Concomitant Crystallization of ROY on Patterned Substrates: Using a High Throughput Method to Improve the Chances of Crystallization of Different Polymorphs

Abstract

In this study, we demonstrate 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. Crystallization experiments were conducted using patterned substrates of self-assembled monolayers (SAMs) with solutions of 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (known as ROY for its red, orange, and yellow crystals) 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 The patterned bifunctional surface was immersed and slowly withdrawn from undersaturated solutions.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. In one of the experiments, over 10 000 islands were analyzed, and we calculated the probability of crystallizing a particular polymorph on an 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.

Highly Selective, Kinetically Driven Polymorphic Selection in Microfluidic Emulsion-Based Crystallization and Formulation

“…27 Recent pharmaceutical development has seen an increase in the number of lipophilic and nonpolar API molecules, 9 such as ROY, which do not easily self-assemble and are prone to liquid−liquid phase separation. 25,29 Further, the metastable liquid−liquid state is known to hinder primary and secondary nucleation, leading to long crystallization process times of up to 35 h; 30 often, special measures are needed to move the system away from this part of the phase diagram to promote nucleation and growth of crystals. 27,29−31 This is in keeping with our observations of longer crystallization times for this case, as compared to the results with excipient.…”

Supersaturation rates and schedules: Nucleation kinetics from isothermal metastable zone widths

“…3 shows that for points over the entire range of B and Da in Fig. 2, the exact expression (12) deviates from the approximate expression (14) in a very predictable manner.…”

“…Several theories and experimental techniques have been developed to identify and interpret the metastability limit, which is often called the metastable zone width (MZW) [3][4][5][6][7][8]. The MZW is important for many experiments and processes that carefully control the number of nuclei and crystallites under conditions where the supersaturation varies in time [3][4][5][6][9][10][11][12][13][14][15][16]. Polythermal MZW experiments often involve steadily changing the temperature, which changes the supersaturation and increases the rate of nucleation [17][18][19][20][21][22][23].…”

Polymorphism and Solvatomorphism 2009

“…In one study, patterned bifunctional surfaces were immersed and slowly withdrawn from unsaturated dimethylsulfoxide solutions containing 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (ROY), whereupon crystals exclusively nucleated on the lyophilic metallic islands. 27 Comparison of crystallization outcome has been made between a high-throughput method based on patterned substrates of self-assembled monolayers and cooling crystallization and slurry aging experiments on sulfathiazole, mefenamic acid, flufenamic acid, and ROY. 28 It was shown that the same number of polymorphs were obtained in the case of sulfathiazole and mefenamic acid using the two approaches, whereas three of the forms of ROY could not be produced using the semiautomated approach.…”