Make The Most of Antisolvent Crystallization

Impinging Jet System

Figure 4. Product ripening in stirred tank fosters diffusion of trapped mother liquor in the nucleated solids.

CONTINUOUS OPERATION
Some applications require a small mean crystal size and narrow size distribution. Examples include pharmaceutical materials requiring sub-micron or several-micron mean size where the active ingredient has marginal water solubility limiting bioavailability. Inhalation products also need these attributes. Making such products demands continuous processing via an in-line mixing device or a stirred vessel.

In-line mixing. At times this technique is used to obviate micronization or excessive milling. However, it can cause negative results such as dusting, caking, electrostatic charges and a polymorphic transformation.

In-line mixing equipment for crystallization includes impinging jets, vortex mixers, Y mixers and rotor-stator configurations. The antisolvent and product solution (which may contain seeds) are mixed in a very small active volume; this yields extremely high supersaturation values that are above the MZ, resulting in the production of a large number of nuclei. The two streams are mixed at the molecular level with excellent micromixing, with mixing times often being less than the nucleation induction time. Good control of nucleation can be achieved in the intensely mixed volume.

Impinging jets have high shear and high energy inputs in a small region and rapid localized intense mixing of the streams. A jet mixer can generate local energy dissipation rates ten times greater than those achieved in a stirred vessel.

Scaleup to commercial production from the laboratory or pilot plant often is feasible. Naturally, downstream recovery presents problems in terms of filtration, washing and drying.

Figure 4 depicts a flow diagram for one type of impinging jet configuration. In this case the product is ripened in a stirred tank following contact of the product and antisolvent streams in the jet mixer. The ripening can be batch or continuous and is designed to facilitate diffusion of the trapped mother liquor in the nucleated solids. Adequate ripening time also is provided to convert amorphous solids into crystalline structures. In some applications seeds are added to the antisolvent stream or the ripening vessel.

Stirred tanks. When using such equipment, it's important to recognize that three types of mixing may impact product characteristics:
1. macromixing;
2. micromixing; and
3. mesomixing.

Macromixing relates to bulk blending in stirred vessels.

Micromixing determines the time of blending to a molecular level and the induction time for nucleation. It's influenced by impeller type and speed plus location of the antisolvent feed pipe. Mixing times will vary greatly — by a factor of more than 20 — throughout the vessel when operating at the same speed. Local energy dissipation rates can easily vary by over a 100 fold throughout the vessel. (Micromixing times can be an order of magnitude less for continuous in-line mixers.)

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 [2] presents a detailed analysis of mixing in stirred tanks.

IMPROVING PERFORMANCE
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 [3] 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 [email protected].

References
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