[Illinois] A Microfluidic Approach for Cocrystallization of Drugs and Analysis via X-ray Diffraction
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Abstract
The process of pharmaceutical drug development is cost- and time-intensive. Candidate drugs (CDs) are screened with many counter ions (salt or cocrystal formers) to find solid forms of the drug with appropriate physicochemical (e.g., solubility, dissolution rate) properties. Cocrystals are multicomponent assemblies, such as CD and counter ion, which are held together with non-covalent interactions (typically hydrogen bonding). Cocrystallization is a convenient way to alter the physical properties of a solid form without affecting the chemical identity of the CD.Cocrystals can be generated via methods including solvent-assisted grinding, temperature control, antisolvent addition, and solvent evaporation. A crystal structure of the resulting cocrystal is often desired. However, growing good quality cocrystals that can be analysed using single crystal x-ray analysis is challenging. My research objective is to develop an integrated microscale total analysis system to enhance cocrystallization by utilizing an on-chip seeding approach followed by on-chip analysis of solid forms via Raman spectroscopy and x-ray diffraction. The specific aims of my research are: (1) design and fabricate a solvent compatible and x-ray transparent multiplexed microfluidic platform (72 individually addressable, 100 nl wells) for cocrystal seeding to grow diffraction quality crystals; (2) employ Raman spectroscopy and x-ray diffraction to identify cocrystals on-chip. The microfluidic platform is comprised of thin poly (dimethylsiloxane) fluid and control layers. These layers are sandwiched between cyclic olefin copolymer substrates that are solvent impermeable thereby minimizing solvent loss during crystallization. The control layers have normally closed valves that are used for fluid routing and mixing. The microfluidic platform allows for portability between the solution loading and the analysis stations. To conduct Raman and x-ray analysis on-chip, the device materials need to be Raman and x-ray transparent in order to minimize background noise. Cyclic olefin copolymer is Raman and x-ray transparent and the poly (dimethylsiloxane) layers were minimized to decrease x-ray absorption. This platform was designed to be less than 200 um thick. To circumvent the need to harvest the crystals for downstream analyses and the need to grow large isolated x-ray quality crystals, I intend to grow many, small crystals on-chip via seeding approach and collect small wedges of x-ray data. The many small crystals on the platform are assumed to be randomly oriented. By taking small wedges of data from many crystals a complete crystal structure can be solved.Harvesting crystals from the microfluidic platform is a tedious process that may damage the crystals and compromise the x-ray data and therefore is avoided. On-chip analysis allows for x-ray data to be collected at room temperature which provides more accurate lattice parameters as opposed to cryocooling of single crystals during traditional x-ray analysis.
Bio
Liz is a second year graduate student in Chemical Engineering. She is currently working on her Masters Degree and plans to complete her PhD. She completed her Bachelors Degree in Chemical Engineering at the University of California, Riverside in 2012. She is a student of Dr. Paul Kenis at Illinois. Source
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University of Illinois at Urbana-Champaign