A molecule can crystallise in more than one crystal structure, a common
phenomenon in organic compounds known as polymorphism. Different polymorphic
forms may have significantly different physical properties, and a reliable prediction
would be beneficial to the pharmaceutical industry. However, crystal structure
prediction (CSP) based on the knowledge of the chemical structure had long been
considered impossible. Previous failures of some CSP attempts led to speculation
that the thermodynamic calculations in CSP methodologies failed to predict the
kinetically favoured structures. Similarly, regarding the stabilities of co-crystals
relative to their pure components, the results from lattice energy calculations and full
CSP studies were inconclusive. In this thesis, these problems are addressed using the
state-of-the-art CSP methodology implemented in the GRACE software. Firstly, it is
shown that the low-energy predicted structures of four organic molecules, which
have previously been considered difficult for CSP, correspond to their experimental
structures. The possible outcomes of crystallisation can be reliably predicted by
sufficiently accurate thermodynamic calculations. Then, the polymorphism of 5-
chloroaspirin is investigated theoretically. The order of polymorph stability is
predicted correctly and the isostructural relationships between a number of predicted
structures and the experimental structures of other aspirin derivatives are established.
Regarding the stabilities of co-crystals, 99 out of 102 co-crystals and salts of
nicotinamide, isonicotinamide and picolinamide reported in the Cambridge Structural
Database (CSD) are found to be more stable than their corresponding co-formers.
Finally, full CSP studies of two co-crystal systems are conducted to explain why the
co-crystals are not easily obtained experimentally.
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