Introduction to Crystallization of Fine Chemicals and Pharmaceuticals - Molecules: Nucleation, Aggregation and Crystallization - page 168

After the initial nucleation peak, the solid mass increases rapidly since the
supersaturation is still high. The supersaturation is quickly consumed, and
the primary nucleation subsides. Due to the increasing magma density,
secondary nucleation starts, but is stabilized at a fairly low level. With
controlled cooling, the cooling rate is better adjusted to the surface area
that is available for consumption of the supersaturation. For a fairly long
time, a crystal surface is gradually developed that is able to counteract a
fast increase in supersaturation. The peak in supersaturation occurs late,
and is much lower. Due to higher supersaturation late in the process in
comparison with natural cooling, the secondary nucleation is substantially
higher towards the end. With seeding, the early peak in supersaturation is
further reduced, and thereby also the primary nucleation. The seed crys-
tals provide area at the beginning of the process and contribute to keeping
the supersaturation level under control. With seeding, the size distribution
may become bimodal, i.e. it will consist of two distinct peaks correspon-
ding to the seeded crystals and the crystals formed through nucleation.
The mean weight size and the CV depend on the amount of seeds added.
For controlled cooling, a long period of time is used for cooling just
a few degrees early in the process. It is therefore crucial that the controlled
cooling starts rather precisely when the solution is saturated. When seeds
are used, it is important that these are added when the solution is within
the metastable zone. If the solution is undersaturated, the seeds will sim-
ply dissolve. In practice, it is often hard to know exactly when the solu-
tion is saturated, as the solubility can vary from one batch to another, and
the precision of temperature measurement is not always sufficiently good
in terms of supersaturation. Simulations of batch crystallizations show
that the process is very sensitive to initial supersaturation, the shape of the
cooling curve, and seeding (Bohlin, Rasmuson, 1992).
Seeding is used to control the product size in batch crystallizations, and
to improve the reproducibility. There are three different principles for choos-
ing the number and size of the seed crystals. One strategy is to add just the
number of crystals that are desired in the end product, of a size that will
lead to crystals of the required size after growth. This method demands
that the process is operated so that nucleation is avoided. A second strategy