽

Injectable Dosage

Objective: Development of a lyophilized injectable dosage form LCS-1208, an original antitumor drug based on an indolocarbazole derivative. Methods: The prepared solution of the injectable dosage form LCS-1208 is transferred to sterilizing filtration, which is carried out under vacuum on a «Stericup» filter unit with a filter pore size of 0.22 μm. The sterile solution of the injectable dosage form LCS-1208 is poured into sterile vials using a dispenser and lyophilized in a freeze-drying chamber. At the end of drying, the preparation is corked in the chamber of a sublimation unit using a hydraulic device and transferred to crimping with aluminum caps using a seaming machine. Quantitative determination of the drug content was determined by spectrophotometry using a standard sample at λ = 320±2 nm. The pH was determined by potentiometry. Results: A freeze-drying regimen for the injectable dosage form LCS-1208 has been developed. The required solution freezing temperature was established taking into account the presence of 2 eutectic zones: a solution of LCS-1208 in DMSO (-35 ÷-32) °С, an aqueous solution of Kollidon 17PF (-10 ÷-8) °С. As a result of a series of experiments, the optimal lyophilization regime was chosen that does not require preliminary freezing in a low-temperature chamber, with freezing on the shelves of freeze-drying at a temperature of-47 °C without their preliminary cooling. The most acceptable vial filling volume was determined, amounting to 3 ml, and the rate of temperature rise during secondary drying of the preparation was justified. When using the developed regime of lyophilization of the LCS-1208 solution, it was shown that it can be sublimated while preserving the initial qualitative and quantitative characteristics. Conclusion: In this article, using the example of creating a lyophilized injectable dosage form LCS-1208 (the original antitumor drug from the indolocarbazole group), the main problems that arose during the lyophilization of the selected composition of the model solution, as well as ways to improve the process.

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Design of a new lyoprotectant increasing freeze-dried Lactobacillus strain survival to long-term storage

BMC Biotechnology ◽

10.1186/s12896-021-00726-2 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Aurore Bodzen ◽

Audrey Jossier ◽

Sébastien Dupont ◽

Pierre-Yves Mousset ◽

Laurent Beney ◽

...

Keyword(s):

Water Content ◽

Water Activity ◽

Freeze Drying ◽

Sucrose Solution ◽

Bound Water ◽

Long Term Storage ◽

Freeze Dried ◽

Micellar Casein ◽

Term Storage

Abstract Background Stabilization of freeze-dried lactic acid bacteria during long-term storage is challenging for the food industry. Water activity of the lyophilizates is clearly related to the water availability and maintaining a low aw during storage allows to increase bacteria viability. The aim of this study was to achieve a low water activity after freeze-drying and subsequently during long-term storage through the design of a lyoprotectant. Indeed, for the same water content as sucrose (commonly used lyoprotectant), water activity is lower for some components such as whey, micellar casein or inulin. We hypothesized that the addition of these components in a lyoprotectant, with a higher bound water content than sucrose would improve lactobacilli strains survival to long-term storage. Therefore, in this study, 5% whey (w/v), 5% micellar casein (w/v) or 5% inulin (w/v) were added to a 5% sucrose solution (w/v) and compared with a lyoprotectant only composed of 5% sucrose (w/v). Protective effect of the four lyoprotectants was assessed measuring Lactiplantibacillus plantarum CNCM I-4459 survival and water activity after freeze-drying and during 9 months storage at 25 °C. Results The addition whey and inulin were not effective in increasing Lactiplantibacillus plantarum CNCM I-4459 survival to long-term-storage (4 log reduction at 9 months storage). However, the addition of micellar casein to sucrose increased drastically the protective effect of the lyoprotectant (3.6 log i.e. 0.4 log reduction at 9 months storage). Comparing to a lyoprotectant containing whey or inulin, a lyoprotectant containing micellar casein resulted in a lower water activity after freeze-drying and its maintenance during storage (0.13 ± 0.05). Conclusions The addition of micellar casein to a sucrose solution, contrary to the addition of whey and inulin, resulted in a higher bacterial viability to long-term storage. Indeed, for the same water content as the others lyoprotectants, a significant lower water activity was obtained with micellar casein during storage. Probably due to high bound water content of micellar casein, less water could be available for chemical degradation reactions, responsible for bacterial damages during long-term storage. Therefore, the addition of this component to a sucrose solution could be an effective strategy for dried bacteria stabilization during long-term storage.

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The Freeze-Drying of Foods—The Characteristic of the Process Course and the Effect of Its Parameters on the Physical Properties of Food Materials

Foods ◽

10.3390/foods9101488 ◽

2020 ◽

Vol 9 (10) ◽

pp. 1488 ◽

Cited By ~ 1

Author(s):

Dorota Nowak ◽

Ewa Jakubczyk

Keyword(s):

Mechanical Properties ◽

Physical Properties ◽

Structural Properties ◽

Freeze Drying ◽

Process Conditions ◽

Drying Process ◽

High Quality ◽

Freeze Dried ◽

Secondary Drying ◽

Selection Of

Freeze-drying, also known as lyophilization, is a process in which water in the form of ice under low pressure is removed from a material by sublimation. This process has found many applications for the production of high quality food and pharmaceuticals. The main steps of the freeze-drying process, such as the freezing of the product and primary and secondary drying, are described in this paper. The problems and mechanisms of each step of the freeze-drying process are also analyzed. The methods necessary for the selection of the primary and secondary end processes are characterized. The review contains a description of the effects of process conditions and the selected physical properties of freeze-dried materials, such as structural properties (shrinkage and density porosity), color, and texture. The study shows that little attention is given to the mechanical properties and texture of freeze-dried materials obtained from different conditions of the lyophilization process.

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