Mesomixing, in the context of this article, refers to the dispersion of the plume of antisolvent generated at the feed point as the solvent is added to the bulk solution/slurry. Without proper feed-point location and the right feed device/pipe, pockets of high supersaturation can occur, resulting in undesired nucleation. The time constant for mesomixing depends on the addition rate, feed point and diameter of the feed pipe. Too high a value can lead to premature nucleation.
Feed pipe location, pipe diameter and antisolvent flow can impact both micromixing and mesomixing times. A change in mean particle size and crystal size distribution (CSD) at different pipe locations would confirm product sensitivity to mixing.
Mesomixing can influence the product when the antisolvent feed rate is faster than the local mixing rate, resulting in a plume of highly concentrated antisolvent that isn't mixed at the molecular level. This can yield a high localized nucleation rate; the phenomenon can present scaleup difficulties, requiring a thorough engineering analysis for success.
The shortest mixing time constant occurs at the location of maximum turbulence in the vessel, which is just above the impeller for a down-pumping pitched-blade turbine (PBT), or at the point of discharge flow for a radial flat-blade agitator.
If the antisolvent is added in a poorly mixed zone such as at or near the surface or a baffle, a number of potentially undesirable results such as crash nucleation, oiling out or agglomeration may occur.
Subsurface addition of antisolvent at times can help avoid high levels of supersaturation and resultant nucleation when introduction is made at a zone of intensive micromixing. Results depend on the feed point location plus pipe diameter and antisolvent feed rate. For example, too large a pipe diameter could prompt a high supersaturation region prior to blending at a molecular level. Reverse flow with potential pluggage also could occur.
Genck  presents a detailed analysis of mixing in stirred tanks.
Unfortunately, many industrial antisolvent crystallization operations are far from optimum. So, let's now look at a case history that illustrates a number of the challenges and some procedures that can mitigate them.
A drug maker was experiencing a problem in producing an active pharmaceutical ingredient (API). Crystallization gave poor product characteristics: an oily/waxy or amorphous solid, small crystals with high surface area (exceeding 30 m2/gm) that were difficult to filter and wash, and a small MZ. The company wanted to improve CSD, filterability and crystallinity.
The process took place in a fully baffled crystallizer with a 1.6-ft.-dia. 4-blade PBT operating at 60 rpm. The API was dissolved in isopropanol (IP) and crystallized by subsurface linear addition of isopropyl acetate (IPAc) for 1 hr. via a 2-in.-dia. pipe near a baffle. This led to a volume increase to approximately 1,000 gal. from the original 500 gal. No seeding was used. The slurry was aged at 20°C and cooled to 10°C.
Simulation using Visimix software  provided insights on the original operation as well as potential modifications. It showed that 60 rpm was inadequate, lacking in effective energy dissipation rates and having relatively high microscales of turbulence for dispersion of the antisolvent. In addition, the simulation indicated the characteristic micromixing time and mean time of circulation were high. Trial and error led to selection of 90 rpm and a modified procedure (Table 1).
The changes provided substantial improvements:
• Cake permeability increased by more than 100 times, resulting in easy filtration and washing.
• Mean particle size and CSD rose significantly.
• A highly crystalline product was formed.
• There was no evidence of breakage or extensive secondary nucleation.
As this points up, antisolvent crystallization can offer an attractive option but requires care in its implementation.
WAYNE J. GENCK, PhD, is principal of Genck International, Park Forest, Ill. E-mail him at firstname.lastname@example.org.
1. Genck, Wayne J., "Better Growth in Batch Crystallizers," Chem. Eng., p. 90 (Aug. 2000).
2. Genck, Wayne J., "It's Crystal Clear, Part II — Scaleup, Simulation and New Technologies," p. 37, Chem. Proc. (Dec. 2003).
3. VisiMix, Ltd., www.visimix.com