Aniruddh Singh, In Sung Lee, and Allan S. Myerson. Department of Chemical and Biological Engineering, Illinois Institute of Technology, 10 West 33rd St., Suite 223, Chicago, IL 60616
Polymorphism is the ability of a chemical compound to exist in more than one crystal structure. Different polymorphs of a drug substance can have different physicochemical properties and bioavailability. Thus, polymorph screening is essential in the early stages of the drug development process. The compound 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (known as ROY for its red, orange and yellow crystals) is an often studied system because of the large number of polymorphs which are known to exist. ROY has ten known polymorphs, seven with solved structures and three whose structures have not been solved. Recently, our group has engineered patterned substrates of self-assembled monolayers (SAMs), which consist of lyophilic gold islands surrounded by a lyophobic domain. With this approach, we have demonstrated the concomitant nucleation of multiple polymorphic forms under the same conditions with glycine, mefenamic acid, and sulfathiazole. In this work, crystallization experiments were conducted using patterned substrates of SAMs with solutions of ROY in dimethylsulfoxide (DMSO). The patterned bifunctional surface was immersed and slowly withdrawn from undersaturated solutions. The solution preferentially wetted the metallic islands, and as the solvent evaporated, ROY crystals exclusively nucleated on the lyophilic metallic islands. Raman microscopy was utilized to characterize the crystalline form on each metallic island. We were able to crystallize six of the seven stable polymorphs of ROY using this method, including form YT04, which to the best of our knowledge, has never been obtained from solution crystallization. In one of the experiments, over 10,000 islands were analyzed and three forms of ROY were obtained in very low percentages. This result shows how increasing the number of crystallization trials can help crystallize polymorphs which may not be obtained in a fewer number of trials due to statistical reasons.