Polymorphysm and crystallization: practical strategies for identifying, predicting and controlling

Polymorphism of molecular crystals is defined as the occurrence of more than one crystal phase of a chemically defined species. The phenomenon is an important subject for both fundamental and applied reasons. Since many drug substances are crystalline, polymorphism may affect the preparation, processing, storage, use and finally the efficacy of drug products. However, the isolation and detection of new polymorphs is still somewhat unpredictable. Basically it is still an open question to the academic world, and therefore increasingly researched. Much more crystal structures of polymorphic modifications will have to be determined before definite pronouncements can be made. Unlike inorganic solids, the frequency of polymorphism has not well-established for organic substances due to their directional chemical forces. The proposed research project is aimed at the better understanding of the molecular basis of polymorphism and contributes to the goal of making polymorphism more predictable. Here we intend to investigate a homologous series of drug compounds (e.g. local anaesthetics) which show structural differences due to substitutional variation in the molecular structure. When the variation includes the molecular part of one motif, or even of both motifs separately, the balance should be affected. The scales will shift during variation from giving more weight to the first motif to giving more weight to the second motif. The system may possibly go through a stage, where both influences are in balance, making it accessible to polymorphism. It therefore will be possible to fine-tune the eligibility for polymorphism. This research project is intended to give new insight into the basic structural features of polymorphism by applying crystal engineering approaches and it should make clearer how polymorphism is influenced by small changes in the molecular structure.