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Thinking Inside the BoxCan Coca-Cola Reduce Your Primary Drying Time?

Or why does no-one use formulation to control ice crystal architecture?

In an earlier blog Converting Your Freeze Drier to Controlled Nucleation for under £10, I discussed the potential advantages of using bottom up nucleation – and pointed out that, on the lab scale, this may need nothing more complicated than a cardboard box. This idea did not come from the pharmaceutical industry but came from the ceramics and food industries. In particular, there is a lot of interest in controlling ice crystal architecture in order to make biocompatible scaffolds for tissue engineering by using ice crystal templating – essentially freezing a suspension, or slurry, using ice crystal architecture to direct the morphology of the scaffold, and then removing the ice by sublimation. Although the ceramic/biocompatible scaffold is usually then annealed at high temperatures, the process is essentially freeze drying.

In pharmaceutical freeze drying we are quite familiar with the concept that different products have different resistances to ice sublimation and this is somehow related to the cake morphology – which is templated by the ice crystal architecture. This is illustrated in the diagram below taken from reference 1, although the original data was from Mike Pikal.

This can, in part at least be explained by the cake morphology as illustrated in the three images below. These are (left to right) freeze dried mannitol, (ref 1) Sucrose (ref 1) and Factor VIII formulated with sucrose and buffer salts.


The more open the structure and the better the connectivity of the ice crystal network to the surface, the higher the rate of ice sublimation, and hence the shorter the primary drying time. Controlled nucleation primarily addresses the connectivity issue, by attempting to produce uni-axially aligned ice crystals running vertically through the frozen solution. An ideal solution would be an open well connected network such as that shown in the image below.










This image of freeze dried alumina is taken from an excellent and highly recommended review on ice templating by Sylvain DeVille (ref. 2). This remarkably homogenous structure results not just from controlling the direction and nature of temperature gradients but also from the use of additives to influence the ice architecture. With the notable exception of tertiary butyl alcohol, in the pharmaceutical world the use of additives, or should we say formulation, to control cake morphology is essentially unexplored, yet clearly deserves investigation.

What additive was used to produce the alumina structure? It was 50% water, 50 % Coca-cola!

In a pharmaceutical context, however, this suggests that a formulation based upon sucrose, with the addition of citric acid and/or phosphoric acid, in combination with controlled, ideally bottom up, nucleation may yield exactly the kind of structure that would be mechanically strong, yet have a short sublimation time, and be readily rehydrated. There is other evidence given in the DeVille review, that srongly suggests such a formulation is worth investigating. One thing is for sure, research into the use of formulation to control ice crystal architecture and cake morphology is long overdue. Coca-cola could be a very good place to start.


1. Freeze-drying of Pharmaceuticals and Biopharmaceuticals; principles and practice
   Felix Franks in association with Tony Auffret.
   Publishers; Royal Society of Chemistry. ISBN-13:978-0-85404-268-5 (2007).

2. S. DeVille.  J. Mater. Res. 28(17) 2202 -2219, 2013
    Ice-templating, freeze casting: Beyond materials processing.

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Tony Auffret also writes a regular blog article for the BioUpdate Foundation.

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