Capillary precipitation of a highly polymorphic organic compound

Crystallization of pharmaceutically active compounds from saturated solutions by means of solvent evaporation typically involves a nucleation and growth process. At slow solvent evaporation rates, nuclei of the stable forms (polymorphs) will grow at the expense of any metastable forms present in the crystallizing mixture. A relatively phase-pure product is thus produced. However, if nucleation can be suppressed such that sufficiently high supersaturation ratios are obtained, then even nuclei of the metastable forms will grow rapidly and may persist in the end product. This work details the investigation of the crystallization of 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (ROY, a synthetic drug-substance intermediate) from supersaturated ethanol solutions. Nucleation was suppressed by crystallizing from small liquid volumes in glass-capillary tubes. It was found that the resultant crystals displayed a range of metastable forms. Results are discussed relative to classic nucleation theory.