A microfluidic platform for pharmaceutical salt screening

Abstract

We describe a microfluidic platform comprised of 48 wells to screen for pharmaceutical salts. Solutions of pharmaceutical parent compounds (PCs) and salt formers (SFs) are mixed on-chip in a combinatorial fashion in arrays of 87.5-nanolitre wells, which constitutes a drastic reduction of the volume of PC solution needed per condition screened compared to typical high throughput pharmaceutical screening approaches. Nucleation and growth of salt crystals is induced by diffusive and/or convective mixing of solutions containing, respectively, PCs and SFs in a variety of solvents. To enable long term experiments, solvent loss was minimized by reducing the thickness of the absorptive polymeric material, polydimethylsiloxane (PDMS), and by using solvent impermeable top and bottom layers. Additionally, well isolation was enhanced via the incorporation of pneumatic valves that are closed at rest. Brightfield and polarized light microscopy and Raman spectroscopy were used for on-chip analysis and crystal identification. Using a gold-coated glass substrate and minimizing the thickness of the PDMS control layer drastically improved the signal-to-noise ratio for Raman spectra. Two drugs, naproxen (acid) and ephedrine (base), were used for validation of the platform's ability to screen for salts. Each PC was mixed combinatorially with potential SFs in a variety of solvents. Crystals were visualized using brightfield polarized light microscopy. Subsequent on-chip analyses of the crystals with Raman spectroscopy identified four different naproxen salts and five different ephedrine salts.

Normally-Closed Electrostatic Microvalve Fabricated Using Exclusively Soft-Lithographic Techniques and Operated With Portable Electronics

“…In their present state, even without the various further improvements we suggest above, the microvalves should already find utility in a variety of applications, including fully portable chips for solid form screening of pharmaceuticals [5], genomic analysis of cells [4], and antibiotic susceptibility screening of microbes [28].…”

“…Due to this desirable combination of traits, pneumatic microsystems are making significant strides toward addressing important issues, e.g., prenatal measurement of the fetal genome [4] and pharmaceutical screening [5]. However, portable applications, such as mobile chemical sensing and pointof-care diagnostics, have yet to benefit from the valves' complex fluid handling capabilities.…”

An advanced centrifugal microsystem toward high-throughput multiplex colloidal nanocrystal synthesis

“…For example, Lee et al and other groups reported massively parallel chemical synthesis on a microfluidic network using a large number of pneumatic valves [9][10][11][12]. Discrete nanolitre-to picoliter-sized droplet based platform was also presented for independent parallel chemical synthesis [13][14][15][16].…”

Fabrication of X-ray compatible microfluidic platforms for protein crystallization

“…Microfluidic platforms have gained widespread use in diverse fields like chemical synthesis, enzymatic and DNA analysis [1, 2], proteomics [3, 4], point-of-care, medical and clinical diagnostics [5–7], energy conversion [8, 9], and protein / pharmaceutical crystallization [10–14]. Microfluidics offers several advantages in terms of reduced sample size and easy preparation, fine control over transport phenomena on the microscale, ease of scalability, detection and sample analysis on a single, integrated platform [15, 16].…”