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Crystallization and Polymorphism of Chiral Compounds

Qi Gao and Alicia Ng. Analytical R&D, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ 08901

It is a commonly shared experience among chemists/engineers working in the field of crystallization - and often a source of frustration - that chiral compounds tend to be more difficult to crystallize than racemic compounds. Indeed, racemic crystals occur more frequently than enantiomorphic crystals. This has been attributed to Wallach's rule, which states that racemic crystals tend to be denser - the left and right hands are arranged around centers of symmetry, and their packing is thus more efficient than their enantiomorphic counterparts, and therefore more stable. In addition, symmetry constraints limit the number of favorable packing arrangements available to chiral molecules. Using our own examples and some from the Cambridge Crystal Structure Database, this paper discusses polymorphism of chiral compounds, structure-stability relationships of polymorphs, and how they are related to their racemates.