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1.
ACS Omega ; 8(44): 41502-41511, 2023 Nov 07.
Article in English | MEDLINE | ID: mdl-37969966

ABSTRACT

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.

2.
Lab Chip ; 22(2): 211-224, 2022 01 18.
Article in English | MEDLINE | ID: mdl-34989369

ABSTRACT

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.


Subject(s)
Metal-Organic Frameworks , Lab-On-A-Chip Devices , Metal-Organic Frameworks/chemistry , Microfluidics , Porosity , Spectroscopy, Fourier Transform Infrared
3.
Lab Chip ; 21(12): 2333-2342, 2021 06 15.
Article in English | MEDLINE | ID: mdl-34096561

ABSTRACT

A flow-controlled microfluidic device for parallel and combinatorial screening of crystalline materials can profoundly impact the discovery and development of active pharmaceutical ingredients and other crystalline materials. While the existing continuous-flow microfluidic devices allow crystals to nucleate under controlled conditions in the channels, their growth consumes solute from the solution leading to variation in the downstream composition. The materials screened under such varying conditions are less reproducible in large-scale synthesis. There exists no continuous-flow microfluidic device that traps and grows crystals under controlled conditions for parallel screening. Here we show a blueprint of such a microfluidic device that has parallel-connected micromixers to trap and grow crystals under multiple conditions simultaneously. The efficacy of a multi-well microfluidic device is demonstrated to screen polymorphs, morphology, and growth rates of l-histidine via antisolvent crystallization at eight different solution conditions, including variation in molar concentration, vol% of ethanol, and supersaturation. The overall screening time for l-histidine using the multi-well microfluidic device is ∼30 min, which is at least eight times shorter than the sequential screening process. The screening results are also compared with the conventional 96-well microtiter device, which significantly overestimates the fraction of stable form as compared to metastable form and shows high uncertainty in measuring growth rates. The multi-well microfluidic device paves the way for next-generation microfluidic devices that are amenable to automation for high-throughput screening of crystalline materials.


Subject(s)
Lab-On-A-Chip Devices , Microfluidic Analytical Techniques , Crystallization , High-Throughput Screening Assays , Kinetics , Solutions
4.
J Org Chem ; 84(8): 4661-4669, 2019 04 19.
Article in English | MEDLINE | ID: mdl-30388009

ABSTRACT

The development of an improved short and efficient commercial synthesis of the JAK2 inhibitor, a complex pyrrolopyridine, BMS-911543, is described. During the discovery and development of this synthesis, a Pd-catalyzed C-H functionalization was invented which enabled the rapid union of the key pyrrole and imidazole fragments. The synthesis of this complex, nitrogen-rich heterocycle was accomplished in only six steps (longest linear sequence) from readily available materials.


Subject(s)
Heterocyclic Compounds, 3-Ring/pharmacology , Protein Kinase Inhibitors/pharmacology , Catalysis , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemistry , Humans , Janus Kinase 2/antagonists & inhibitors , Janus Kinase 2/metabolism , Ligands , Molecular Structure , Palladium/chemistry , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry
5.
J Org Chem ; 80(12): 6001-11, 2015 Jun 19.
Article in English | MEDLINE | ID: mdl-25848821

ABSTRACT

BMS-911543 is a complex pyrrolopyridine investigated as a potential treatment for myeloproliferative disorders. The development of a short and efficient synthesis of this molecule is described. During the course of our studies, a Ni-mediated C-N bond formation was invented, which enabled the rapid construction of the highly substituted 2-aminopyridine core. The synthesis of this complex, nitrogen-rich heterocycle was accomplished in only eight steps starting from readily available materials.


Subject(s)
Heterocyclic Compounds, 3-Ring/chemical synthesis , Janus Kinase 2/antagonists & inhibitors , Nickel/chemistry , Catalysis , Heterocyclic Compounds, 3-Ring/chemistry , Hydrogen Bonding , Janus Kinase 2/chemistry , Molecular Structure
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