FRESH PERSPECTIVES
ice structure inside the vial. The rate of ice crystal growth varies due to changes in heat fl ow from the vial.
The maximal freeze concentrate is formed when all the freezable water is converted to ice. The point where the maximal freeze concentrate is formed can be identifi ed by the end of latent heat production. The maximal freeze concentrate either goes through freeze separation if it is a eutectic material or solidifi cation if it is an amorphous material. Once the temperature of an amorphous product has been reduced below its glass transition temperature and the heat fl ow between the shelf and vial has reduced to a steady state condition, the product can be considered frozen and stable. The end of freezing can be identifi ed when the heat fl ow approaches zero, indicating there is no longer a phase change or product temperature change.
Freezing in a Freeze Dryer
Effi cient freeze-drying requires larger crystals and therefore larger pores in the frozen matrix. Larger pores reduce product resistance and reduce primary drying times. The uniformity of the pores throughout the product further reduces drying times.
In the pharmaceutical freeze-drying world, vials are placed on a liquid-fi lled shelf where the fl uid is temperature-controlled. The shelf temperature is reduced at 0.50C/min down to a predetermined hold temperature, such as -400C. Once the shelf has reached the hold temperature, the shelf is maintained for a period of time, such as 90 minutes, to allow the product in the vials to all reach the same temperature.
The result of simply placing vials on a shelf and reducing the shelf temperature is heterogeneous nucleation across the batch. The randomness of nucleation is caused by diff erent degrees of super- cooling both in the vial across the batch, as well as temperature diff erences across the shelf. Some vials may nucleate at -100C, while others at -150C. In cleaner processing environments, the product in the vial achieves lower super-cooled temperatures due to the lack of nucleation sites. The lower the nucleation temperature the smaller the pores, which results in higher product cake resistance and longer drying times.
Uncontrolled nucleation starts at the bottom of the vial and proceeds toward the top, as the ice crystal structure forms, the rate of crystal growth slows resulting in smaller crystals at the bottom and larger crystals at the top. The result of non-uniform crystal structures is non-uniform drying and the potential for melt-back or collapse. In studies performed with sucrose, this is evident by excessive shrinkage at the bottom of the cake toward the end of primary drying.
Adding to the complexity of the process, the same shelf inlet temperature does not translate to a
69 American Pharmaceutical Review | Fresh Perspectives 2013 845-339-5700
uniform shelf surface temperature or uniform heat fl ow from the shelf to the vial. During freezing, the inlet shelf temperature will be much cooler than the outlet temperature. The temperature diff erential across the shelf varies by equipment design, fl uid fl ow, type of fl uid inside the shelf and the load on the shelf. The heat fl ow varies depending on shelf fi nish, fl uid fl ow, vial type, and other variables. During temperature transition on a fully loaded shelf, the temperature diff erence across the shelf can be signifi cant, for example greater than 100C.
Controlled Nucleation For Your Freeze Dryer
FreezeBooster™ Portable Nucleation Station
Features Portable (can be used for multiple freeze dryers)
Easy connection/ disconnection via sanitary fitting
Non-Invasive, simply replace your chamber door
Sterilizable via H2O2 Retrofittable to all freeze dryer brands
Includes cart with height adjustment
*Patents Pending Cost effective solution
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