ABSTRACT
INTRODUCTION A computational method of predicting all polymorphs of a given pharmaceutical molecule, and the conditions under which they could be found, requires a fundamental understanding of the causes of polymorphism. A computational model would only be reliable if it incorporated all the factors that can affect which polymorphs can be found. Given the diversity of methods that can generate new polymorphs (1) , and the disappearance of polymorphs due to changes in impurity profi les (2) , modelling all relevant factors currently seems almost impossible. At the moment, we can aspire to compute the crystal energy landscape, the set of structures that are thermodynamically feasible, for a specifi c compound (3) . We can predict the most thermodynamically stable structure that should exist at specifi ed thermodynamic conditions, if we have performed the calculation of the relative energies suffi ciently accurately. Currently, this is the only crystal structure that can be predicted, by assuming thermodynamic control of crystallization. However, comparing the other low-energy structures on the computed crystal energy landscape with each other and with the known polymorphs can provide considerable insight into the possible solid form diversity (4) . Using computational modelling in conjunction with the experimentally determined crystal structures can help provide an atomic level picture of the factors that are infl uencing the crystallization of a molecule, from guiding the experimental search to seek polymorphs with alternative packing motifs, to using the similarity between predicted structures to suggest the likely forms of disorder or crystal growth problems. Gaining a molecular level of understanding of crystallization presents challenges to both experimental characterization of solids and nucleation processes (5) , and computational chemistry (6) . Thus, this chapter seeks to demonstrate the types of insight into polymorphism that can come from combining various computational tools with experimental work, with due allowance for the limitations of the complementary techniques.
