FRESH PERSPECTIVES
Table 1. Cake Resistance Versus Freezing Process.
Controlled Nucleation
AccuFlux Heat Flow Control During Freezing
No Yes Yes
No No Yes
Ice Crystal Structure Across the Batch
Ice Crystal Structure Inside the Vial
Cake Resistance (Torr cm2 Hr)
Non-Uniform Non-Uniform 4.38 Uniform Uniform
Non-Uniform 3.87 Uniform 1.77
eff ects of random nucleation in adjacent vials and allows re-modeling of the ice crystals. The result is signifi cantly better ice crystal structures and better product uniformity, which lowers cake resistance and promotes more effi cient primary drying.
The Eff ect of Freezing and Heat Flow Control on Primary Drying
Controlled Nucleation has been promoted as a method to reduce primary drying times. However, to have a dramatic improvement in drying times, a method to control the ice crystal growth post-nucleation is necessary.
To determine the eff ect of proper freezing on primary drying time, a series of experiments were performed. The concept of uncontrolled versus controlled nucleation and post-nucleation heat fl ow control were tested.
The experiments were performed using a 3 ml fi ll of 5% sucrose in a 10 ml vial. When controlled nucleation was used, the product was super- cooled to -50C. This level of super-cooling induced approximately 8% of the available water to nucleate.
Summary of Experiments
Controlled nucleation has a positive impact on primary drying. It produces a uniform starting point across the batch. However, only 8% of the water nucleates and the majority (92%) of ice crystal formation takes place post-nucleation.
Controlled nucleation without controlled post-nucleation freezing resulted in a reduction in primary drying from 41 hours to 30 hours. To further improve the process, AccuFlux Heat Flow Control was used post-nucleation. The result of AccuFlux Heat Flow control during freezing is greatly improved ice crystal structure and reduced cake resistance. AccuFlux reduced primary drying to 28 hours. When reviewing the graphic information (Figure 8) we can see that the product temperature was dramatically reduced due to
Table 2. Table of Experiments
Figure Controlled Nucleation
6 7
8
No Yes
Yes
Post-Nucleation Freezing Method
-0.50 C/min -0.50 C.min
AccuFlux
Shelf Temperature Primary Drying (0C)
-20 -20
-20
Primary Drying time (hrs)
41 30
28 Comment Cake shrinkage. Non-uniform crystal structure across the batch and inside the vial.
Some cake shrinkage. Uniform cake structure across the batch. Non-uniform cake structure inside the vial.
FreezeBooster Controlled Nucleation combined with AccuFlux freezing control resulted in much lower cake resistance. Uniform and reduced cake resistance across the batch and inside the vial. During primary drying, the product temperature was several degrees lower.
9 10 Yes Yes AccuFlux AccuFlux -12 AccuFlux 22 19
FreezeBooster Controlled Nucleation combined with AccuFlux freezing control resulted in much lower cake resistance. The shelf temperature was increased to -120C.
Closed loop control of the shelf kept the shelf temperature maximized while keeping product below its critical temperature throughout the entire primary drying cycle. A 53% reduction in primary drying time while producing a more uniform result.
72 American Pharmaceutical Review | Fresh Perspectives 2013
Figure 6 - The primary drying portion of vials that were frozen without controlled nucleation and the shelf temperature was reduced at 0.5°C/min to -45°C. The result was a 41+ hour primary drying cycle.
the improved cake resistance, therefore the shelf temperature could be increased to -120C to produce a shorter primary drying cycle of 22 hours (Figure 9).
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