| dc.description.abstract | Controlling crystal polymorphism, the ability of a molecule to crystallise in
different solid forms, is one of the grand, ongoing challenges in materials science.
In the pharmaceutical industry particularly, where up to half of the
active pharmaceutical active ingredients exhibit polymorphic behaviour,
it is of paramount importance to rationalise the impact of experimental
conditions, such as the nature of the solvent, on the obtainment of a specific c crystal form. As strategies for the selection of polymorphs is still, by and large, based on a trial-and-error approach, it is necessary to acquire
a fundamental understanding of the factors controlling the formation of a
speci fic solid-state structure during crystallisation from solution.
During this doctoral research project, we have conducted a computer simulation
study of the early stages of crystallisation of meta-aminobenzoic
acid, an important model system in the investigation of polymorphic phenomena.
This molecule can in fact form five different polymorphic forms
whose selective crystallisation from solution chiefly depends on the nature
of the solvent.
Molecular models and computational chemistry methods, based on density
functional theory and molecular dynamics, have been developed and
applied to quantify the processes surrounding the crystallisation of meta-aminobenzoic acid: solvent-solute separation, solute aggregation and surface
reactivity. The aim was to identify what controls, at the molecular
level, the polymorphic selection process during crystallisation from solution
of this important active pharmaceutical ingredient.
The results show that the solvent play a signi cant role during the key
stages of meta-aminobenzoic acid crystallisation by controlling both the
kinetics and thermodynamics of solute desolvation, formation of prenucleation
clusters and surface reactivity. This work represents a paradigm
of the role of molecular processes during the early stages of nucleation in
affecting polymorph selection during crystallisation from solution. | en_US |
