Addition strategies. Often addition takes place at a constant rate. This linear-profile procedure can yield a variable supersaturation whereby the MZ is exceeded early on, resulting in too much nucleation.
As Figure 3 shows, an initial slow addition rate followed by a gradual increase in rate can achieve a fairly constant supersaturation within the zone. This non-linear profile is analogous to the ones utilized for batch cooling or evaporative crystallizations . The goal is to maintain the supersaturation of the solution consistently within the MZ while achieving constant relief of the same as growth on existing crystal surface area. As already noted, seeding techniques can help produce this desired outcome.
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:
2. micromixing; and
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.)