Crystallization

Crystallization of
organic solids
Crystallization: a first order phase change in which
solid product is isolated from a solution, melt, vapor
or even from solid phase
Supersaturation: prerequisite for achieving
crystallization from solution

Solution Melt Crystallization Hydrothermal and

Crystallization -Solution evaporation Solvothermal Crystallization
-crystallization of an leads to solvent -Crystallization in the
organic compound inclusion or co-crystal presence of a solvent at
dissolved in a solvent formation (melt temperatures higher than the
or solvent mixture cooling) boiling point of solvent

Crystallization from a Crystallization of Chiral

Solid Phase Solids
-nucleation of a new - Chiral: type
compound from a solid of molecule that has a
phase non-superposable mirror
image
 Solubility Diagram
Crystallization-occurs ONLY in the
supersaturated region
Undersaturated-Below the
solubility
Metastable Zone Width (MSZW)-
is a critical parameter in the
crystallisation process as it reveals
the nucleation behaviour of the
system
MSZW- a nucleation kinetic-
limited parameter that is highly
dependent on process conditions
 Nucleation
Initiation of a phase change in a
small region, such as the formation
of a solid crystal from a liquid
solution
Consequence of rapid local
fluctuations on a molecular scale in a
homogeneous phase that is in a
state of metastable equilibrium
This transformation requires
traversing a free energy barrier
Primary nucleation (homogeneous)-
spontaneous
Secondary nucleation
(heterogenous)-induced by the
presence of foreign particles
 Crystal Growth
Crystal growth is a major stage of
a crystallization process, and consists
in the addition of new atoms, ions,
or polymer strings into the
characteristic arrangement of a
crystalline Bravais lattice
Once a crystal is stabilized from the
critical nucleus, the growth units can
diffuse from the surrounding
supersaturated solution to the
surface of the critical nucleus an
incorporate themselves onto the
crystal
Bravais lattice: is an infinite array of
discrete points generated by a set of
discrete translation operations
described by:

where ni are any integers and ai are

known as the primitive vectors which
lie in different directions and span
the lattice
 Polymorphism
Polymorph: Crystals in which chemical compound
takes different arrangements of molecules-solid
state phenomenon
Different morphologis, solubilities, color, melting,
sublimation temperatures, densities, thermal/
elctrical conductivities
Pharmaceutical industry-affect processing
properties such as filtering, drying, flow,
tabletting, rate of dissolution, shelf life and
bioavailability
 Thermodynamics of Polymorphism
Monotropic forms- A is
more stable that the other
at all temperatures
Enantiotropic forms-there
is a transition temperature
below melting point
Transition temp:
temperature at which the
free energy of polymorph
A intersects the free
energy of polymorph B
 Intermolecular interactions
A molecular crystal- periodic
assembly of molecules
Van der Waals Interactions: total
of attractive and repulsive forces
between molecules, inclusive of
hydrogen bonds.
Hydrogen Bonds: stabilizing
interaction between donor X..H
and acceptor Y..Z
Halogen Bonds
Other interactions: polarization
 Crystal Engineering
Understanding of
intermolecular
interactions - context
of crystal packing-
utilization of such
understanding -
designing of new
solids with desired
physical and chemical
properties