Crystal Growth of Aspirin Using a Temperature-Controlled Microfluidic Device (original) (raw)
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Crystal Growth & Design, 2015
We describe a microfluidic approach to optimize crystallization of active pharmaceutical ingredients (APIs) and their solid forms (cocrystals) via crystal seeding. Subsequent on-chip X-ray diffraction is used to verify crystal from. The microfluidic platform is comprised of an 8 x 9 well array, that enables screening of seeding conditions (dilutions) by metering of API solution or API/cocrystal former solution and seed solution in ratios of 1:4 to 4:1respectively across each row. Slow solvent evaporation leads to seed growth and results in isolated diffraction quality crystals. To validate this microfluidic crystal seeding approach, three APIs (piroxicam, piracetam, and carbamazepine) and a cocrystal (carbamazepine / 4-hydroxy benzoic acid) were used as model compounds. X-ray diffraction data was collected on-chip at room temperature to determine the crystal structure of the model compounds for comparison to published structural data. This on-chip seeding approach aided in crystallization of a desired solid form (e.g., a specific polymorph) over a mixture of solid forms. Easy handling, automated seeding and dilution, high throughput screening using small quantities of API (about 5 µg /well), and on-chip X-ray analysis of multiple crystals makes this platform attractive for solid form identification and characterization.
Advances in the Use of Microfluidics to Study Crystallization Fundamentals
Annual Review of Chemical and Biomolecular Engineering
This review compares droplet-based microfluidic systems used to study crystallization fundamentals in chemistry and biology. An original high-throughput droplet-based microfluidic platform is presented. It uses nanoliter droplets, generates a chemical library, and directly solubilizes powder, thus economizing both material and time. It is compatible with all solvents without the need for surfactant. Its flexibility permits phase diagram determination and crystallization studies (screening and optimizing experiments) and makes it easy to use for nonspecialists in microfluidics. Moreover, it allows concentration measurement via ultraviolet spectroscopy and solid characterization via X-ray diffraction analysis. Expected final online publication date for the Annual Review of Chemical and Biomolecular Engineering Volume 10 is June 7, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Single-Step Drug Crystallization and Formulation–‘Designer’Pharmaceuticals Enabled by Microfluidics
We present a single step formulation platform for the fabrication of 'designer' pharmaceuticals where we specifically co-formulate drugs and excipient as monodisperse spherical microparticles of ~200 µm size containing crystals of a hydrophobic model drug (ROY) embedded within a hydrophilic matrix of an excipient (sucrose) and a hydrophilic model drug (glycine). For this we use capillary-based microfluidic double emulsions to perform formulation followed by spherical crystallization via solvent evaporation. The method completely circumvents several energy intensive 'topdown' processes in traditional manufacturing, thereby offering the potential for continuous, sustainable pharmaceutical crystallization coupled with advanced formulations.
Microfluidic devices were designed to perform on micromoles of biological macromolecules and viruses the search and the optimization of crystallization conditions by counter-diffusion, as well as the on-chip analysis of crystals by X-ray diffraction. Chips composed of microchannels were fabricated in poly-dimethylsiloxane (PDMS), poly-methyl-methacrylate (PMMA) and cyclo-olefincopolymer (COC) by three distinct methods, namely replica casting, laser ablation and hot embossing. The geometry of the channels was chosen to ensure that crystallization occurs in a convection-free environment. The transparency of the materials is compatible with crystal growth monitoring by optical microscopy. The quality of the protein 3D structures derived from on-chip crystal analysis by X-ray diffraction using a synchrotron radiation was used to identify the most appropriate polymers. Altogether the results demonstrate that for a novel biomolecule, all steps from the initial search of crystallization conditions to X-ray diffraction data collection for 3D structure determination can be performed in a single chip.
Crystallization via tubing microfluidics permits both in situ and ex situ X-ray diffraction
Acta crystallographica. Section F, Structural biology communications, 2017
A microfluidic platform was used to address the problems of obtaining diffraction-quality crystals and crystal handling during transfer to the X-ray diffractometer. Crystallization conditions of a protein of pharmaceutical interest were optimized and X-ray data were collected both in situ and ex situ.
Microfluidic approach to polymorph screening through antisolvent crystallization
2012
Here we present a microfluidic platform comprised of 48 wells to screen for polymorphs of active pharmaceutical ingredients (API) through antisolvent crystallization. API solutions and anti-solvents are precisely metered in various volumetric ratios (range from 50: 10 to 10: 50), and mixed via diffusive mixing on-chip. Optical microscopy and Raman spectroscopy were used to analyze the resultant solids.
Determining optimal conditions for the production of well diffracting crystals is a key step in every biocrystallography project. Here, a microfluidic device is described that enables the production of crystals by counter-diffusion and their direct on-chip analysis by serial crystallography at room temperature. Nine 'nonmodel' and diverse biomacromolecules, including seven soluble proteins, a membrane protein and an RNA duplex, were crystallized and treated on-chip with a variety of standard techniques including micro-seeding, crystal soaking with ligands and crystal detection by fluorescence. Furthermore, the crystal structures of four proteins and an RNA were determined based on serial data collected on four synchrotron beamlines, demonstrating the general applicability of this multipurpose chip concept.
Microfluidic platforms for the screening of solid forms of candidate drugs
ABSTRACT This paper reports a microfluidic platform to screen for crystallization conditions of candidate drugs (CD). Identification of solid forms of CDs on a microfluidic platform provides critical information regarding a given CD's physiological properties, which is crucial in the selection of the most promising CDs. On-chip screening for crystallization conditions is carried out through three different methods: free interface diffusion, temperature control, and/or directed evaporation.
Microfluidic platform for optimization of crystallization conditions
Journal of Crystal Growth, 2017
We describe a universal, high-throughput droplet-based microfluidic platform for crystallization. It is suitable for a multitude of applications, due to its flexibility, ease of use, compatibility with all solvents and low cost. The platform offers four modular functions: droplet formation, on-line characterization, incubation and observation. We use it to generate droplet arrays with a concentration gradient in continuous long tubing, without using surfactant. We control droplet properties (size, frequency and spacing) in long tubing by using hydrodynamic empirical relations. We measure droplet chemical composition using both an off-line and a realtime on-line method. Applying this platform to a complicated chemical environment, membrane proteins, we successfully handle crystallization, suggesting that the platform is likely to perform well in other circumstances. We validate the platform for fine-gradient screening and optimization of crystallization conditions. Additional on-line detection methods may well be integrated into this platform in the future, for instance, an on-line diffraction technique. We believe this method could find applications in fields such as fluid interaction engineering, live cell study and enzyme kinetics.