Factors Affecting Nucleation and Growth

Distillation is analogous to the cooling rate in creating supersaturation and may be controlled by similar methods to match the evaporation rate with the surface area available for growth. However, the wall and vapor disengagement effects on local concentration can cause excessive nucleation such that a predictable growth rate may not be achieved. Other factors that are difficult to control are as follows  

All of the noted problems with control of nucleation and growth are exacerbated on scale-up, thereby increasing the risk of an unpredictable PSD and other physical attributes. The causes of these scale-up problems include 

These factors may have conflicting effects on PSD. They are difficult to quantify and are system specific, depending primarily on the crystallization characteristics of the substrate. Therefore, laboratory results can vary greatly from pilot scale results and from pilot scale to manufacturing scale. 

The net result of these control issues is that crystallization by evaporation of solvent may be satisfactory for intermediates when control of PSD and other physical factors may not be a significant issue (with the possible exception of downstream operations such as filtration). However, for final bulk drug products where control of these attributes is critical, this method has proven to be unsatisfactory. 

Evaporative crystallization can be carried out in a wide variety of equipment for both semibatch and continuous operation. Discussions of these systems may be found in several references including Myerson (2002, chapter 10) and Mullin (2001, chapter 7). They are utilized in some areas of the chemical industry that require the high production rates that can be achieved with these specialized designs. 

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