Crystallization and polymorphism of conformationally flexible molecules: Problems, patterns, and strategies

Two effects of conformational flexibility on crystallization, namely conformational polymorphism and reduction of crystallization tendency, are discussed using examples from the literature and our own studies. The preferred molecular conformations observed in several polymorphic systems are correlated with the nature of the forces present in the crystals. The reduction of crystallization tendency for conformationally flexible molecules arises from the presence of multiple conformers in the crystallizing media and the need for certain molecules to crystallize in high-energy conformations. Despite their peculiarities, the control of crystallization of conformationally flexible molecules should begin with traditional approaches applicable to most crystallization situations. However, special techniques, including conformational mimicry, solvent-mediated self-assembly, and templated growth, have been devised to introduce molecular-level control to the crystallization process.