Advancing Discovery and Growth of Crystalline Materials using Continuous-Flow, Well-Mixed Microfluidic Devices

Crystallization is an important step in various industrial applications. However, due to the various factors involved, developing effective and controlled crystallization processes have remained a long-time challenge. This has recently attracted research attention owing to its considerable effects on the physical properties of the resulting crystals. Presently, prediction of the crystallization taking into consideration the polymorphs, morphology and crystal sizes depend mainly on the estimated model parameters. Unfortunately, the prediction accuracy is limited to the range of crystallization within the model parameters.

To facilitate the design of crystallization processes in the early stages of materials discovery, the focus has shifted to the development of experimental screening techniques that can screen several factors to obtain specific crystal polymorphs and morphology. Based on the size scales, these techniques include mL-1 L batch crystallizers, mini-batch crystallizers, microfluidic device, and microtiter plates.

Recent advancement of screening techniques includes miniaturizing the compartments to accommodate several experiments in a single device. Whereas the external conditions i.e. temperature and solvent composition can be kept constant, the decrease in the internal conditions i.e. supersaturation greatly influence the formation of the polymorphs and morphology. Additionally, supersaturation has considerable effects on the crystallization kinetics, morphology and crystal sizes which may also lead to the gravitation of the produced polymorphs into different undesirable forms. Therefore, the development of a more controlled screening technique permitting nucleation and growth of crystals in a controlled supersaturation crystallization manner is highly desirable.

To this note, University of Illinois at Chicago researchers: Paria Coliaie (PhD candidate) and Dr. Meenesh Singh together with Dr. Manish Kelkar and Dr. Nandkishor Nere at the Center of Excellence for Isolation & Separation Technologies (CoExIST), Process R&D, AbbVie Inc. have developed an innovative continuous-flow, well-mixed microfluidic device for effective screening of polymorphs and morphology in a controlled supersaturated environment. Generally, the device depends on the continuous flow of solvents and antisolvents to create a vortex in the micromixer to allow the continuous crystallization of the solute at constant supersaturation. The scientists developed and validated their continuous-flow microfluidic device for the screening of crystal polymorphs at controlled supersaturation environments. The work was published and was featured on the cover of the research journal, Lab on a Chip.

Briefly, the research team cross-examined different types of microfluidic devices: T-junction, cell sorter, cross-flow, H-shaped and cyclone mixture. These devices typically entail three critical sections i.e. thermalizer used for cooling or heating the entering solution, mixer for mixing the antisolvent and solution and a diffuser to isolate the crystal from the flowing solution. Particularly, the H-shaped and cyclone mixer designs were used to validate the crystallization at constant supersaturation.

The developed device allowed for continuous crystallization of the solute through cooling the saturated solution or mixing the antisolvent. This was attributed to the fact that the H-shaped design was effective for screening crystals with slower kinetics while the cyclone mixer was used for crystals with faster kinetics. To actualize the study, it was necessary to analyze the polymorphs and morphology of o-aminobenzoic acid at different supersaturations and the results compared to that of the microtiter design. Interestingly, the design was observed to constantly screen stable polymorphs unlike in the microtiter plate where the polymorphs were affected by the depleting supersaturation. Altogether, the study by Dr. Meenesh Singh and the research team provides an excellent solution that will advance continuous manufacturing operations in pharmaceuticals industry and other materials manufacturing industries.