Fluid Dynamics of Pharmaceutical Freeze-Drying

    Graduate Student: Arnab Ganguly  (Purdue/AAE)           

    Collaborators: Dr. Steve Nail (Baxter BioPharma Solutions) and Frank DeMarco (IMA Life)


    Freeze-drying is widely used in pharmaceutical manufacturing to extend the shelf life of medical drugs and to provide easy shipping and storage. A successful drying process ensures that the solvent is removed while the sensitive molecular structure of the active substance of the drug is preserved. It involves a 3-stage process (figure 1a) initiated by freezing ((stage A-B), following which, the pressure below the triple point (stage B-C). Heat is then provided for sublimation of the ice in the primary drying (stage C-D). Figure 1b shows the schematic of a typical freeze-dryer. Freeze-drying cycles are run as a batch process es and are thus, both, time and energy intensive. Currently, the design of freeze-drying equipment is based largely on empirical knowledge and many aspects of fluid dynamics involved in pharmaceutical freeze-drying remain uncertain. The main objective of this work is to develop the modeling and computational framework for analysis of vapor and ice dynamics in freeze-dryer condensers.

                                    Figure 1a: Water Vapor Phase Diagram superimposed indicating the vapor                 Figure 1b: Schematic of a freeze-dryer                                                                  flow path on the schematic of a typical Freeze Drying Cycle

    Icing Measurements:

    The ice distribution on the coils of the condenser is highly non-uniform. The video attached is a result of time lapse imaging of the ice growth over a period of 24 hours in a typical laboratory scale freeze-dryer condenser.Though, at the beginning of the cycle, the ice deposits uniformly, as the cycle proceeds, there is a preferential ice build-up on the coils closest to the duct exit. The non-uniformity leads to an increase in the pressure close to the exit of the duct, reducing the pressure gradient driving the vapor into the condenser. Not only does the increasing pressure in the condenser reduce the efficiency of the dryer, an uncontrolled increase in the pressure in the condenser can eventually lead to product collapse. 


            

    Ice Accretion on the Coils of a Laboratory Scale Freeze-Dryer Condenser

    Figure 2: Photograph of the non-uniform ice-buildup at 1.1 mm growth rate per hour














    Modeling Approach: 

    One of the most important physical processes relevant to condenser design is the ice accretion on condensing coils.  Low-temperature water vapor molecular model[1] is applied in the DSMC solver SMILE to simulate the flowfield structure as it develops in the condenser chamber. The developing ice front is tracked based on the  mass fluxes computed at the nodes of  the DSMC surface mesh. The position of a node in space is a function of its initial spatial coordinates, the mass flux at the node and the time over which the ice buildup is to be predicted.


    Results:

    As can be seen in figure 3 (a) the coils closest to the vapor inlet have the largest mass flux, leading to accumulation of ice around these coils. Figure 23 b) shows ice accretion on the coils at a chamber pressure of 115 mTorr. The DSMC simulations demonstrate that by tailoring the condenser topology to the flow-field structure of the water vapor jet expanding into a low-pressure reservoir, it is possible to significantly increase water vapor removal rates and improve the overall efficiency of freeze-drying process.  

                                                                                                        


     Figure3(a-b): Water vapor mass flux and streamline in a section of the condenser of a Lyostar II freeze-dryer with the predicted steady non-uniform ice buildup shown on the right after 24 hours. The simulation parameters correspond to m= 55 g/hr, Duct pressure: 115 mTorr (same as the video). The large non-uniformity in the ice growth between the coils close to the duct exit (center) and those away from the exit is purely a result of the non-uniform mass flux of the water vapor exiting from the duct

    Relevant Publications

    [1]     A. A. Alexeenko, A Ganguly, S.L Nail, "Computational Analysis of Fluid Dynamics in Pharmaceutical Freeze-Drying", J. Pharmaceutical Sciences, Vol. 98, No. 9, 2009, pp 3483-3494.

    [2]  A. Ganguly, S. Nail, A. Alexeenko, "Experimental Determination of Key Heat Transfer Mechanisms in Pharmaceutical Freeze Drying", AIAA Paper 2010-4654, 10th AIAA/ASME Joint Thermophysics and Heat Transfer Conference, Chicago, IL, June 28- July1, 2010.

    [3]  A. Ganguly, A. Venkattraman, A. Alexeenko, “3D DSMC Simulations of Vapor/Ice Dynamics in a Freeze-Dryer Condenser”, 27th International Symposium on Rarefied Gas Dynamics, Pacific Grove, CA, July 10-15, 2010.

    [4] Arnab Ganguly,  "Simulation and Experiments of Low-Pressure Water Vapor Flows Applied to Freeze-drying", (Master's Thesis) May 2010.

    Acknowledgements

    We gratefully acknowledge support of this research from NSF/CBET, Baxter BioPharma Solutions and IMA Life (formerly IMA Edwards Pharmaceutical Systems).
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    Alina Alexeenko,
    Sep 30, 2013, 10:19 AM
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