The Effect of Controlled Mixing on ROY Polymorphism ^†

In this work, we report the investigation of various experimental conditions and their influence on the polymorphism of 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophen carbonitrile, commonly known as ROY. These conditions include an in-house-developed microfluidic chip with controlled mixing of parallel flows. ROY is known for its ability to form a large variety of polymorphs, including at least ten forming under standard conditions. Nucleation is triggered by adding water as an antisolvent to ROY dissolved in acetone. We observe that different ROY concentrations and different solvent-to-antisolvent ratios naturally favor different polymorphs. Nevertheless, identical samples prepared with different mixing methods, such as shaking and magnetic stirring, consistently lead to the formation of different polymorphs. In addition, different mixing rates that can be linked to shear stress strongly influence the crystallization. A fourth parameter, namely confinement of the sample, is also found to be critical. Untangling all of these parameters and their influences on polymorphism calls for an experimental setup allowing all four to be controlled accurately. To that end, we developed a novel customized microfluidic setup allowing reproducible and controlled mixing conditions. Two parallel flows of antisolvent and ROY dissolved in solvent are injected into a transparent microchannel. Next, slow and progressive mixing can be achieved through molecular diffusion. Additionally, the microfluidic chip is equipped with a piezoceramic element, allowing the implementation of various mixing rates through acoustic mixing. With this device, we demonstrate the importance of parameters other than concentration that are involved in the polymorphism of ROY.