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Understand the impact of mixing on crystallization dynamics and determine the optimum conditions for scaleup.
CRYSTALLIZATION HAS BECOME increasingly popular as a unit operation in the chemical industries due to its ability to purify while producing a solid with the desired physical properties. Increasing requirements for higher product purity and consistency have placed new demands on this process, especially in the pharmaceutical industry, which is being confronted with the production of more-complex molecules as well as the tightening of specifications for both existing and new drugs. Issues such as the production of a single enantiomer or a specific polymorph have become even more important. And the need to reduce the time from drug discovery to market introduction is an inherent concern. Furthermore, well over 90% of commodity, fine and specialty chemicals, and pharmaceuticals manufactured today are produced and sold in a solid form. Most of these are first optimized at the bench scale or in a pilot plant. The engineer must then make a product with similar properties as the scale is increased - a task that is profoundly influenced by mixing.
In this article, we will explore how mixing parameters impact the crystallization process and recommend ways to improve the likelihood of successful scaleup. The concepts of nucleation and growth, types of mixing, design considerations, agitator parameters and scaleup criteria will be presented. In addition, a computer simulation for a liquid-solid system will be demonstrated.
Mechanics of crystallization
There are two essential steps for particle formation by crystallization: nucleation and crystal growth. Together, these processes govern the crystal size distribution (CSD) by determining the number and size of crystals present in the crystallizer at the end of operation. Mixing can have a dramatic effect on the properties of the product, including CSD, purity, morphology and polymorphic form (i.e., where different lattice packing arrangements of the same solute species within the crystal can effect chemical and physical characteristics of the product). In turn, these parameters influence the choice of downstream processing, such as centrifugation/filtration, drying, milling, solids-handling and means of preventing product caking. Figures 1 and 2 demonstrate the significant changes in the CSD and morphology of an antibiotic that is crystallized under different agitation conditions. Figure 1 displays crystals with a highly desirable...