New Developments in Controlled Nucleation

Nucleation technology has advanced; maybe it’s time to advance yours

By Eugene Wexler, senior manager, Chemicals & Environment, Linde; and Joe Brower, Process Services Manager, IMA Life

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Freeze drying, also known as lyophilization, plays an important role in drug manufacturing by stabilizing delicate pharmaceutical and biological products. Over the past several decades, significant progress has been made in the design of freeze-drying processes enabling the industry to take full advantage of the recently developed technologies, including those in the field of controlled nucleation.

Freeze drying was developed commercially in the 1940s to produce a dry product that can be readily reconstituted to its original form by adding solvent (usually, water) when required [1]. Removing moisture slows down chemical, microbiological and physical degradation processes, therefore extending the shelf life of the products.

Freeze drying is a process comprised of three main steps: freezing (solidification), primary drying (ice sublimation), and secondary drying (moisture desorption), and can take several days to accomplish. The overall efficiency and consistency of the entire process, as well as ensuring high quality of the products, largely depends on the nucleation temperature. Temperature directly affects the size of ice crystals which, in turn, determines the pore size distribution, and therefore, resistance of the porous freeze-dried matrix to vapor flow.

FIRST, MEET THESE TWO CONDITIONS

In order for nucleation to occur, two process conditions must be met: the product temperature has to be lower than the freezing point of the solution and there have to be nucleation sites present to trigger the process. The temperature difference between the equilibrium freezing point and the ice nucleation point is known as super-cooling. A lower nucleation temperature, or a higher degree of super-cooling, results in more ice-nuclei and smaller ice crystals. On the other hand, higher nucleation temperature, or a lower degree of super-cooling, results in fewer ice-nuclei and larger ice crystals, which eventually form pores and pore networks. Larger pores enable higher sublimation rates, hence shorter drying cycles, as well as reduced reconstitution times and improved finished product attributes. It is also important that all vials nucleate at the same temperature, to ensure consistency of the product morphology, resultant cake structure and appearance, as well as uniformity of the product from vial to vial. However, in absence of nucleation sites (uncontrolled conditions), which is very common in the case of smooth-wall sterilized glass vials, the spread in nucleation temperatures between different vials, and hence, non-uniformity of the final product, could be quite significant.

The freezing step, therefore, is one of the most important steps in the lyophilization process. Handling freezing in a “controlled” versus “uncontrolled” or “random” fashion results in a number of benefits to the product manufacturers as well as end-users.

Products that could benefit from implementation of controlled nucleation include: biological products like protein and peptide formulations, vaccines, liposome and small-chemical drugs susceptible to physical and chemical degradation, as well as other injectables, which must remain effective from manufacture to patient administration [2]. Due to the rapid growth in biological therapies, the demand for freeze drying has never been higher, and this trend is expected to continue for the next decade [3].

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