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.

Single-Walled Zeolitic Nanotubes: Advantaged Supports for Poly(ethylenimine) in CO2 Separation from Simulated Air and Flue Gas.

Previous research has demonstrated that amine polymers rich in primary and secondary amines supported on mesoporous substrates are effective, selective sorbent materials for removal of CO2 from simulated flue gas and air. Common substrates used include mesoporous alumina and silica (such as SBA-15 and MCM-41). Conventional microporous materials are generally less effective, since the pores are too small to support low volatility amines. Here, we deploy our newly discovered zeolite nanotubes, a first-of-their-kind quasi-1D hierarchical zeolite, as a substrate for poly(ethylenimine) (PEI) for CO2 capture from dilute feeds. PEI is impregnated into the zeolite at specific organic loadings. Thermogravimetric analysis and porosity measurements are obtained to determine organic loading, pore filling, and surface area of the supported PEI prior to CO2 capture studies. MCM-41 with comparable pore size and surface area is also impregnated with PEI to provide a benchmark material that allows for insight into the role of the zeolite nanotube intrawall micropores on CO2 uptake rates and capacities. Over a range of PEI loadings, from 20 to 70 w/w%, the zeolite allows for increased CO2 capture capacity over the mesoporous silica by ∼25%. Additionally, uptake kinetics for nanotube-supported PEI are roughly 4 times faster than that of a comparable PEI impregnated in SBA-15. It is anticipated that this new zeolite will offer numerous opportunities for engineering additional advantaged reaction and separation processes.

In-line measurement of liquid-liquid phase separation boundaries using a turbidity-sensor-integrated continuous-flow microfluidic device.

Liquid-liquid phase separation (LLPS), also known as oiling-out, is the appearance of the second liquid phase preceding the crystallization. LLPS is an undesirable phenomenon that can occur during the crystallization of active pharmaceutical ingredients (APIs), proteins, and polymers. It is typically avoided during crystallization due to its detrimental impacts on crystalline products due to lowered crystallization rate, the inclusion of impurities, and alteration in particle morphology and size distribution. In situ monitoring of phase separation enables investigating LLPS and identifying the phase separation boundaries. Various process analytical technologies (PATs) have been implemented to determine the LLPS boundaries prior to crystallization to prevent oiling out of compounds. The LLPS measurements using PATs can be time-consuming, expensive, and challenging. Here, we have implemented a fully integrated continuous-flow microfluidic device with a turbidity sensor to quickly and accurately evaluate the LLPS boundaries for a ß-alanine, water, and IPA mixture. The turbidity-sensor-integrated continuous-flow microfluidic device is also placed under an optical microscope to visually track and record the appearance and disappearance of oil droplets. Streams of an aqueous solution of ß-alanine, pure solvent (water), and pure antisolvent (IPA or ethanol) are pumped into the continuous-flow microfluidic device at various flow rates to obtain the compositions at which the solution becomes turbid. The onset of turbidity is measured using a custom-designed, in-line turbidity sensor. The LLPS boundaries can be estimated using the turbidity-sensor-integrated microfluidic device in less than 30 min, which will significantly improve and enhance the workflow of the pharmaceutical drug (or crystalline material) development process.

Machine Learning-Driven, Sensor-Integrated Microfluidic Device for Monitoring and Control of Supersaturation for Automated Screening of Crystalline Materials.

Integrating sensors in miniaturized devices allow for fast and sensitive detection and precise control of experimental conditions. One of the potential applications of a sensor-integrated microfluidic system is to measure the solute concentration during crystallization. In this study, a continuous-flow microfluidic mixer is paired with an electrochemical sensor to enable in situ measurement of the supersaturation. This sensor is investigated as the predictive measurement of the supersaturation during the antisolvent crystallization of l-histidine in the water-ethanol mixture. Among the various metals tested in a batch system for their sensitivity toward l-histidine, Pt showed the highest sensitivity. A Pt-printed electrode was inserted in the continuous-flow microfluidic mixer, and the cyclic voltammograms of the system were obtained for different concentrations of l-histidine and different water-to-ethanol ratios. The sensor was calibrated for different ratios of antisolvent and concentrations of l-histidine with respect to the change of the measured anodic slope. Additionally, a machine-learning algorithm using neural networks was developed to predict the supersaturation of l-histidine from the measured anodic slope. The electrochemical sensors have shown sensitivity toward l-histidine, l-glutamic acid, and o-aminobenzoic acid, which consist of functional groups present in almost 80% of small-molecule drugs on the market. The machine learning-guided electrochemical sensors can be applied to other small molecules with similar functional groups for automated screening of crystallization conditions in microfluidic devices.

