Introduction to Crystallization of Fine Chemicals and Pharmaceuticals - Molecules: Nucleation, Aggregation and Crystallization - page 162

be dealt with by trying to reduce the degree of agglomeration, or chang-
ing the nature of the agglomerates, making them easier to wash.
Unfortunately, our knowledge concerning agglomeration is incomplete
and it is not possible to give general guidelines for reducing or increasing
the agglomeration in a process. Some studies have been reported in the lit-
erature, however (Åslund, Rasmuson, 1992). Agglomerates are formed as
a result of (i) particles colliding, (ii) particles held together in aggregates,
and (iii) the aggregates being cemented by continued crystal growth.
Agglomeration generally increases with increasing supersaturation.
Increased supersaturation often leads to more particles per unit volume,
and increases the growth rate of crystalline “bridges.” Normally, aggrega-
tion of particles is increased as the particle concentration goes up.
Agglomeration depends on crystal size, and is particularly important for
particles from 1 m. In general, agglomeration bene-

fits from reduced agitation, but in some cases agglomeration increases
with increasing stirring rate, and in others there is no dependence at all.
The size of agglomerates generally decreases with increased agitation.
Some other important factors for agglomeration are temperature, pH,
and additives/impurities. In crystallization of pharmaceuticals and fine
chemicals, often the solvent can have a profound influence on the ten-
dency for agglomeration and the properties of the agglomerates (Ålander,
Rasmuson, 2007).

µ m up to about 30 µ

The Process

Supersaturation can be generated by four different methods: cooling,
evaporation, addition of a substance or solvent that lowers the solubility,
and chemical reaction — alone or in combination. Cooling and evapora-
tion crystallizations are the most frequently occurring types.
In a cooling crystallization , the fact that the solubility normally
decreases with reduced temperature is utilized. Cooling can be achieved
by an indirect heat exchanger, by vacuum cooling, or through the use of
direct contact cooling. In vacuum cooling, the pressure is reduced so that
some solvent evaporation occurs. The heat of evaporation is taken from