This is the fourth blog post in a series dedicated to crystallization. In case you missed the previous blog posts in the series, they are available here: Introduction to Crystallization and Precipitation, Common Ways to Reduce Solubility and Drive Crystallization, Supersaturation: Driving Force for Crystal Nucleation & Growth.
The set of PVM images below neatly illustrates the complex size, shape and structure of crystals. From large round “boulders” to beautifully delicate “dendrites”, crystal product is often varied, posing challenges to effective separation and downstream manipulation.
Filtration or centrifugation is typically the step that comes right after crystallization and the crystal size and shape can greatly affect the efficiency of this unit operation. It is not efficient to design a crystallization that is complete in 1 hour if it ends up taking 24 hours to filter!
Looking at the PVM images again some clues as to how these different crystal products will filter can be gathered.
a. These crystals will likely filter quickly and consistently. The larger boulders will leave plenty of space for the filtrate to pass through rapidly
b. Flat plates like these can be some of the most difficult to filter. Plates tend to stack on top of each other effectively creating a layer of crystals that the filtrate cannot get through. This leads to long and potentially variable filtration times, depending on how the crystals are discharged from the crystallizer and stack on the filter cloth.
c. This is another case where filtration times can be long. Small crystals will plug the gaps left by the larger crystals making it difficult for the filtrate to pass through the bed of crystals. This is a common problem because many crystallization processes are designed with a fast cooldown, or antisolvent addition step at the end of the crystallization that leads to excessive secondary nucleation. Additionally, in many cases the agitation is increased at the end of the batch to help with discharge and this leads to crystal breakage.
d. This image is more common than many would expect, at least in organic crystallization systems that are seeded. A structure such as this probably won’t be seen on a microscope slide as it will be crushed during sampling and preparation. However, PVM reveals a beautiful dendritic structure. A dendrite such as this often forms when a crystallization is seeded with milled seed. Imperfections on the crystal surface lead to crystal growth from these areas and long crystal branches growing from a seed core. It is difficult to predict how something like this will filter but it is likely to break apart potentially resulting in variable filtration times.
Filtration is just one aspect of crystallization where particle size is important. For many products, the crystal size impacts the effectiveness of the product; for example the rate of absorption of a pharmaceutical drug in the body or the burn rate of a highly energetic material. Other aspects of the process can also be influenced by particle size and shape – for example flowability and segregation.
An interesting thought experiment would be to consider how the crystals show above would flow?
In the next blog post in this series, we will look at how to design a crystallization process that produces crystal product of the desired size and shape. In the mean time, this reference outlines a nice case study where an enantiomeric crystallization was optimized to improve centrifugation, minimize batch failures and improve product quality: Crystallization Improvements of a Diastereomeric Kinetic Resolution through Understanding of Secondary Nucleation.
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