Controlling Ice Nucleation During the Freezing Step of Lyophilization - Pharmaceutical Technology

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Controlling Ice Nucleation During the Freezing Step of Lyophilization
Lyophilization technologies for controlled nucleation.


Pharmaceutical Technology
Volume 37, Issue 5, pp. 36-40

Controlled nucleation

A successful lyophilization cycle is defined by dried products that are visually and functionally acceptable, and chemically and biologically stable, with a short reconstitution time. "Although ice nucleation is an important parameter for achieving homogeneous product and optimized cycles, there have been very few attempts to achieve it at a commercial scale until recently," observes Brower. The standard practice has been to use an annealing cycle, which involves raising the product tempe-rature after freezing to a temperature above glass transition, and then holding it. This method results in the formation of larger ice crystals at the expense of smaller ones, and helps minimize the variability in drying behavior (15). Brower, however, points out that the benefits of shorter drying times may be offset by the additional time required for the annealing cycle. Moreover, annealing fails to address the root cause of variable ice structure, which is the lack of a uniform ice-nucleation temperature, and can only help to mitigate a flawed condition (15).

Controlled ice nucleation involves cooling the entire batch of vials to a given selected temperature that is below the equilibrium freezing point but above the temperature at which spontaneous heterogeneous nucleation may occur (16). Nucleation is then induced by seeding the vials with ice crystals or by depressurizing the freeze-dryer chamber.

Controlled nucleation makes it possible to achieve uniform ice-crystal formation within a vial as well as between vials in the same batch at a minimum degree of supercooling. "This means more consistent and larger ice crystal sizes resulting in the most open product structure and faster drying," says Brower. "It also allows faster reconstitution of the product prior to use."

The two main techniques for controlling nucleation are ice fog (e.g., Millrock's FreezeBooster nucleation technology and Linde's Veriseq nucleation technology) and depressurization (ControLyo technology, developed by Praxair). "The method of controlled nucleation, whether by injecting ice crystals or depressurization, has no material difference on the initial ice structure," says Thompson. "The key to successful crystal formation is a common starting point and the control of crystal growth after the nucleation event."

In the ice-fog technique, the vials are first cooled to the desired temperature below the equilibrium freezing point and the pressure is reduced to approximately 50 Torr. Cold nitrogen gas is then introduced (through a liquid nitrogen heat exchanger) into the chamber. The cold gas in the humid chamber forms an ice fog, which is forced into the vials to seed ice crystallization in the supercooled solution (16). In short, ice fog generates "seed" crystals that fall into the vials creating the "nucleus" around which ice crystals form during nucleation.

On the other hand, the depressurization technique involves reducing the product temperature in all vials to a selected value, followed by pressurization of the freeze-dryer chamber with an inert gas such as nitrogen or argon. When thermal equilibrium has been achieved, the excess pressure is released rapidly (i.e., depressurization), causing ice crystals to form at the top of the solution and propagate throughout the vial within seconds (16). With this method, ice formation is induced at essentially the same time for all vials in the batch, in contrast to the ice-fog technique where the vials are nucleated within a minute or two.

Thompson, however, points out that a consistent crystal structure in the vial and across the batch is not produced by merely controlling the shelf temperature at a specific ramp rate. "Controlled nucleation provides a method to create a consistent starting point for crystal formation, but by itself only provides moderate improvement of crystal structure. Controlled nucleation needs to be combined with controlled crystal formation to produce the most homogeneous and efficient crystal structure inside the vial and throughout the batch," Thompson explains. Once controlled nucleation has occurred, a method for measuring and controlling the crystal growth is needed.


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