Crystallization of Organic Compounds, 2nd Edition

Chapter 9Anti‐solvent Crystallization

Addition of an anti‐solvent is potentially the most common method to achieve controlled and scalable particle size distribution (PSD). The addition can be either semi‐batch—anti‐solvent added to product solution or product solution added to anti‐solvent (reverse addition)—or continuous using an in‐line mixer or stirred vessel. Of these, the in‐line mixer offers in some cases the highest potential for predictable results, as will be discussed below.

The obvious disadvantage of the anti‐solvent process is the necessity to introduce an additional solvent or solvents, thereby reducing the volumetric productivity and creating a solvent mixture requiring some form of purification/separation for downstream processing and/or recovery.

9.1 OPERATION

9.1.1 Normal Mode of Addition

The addition of an anti‐solvent can be carried out in different ways, as indicated in Figure 9.1, where the concentration of product is shown on the ordinate and the amount of anti‐solvent added is shown on the abscissa. A typical equilibrium solubility curve is indicated as A–B–C (This curve could be concave or linear but is shown as convex for clarity). The metastable region is indicated as the area between B–C and E–D. From point A to point B, addition of anti‐solvent will proceed without crystallization because the solution concentration is below the equilibrium solubility. At point B, equilibrium solubility is reached. As the addition of anti‐solvent continues, supersaturation ...