FRESH PERSPECTIVES
Figure 1 - % water that freezes based on super-cooling temperature
cake resistance, the crystal structure inside the vial is still inconsistent and the crystal structure throughout the batch is non-homogeneous, therefore only marginal improvement in product consistency is achieved. Annealing can also potentially lead to changes in the protein structure.
Controlled Nucleation
The goal for controlled nucleation is to have the solution in all of the vials nucleate at the same time, same temperature, and at the same rate to produce a uniform initial crystal structure.
To produce a controlled nucleation event, the material in the vials is super- cooled and allowed to soak at a predetermined temperature. A ‘catalyst’ is then introduced to synchronize the nucleation event. The catalyst for controlled nucleation often is introduced at the top surface of the material in the vial; therefore, the ice crystal growth starts at the top surface versus the bottom of the vial during an uncontrolled nucleation event.
During a -0.50C/min shelf cool-down, the heat fl ow between the shelf and the vial changes signifi cantly as shelf the temperature drops (Figure 2). Observing the heat fl ux line on the graph in Figure 2, the random nucleation events and the massive change in heat fl ow are evident. The magnitude of heat fl ow increases from 0.5 hours to 1.25 hours and then decreases. The result is non-uniform crystal growth rate. The random nucleation results in diff erent initial ice structures across the batch while the changing heat fl ow results in an inconsistent ice structure inside the vial.
To overcome heterogeneous crystal structures created, both between vials and intra-vial, an annealing step is often added. Annealing is a process where the frozen product temperature is raised to allow the crystals and the interstitial pores to increase in size. Although this does help reduce the
Figure 2 - The graph shows the randomness of heat fl ux during uncontrolled nucleation and a ramp rate of -0.5° C/minute for the freezing process. The heat fl ux line shows diff ering nucleation events and major changes in heat fl ux. The result is a non-uniform ice crystal structure across the batch and in the vial.
The fi rst step of controlled nucleation requires that the vials be cooled to -50C and held for a soak period to ensure that all of the vials have stabilized at about the same temperature. In the case of Millrock Technology’s FreezeBooster™ technique, seeding ice crystals are then introduced into the product chamber to induce nucleation. The nucleation event occurs across the batch at the same temperature, the same time, and at the same rate (Figure 3). The result is a uniform vial-to-vial initial ice structure. The advantages of the FreezeBooster approach include simplicity of implementation, ability to nucleate almost any type of freeze-drying container, and at a low cost.
Controlled nucleation produces reductions in primary drying times due to lower cake resistances, however, proper super-cooling and control of post- nucleation crystal growth are required to produce a signifi cant reduction in primary drying time. For example, sucrose super-cooled to -10°C, nucleated, and then cooled rapidly results in a small crystal structure and minimal improvement in primary drying times. Therefore, post-nucleation thermal treatment is critical to a uniform and freeze-drying friendly ice structure throughout the product.
Figure 3 - Uniformity of product temperature during nucleation when using FreezeBooster Controlled Nucleation technology. All the measured vials nucleate at the same temperature, time, and rate.
70 American Pharmaceutical Review | Fresh Perspectives 2013
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