Introduction to Crystallization of Fine Chemicals and Pharmaceuticals - Molecules: Nucleation, Aggregation and Crystallization - page 150

Primary nucleation

Metastable
limit

Supersaturated

Solubility
curve

Metastable

Supersaturation

Undersaturated

Temperature

Fig. 2. Schematic description of the conditions of nucleation (left) and the behavior of
primary nucleation (right). The diagram on the left shows solute concentration in the
solution, e.g. in units of [kg solute/kg solvent], versus solution temperature in degrees
centigrade or Kelvin. The solid line is the solubility curve, and the dashed line represents
the metastable limit. When the solution conditions reach the metastable limit, i.e. when
the level of supersaturation reaches the metastable limit, usually an enormous number of
new crystals are created very rapidly — primary nucleation [no/kg solvent, s]. The dia-
gram on the right shows that the rate of primary nucleation is strongly dependent on the
supersaturation.

The term secondary nucleation denotes nucleation by mechanisms
that require the presence of crystals in the solution. Secondary nucleation
depends on the amount of crystals in the solution, and is often consider-
able even within the metastable zone. One of the most important mecha-
nisms of secondary nucleation is attributed to collisions in the system.
Crystals collide with one another and with the equipment (walls and
impeller), causing the formation of new nuclei. In cases where there is vis-
ible damage to the mother crystal, this is called fragmentation, otherwise
the term “contact nucleation” can be used. Furthermore, more or less
ordered molecular clusters can be present at the crystal-solution interface.
Collisions, but also shear forces in the liquid, may dislodge these struc-
tures, which may then turn into nuclei. Different substances show varying
degrees of proclivity towards secondary nucleation. Secondary nucleation