Introduction to Crystallization of Fine Chemicals and Pharmaceuticals - Molecules: Nucleation, Aggregation and Crystallization - page 146

to process variables such as concentration, temperature, agitation, and
impurities, as well as being strongly dependent on the properties of the
substance itself. It is therefore not reliable to directly extrapolate the
results for one substance to another, from one set of conditions to another,
or from laboratory scale to full scale. However, understanding the mech-
anisms and phenomena that decide various product properties make it
possible to interpret the results of one process under certain conditions in
a more qualified way, and thereby facilitate work on other processes, or
on the same process under different conditions. Crystallization of fine
chemicals and pharmaceuticals tends to be more complicated since a third
of all organic molecules may occur in different crystalline structures:
polymorphs and an additional third form solvates, i.e. the solvent appears
in the crystalline lattice. In addition, often such molecules are large and
flexible, and impurity molecules can be quite similar to the crystallizing
molecule. Usually, equipment is not specialized for crystallization of a
particular compound, and the agitation is not specialized for the particu-
lar crystallization process.
A crystallization process is evaluated in terms of production capacity
of crystals, purity of the product, and various solid state properties of the
solid material, such as crystal size distribution, crystal shape, crystal
structure and agglomeration. The solid state properties are important for
downstream processing, e.g. filtration, washing and drying, as well as for
the end-use properties like tableting, and dissolution rate.
Fundamentals
The fundamental requirement for a substance to be crystallized from
solution is that the concentration in the solution must be higher than the
solubility of the substance under the conditions in question, i.e. the solu-
tion has to be supersaturated with respect to the compound to be crystal-
lized. In a supersaturated solution, the compound may form nuclei,
extremely small solid particles having a crystalline structure, and crystals
may grow. During the process the crystals may also agglomerate into
larger particles.