Snap-on Adaptor for Microtiter Plates to Enable Continuous-Flow Microfluidic Screening and Harvesting of Crystalline Materials

Microtiter plate assay is a conventional and standard tool for high-throughput (HT) screening that allows the synthesis, harvesting, and analysis of crystals. The microtiter plate screening assays require a small amount of solute in each experiment, which is adequate for a solid-state crystal analysis such as X-ray diffraction (XRD) or Raman spectroscopy. Despite the advantages of these high-throughput assays, their batch operational nature results in a continuous decrease in supersaturation due to crystal nucleation and growth. Continuous-flow microfluidic mixer devices have evolved as an alternate technique for efficiently screening crystals under controlled supersaturation. However, such a microfluidic device requires a minimum of two inlets per micromixer to create cyclonic flow, thereby creating physical limitations for implementing such a device for HT screening. Additionally, the monolithic design of these microfluidic devices makes it challenging to harvest crystals for post-screening analysis. Here, we develop a snap-on adapter that can be reversibly attached to a microtiter plate and convert it into a continuous-flow microfluidic mixer device. The integration of the snap-on adapter with a flow distributor and concentration gradient generator provides greater control over screening conditions while minimizing the number of independent inlets and pumps required. The three-dimensional (3D)-printed snap-on adaptor is plugged into a 24-well plate assay to demonstrate salt screening of naproxen crystals. Different naproxen salts are crystallized using four different salt formers (SFs)sodium hydroxide, potassium hydroxide, pyridine, and arginineand four different solvents–ethanol, methanol, isopropyl alcohol, and deionized water. The wells are further inspected under an optical microscope to identify their morphological forms and yields. The crystals are then harvested for solid-state characterization using XRD and Fourier transform infrared spectroscopy, followed by measurement of their dissolution rates. The flexibility of the snap-on adapter to fit on a wide range of microtiter plates and the ease in harvesting and analyzing crystals postscreening are two significant advantages that make this device versatile for various applications.