Patterned microfluidic devices for rapid screening of metal-organic frameworks yield insights into polymorphism and non-monotonic growth.

Metal-organic frameworks (MOFs) are porous crystalline structures that are composed of coordinated metal ligands and organic linkers. Due to their high porosity, ultra-high surface-to-volume ratio, and chemical and structural flexibility, MOFs have numerous applications. MOFs are primarily synthesized in batch reactors under harsh conditions and long synthesis times. The continuous depletion of metal ligands and linkers in batch processes affects the kinetics of the oligomerization reaction and, hence, their nucleation and growth rates. Therefore, the existing screening systems that rely on batch processes, such as microtiter plates and droplet-based microfluidics, do not provide reliable nucleation and growth rate data. Significant challenges still exist for developing a relatively inexpensive, safe, and readily scalable screening device and ensuring consistency of results before scaling up. Here, we have designed patterned-surface microfluidic devices for continuous-flow synthesis of MOFs that allow effective and rapid screening of synthesis conditions. The patterned surface reduces the induction time of MOF synthesis for rapid screening while providing support to capture MOF crystals for growth measurements. The efficacy of the continuous-flow patterned microfluidic device to screen polymorphs, morphology, and growth rates is demonstrated for the HKUST-1 MOF. The effects of solvent composition and pH modulators on the morphology, polymorphs, and size distribution of HKUST-1 are evaluated using the patterned microfluidic device. Additionally, a time-resolved FT-IR analysis coupled with the patterned microfluidic device provides quantitative insights into the non-monotonic growth of MOF crystals with respect to the progression of the bulk oligomerization reaction. The patterned microfluidic device can be used to screen crystals with a longer induction time, such as proteins, covalent-organic frameworks, and MOFs.

Single-walled zeolitic nanotubes.

We report the synthesis and structure of single-walled aluminosilicate nanotubes with microporous zeolitic walls. This quasi-one-dimensional zeolite is assembled by a bolaform structure-directing agent (SDA) containing a central biphenyl group connected by C10 alkyl chains to quinuclidinium end groups. High-resolution electron microscopy and diffraction, along with other supporting methods, revealed a unique wall structure that is a hybrid of characteristic building layers from two zeolite structure types, beta and MFI. This hybrid structure arises from minimization of strain energy during the formation of a curved nanotube wall. Nanotube formation involves the early appearance of a mesostructure due to self-assembly of the SDA molecules. The biphenyl core groups of the SDA molecules show evidence of π stacking, whereas the peripheral quinuclidinium groups direct the microporous wall structure.

Continuous Zeolite MFI Membranes Fabricated from 2D MFI Nanosheets on Ceramic Hollow Fibers.

High-quality 2D MFI nanosheet coatings were prepared on α-alumina hollow fiber supports by vacuum filtration and then transformed into molecular sieving membranes by two sequential hydrothermal treatments. This processing method eliminates the need for specially engineered silica-based support materials that have so far been necessary to allow the formation of functional membranes from 2D MFI nanosheets. The sequential steps enhance adhesion of the membrane on the fiber support, fill in nanoscale gaps between the 2D nanosheets, and preserve the desirable (0k0) out-of-plane orientation without the need of any support engineering or modification. The membrane exhibits high performance for separation of n-butane from i-butane, and for other technologically important hydrocarbon separations. The present findings have strong implications on strategies for obtaining thin, highly selective zeolite membranes from 2D zeolites in a technologically scalable manner.