B. AntiSolvent Recrystallization
Solute/solvent systems with high solubility at low temperature and the availability of a miscible antisolvent meet the requirements for antisolvent recrystallization. The controlled addition of antisolvent reduces solubility in the mixture and triggers recrystallization. Two common ways of operation are either antisolvent addition to product solution or product solution addition to antisolvent (reverse addition). The disadvantages of antisolvent recrystallization are introduction of an additional solvent, local high supersaturation at the point of addition, reduced volumetric productivity, and the requirement for solvent separation downstream.
C. Evaporative Recrystallization
High solubility at low temperature and the unavailability of an antisolvent often requires evaporative recrystallization. The removal of solvent reduces solubility in the remaining mixture and once sufficient supersaturation is created, recrystallization occurs. Challenges in evaporative recrystallization are the introduction of gas bubbles, which can act as a source of nucleation, difficult to predict seeding points and unpredictable scale-up.
D. Reaction (Precipitation) Recrystallization
When the desired solute is generated through a chemical reaction between two complex compounds or an acid/base neutralization, the method is referred to as reactive recrystallization. The progressing chemical reaction increases supersaturation of the solute, which eventually recrystallizes. Creation of supersaturation can be extremely fast, leading to local high supersaturation at the point of mixing, extensive nucleation, poor process control, and difficult downstream handling.