What Makes Crystallization Such a Complex Process?

As a follow-up on last week’s post regarding the implications of a well-designed crystallization process, including how Tim Bell of DuPont Engineering wrote: “Crystallization is notoriously difficult to scale-up…”, we will now address why crystallization is such a complex process.

The efficiency and profitability of a crystallization process is directly tied to the crystal size distribution produced in the crystallizer vessel. Problems with solids bulk density, flowability, crystal size and shape can often be directly related to the operations of the crystallization step. Missing the crystal size distribution specifications may result in costly rework. The production of excessive fines in the crystallizer vessel can dramatically cut production yields and can reduce throughput due to serious bottlenecks in downstream processes such as filtration and drying. Excessive milling of crystal product can result in further yield losses and result in potential dust hazards. Therefore, an engineered crystal size distribution that meets particle size specifications repeatedly, and avoiding excessive downstream modification through milling and sieving, can dramatically improve overall production efficiency and profitability.

Crystallization, however, is extremely difficult to directly transfer from the laboratory to pilot and production scale. Scale-up difficulties are compounded by the importance of both thermodynamic and kinetic properties in determining the final crystal size distribution.

Supersaturation, the thermodynamic driving force of crystallization, is a critical parameter in determining the final crystal population. In a laboratory vessel that is relatively well-mixed, supersaturation may be effectively constant throughout the vessel. At a larger scale, there are undoubtedly gradients of supersaturation throughout the crystallizer – due to the manner in which the supersaturation is created (most often by cooling or anti-solvent addition), and due to the mixing configuration (including parameters such as the vessel dimensions, baffles, impeller type, and agitation speed) which determines how effectively the supersaturation is dispersed throughout the vessel.  The introduction of the supersaturation gradient plays a very significant role in the difference between laboratory-scale and full-scale crystallization.

Crystallization is further complicated by the fact that it is a multiphase system. The solid crystal product is very often a different density than the liquid phase (mother liquor). Crystals that are denser than the mother liquor have a desire to settle to the bottom of the crystallizer, and the mixing required to keep a liquid based system well-mixed is no longer sufficient to keep the solids suspended. Although a first instinct response might be to increase the agitation speed or to add baffles, one must also be aware of the possibility of crystal breakage and attrition due to the increased energy input. Attrition can be a significant cause of fine crystals or a source of secondary nucleation which will dramatically alter the final crystal size distribution and causes a number of scale-up headaches.

The kinetics of crystallization adds additional complexity to scale-up. Crystallization kinetics is commonly simplified to two parameters: nucleation (birth of new crystals) and growth (rate of increase of crystal dimensions). (More complex crystallization models may also include rates of dissolution, breakage, attrition, and agglomeration to more fully predict the population balance in the crystallizer – but these are usually situations we will work to avoid in a practical crystallization process.)

The nucleation and growth rates are primarily functions of supersaturation.  At relatively low levels of supersaturation, growth tends to dominate. Nucleation rates, however, have a higher order relationship with supersaturation – so that if supersaturation reaches a high enough level, nucleation will dominate the crystallization process.

In addition, the presence of crystals – and the related crystal size distribution – is another critical factor in determining how the supersaturation is consumed and therefore the combination of the the final crystal product. This is because the quantity of crystals present – and specifically the viable crystal surface area available for growth – determines the rate at which supersaturation can be consumed by the existing crystal population.

If avoiding nucleation is desirable, the crystallizer can only generate supersaturation at a rate that the existing crystal surface area can handle at the corresponding growth rate. If the amount of surface area is insufficient to handle the generated supersaturation, then the overall supersaturation level will rise, eventually to the point where nucleation becomes a significant factor. If the amount of surface area is more than the current growth rate will sustain, the supersaturation will drop (implying that the crystallizer is running at less than full capacity.)

If that is not complicated enough, the fact that you have potential gradients of supersaturation and gradients of crystal size distribution throughout the full-scale vessel, also means that you have potential gradients of nucleation and growth rates making the final crystal product extremely difficult to predict from simple kinetic models based on laboratory data.

There have been two traditional ways of dealing with this complexity of crystallization – either crash the solids out of solution and deal with the headaches of the downstream processing bottlenecks, or simply tune down the crystallizer so far that it runs at a low enough level of supersaturation that problems of nucleation are generally avoided. Clearly, neither of these situations is optimized for maximum production yield and throughput, and this in part has fueled the recent push towards real-time monitoring of crystallization using Process Analytical Technology (PAT) that can directly measure critical parameters such as the crystal size and shape distribution, the crystal form, and even the level of supersaturation.

This is an excerpt from the white paper – A Guide to Scale-up of Batch Crystallization from Lab to Plant.

Terry Redman, MSc, MBA
Benjamin Smith, BSC
Mark Barrett BE, PhD

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