Using magnetic levitation to separate mixtures of crystal polymorphs.

The crystallization of an organic compound can produce a mixture of crystalline solids with different solid-state structures (polymorphs). No convenient method now exists to separate crystals of a single polymorph from a mixture of crystals of different polymorphs. Of the physical properties that might be used to separate polymorphs, density is attractive for two reasons: 1) Different packings of molecules in a crystal often result in different densities for polymorphs; 2) Separations by density do not destroy the crystals. Magnetic levitation (MagLev) is a simple system that provides a continuous apparent density gradient in which to measure density and separate objects. MagLev can distinguish small differences in the density (D1= 0.01– 0.0001 gcm , depending on the type of the experiment) of diamagnetic objects. Although several methods to separate crystals by density exist, MagLev offers four advantages: 1) it separates multiple populations in a single step, 2) it quantifies the density of each population, 3) it is applicable to small crystals (100 mm size), and 4) it provides seed crystals for large-scale crystallization. We used MagLev to separate mixtures of polymorphs of four compounds: 5-methyl-2-[(2nitrophenyl)amino]-3-thiophenecarbonitrile (ROY) 1, sulfathiazole 2, carbamazepine 3, and trans-cinnamic acid 4 (Scheme 1).