Elan Patria Nusadi

21030119190081

Applications of the Crystallization Process in the Pharmaceutical Industry

Sohrab ROHANI
Department of Chemical and Biochemical Engineering, University of Western Ontario, London,
Ontario N6A 5B9, Canada

Introduction
Solids are crystalline, partially crystalline, amorphous or subcooled liquids (such as glass). Crystalline
solids have long range order in which atoms, ions or molecules are arranged in unit cells forming the
crystal lattice. The unit cells can be cubic, tetragonal, orthorhombic, rhombohe- dral, hexagonal,
monoclinic or triclinic. The ability of a molecule to crystallize in different crystal forms is referred to
as polymorphism. In the case of elements, this phenomenon is called allotropism. For example, carbon
can exist in the form of diamond, graphite, fullerene and carbon nanotubes.
Crystallization can take place from the melt, from the solution, or from the vapor phase. Crystallization
of pharmaceuticals from the solution is conducted in batch or semi-batch crystallizers by reducing the
solubility of the solute in the solution and creating sufficient supersaturation. The quality of the final
crystal product is defined in terms of its purity, polymorphic and size distributions, habit and
morphology, residual solvent and crystal mechanical strength.
Crystallization can also be used for the preparation of micron-sized pharmaceuticals for pulmonary
administra- tion. Micro-crystallization can produce inhaler drugs with a size distribution between 1 μm
and 5 μm. In addition, we recently prepared magnetic nanoparticles and loaded them with progesterone
and covered the particles with chitosan for targeted and controlled release pulmonary applications.
Preparation of pharmaceuticals by crystallization and control of crystal properties
Crystallization from the solution is used extensively during the synthesis and purification of APIs. The
most efficient method is cooling crystallization. To improve the crystal yield, however, this is often
combined with evaporation or antisolvent addition.
Crystallization process to prepare pharmaceuticals for pulmonary delivery
For pulmonary drug delivery, the drug powder should have a narrow particle size distribution and a
mean particle size of 5 μm with nearly no particles larger than 10 μm. Besides the particle size of the
single particles, the pulmonary available fraction is determined by the aerodynamic behavior of the drug
powder. For a good dry powder inhaler (DPI) formulation, drug particles with low saturated.

Conclusions
Elan Patria Nusadi
21030119190081

Crystallization from the solution is an old process that has many diverse and useful applications in the
pharmaceutical industry. In this contribution, several such applications were highlighted. It was
demonstrated that the crystal properties of APIs prepared by crystallization may be controlled either by
proper selection of process variables such as the geometry of the crystallizer, the degree of mixing,
solvent type, seeding policy, etc., or by imple mentation of external control in the form of feedback or
optimal control. Formation of theophilline-nicotinamide co-crystals by grinding or slow evaporation to
enhance bioavailability of theophilline was demonstrated. Two methods, micro-crystallization and the
use of magnetic nanoparticles, were introduced for the preparation of progesterone for pulmonary
administration. The signifi cance of preferential crystallization for the separation of conglomerates
was discussed. Finally, single crystal information in the resolution of chloro-mandelic acid by
ethylphenylamine confirmed the importance of the CH/π interactions and van der Waals forces between
the less soluble and the more soluble salts when hydrogen-bonding exhibits identical features in systems
for successful resolution.