Microfluidic approach to polymorph screening through antisolvent crystallization

Abstract

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. The small volumes (37 nL) and the ability to screen a wide range of supersaturations through diffusive mixing make this platform especially useful for solid form development at discovery and early development stages in pharmaceutical industry. To validate this microfluidic approach, we conducted on-chip antisolvent crystallization using indomethacin. Solvent choice, supersaturation level, and antisolvent-to-solution ratio were found to affect the resulting crystal form of the solids prepared on chip. We modelled the representative time-dependent concentration profiles during the mixing of the antisolvent and API solutions. Combining this analysis with solubility data yielded spatiotemporal supersaturation profiles, which we correlated with solid formation as observed experimentally. Experimental section Chip assemblyThe crystallization platform is comprised of a thin multilayer polydimethylsiloxane (PDMS, General Electric RTV 650 Part A/B) chip fabricated using standard multilayer soft lithographic procedures reported previously 23,24 with some modifications. The thickness of the control layer was reduced to 70 mm by spin

Fabrication of X-ray compatible microfluidic platforms for protein crystallization

“…After mixing, the mixing valves are closed, the inlets of these control lines are sealed with Crystal Clear tape, and the chips are incubated at either 4°C or room temperature for 8–48 hours. Previously, we have used a similar microfluidic array chip for solid form screening of candidate pharmaceuticals [14], but this platform lacked X-ray transparency.…”

“…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].…”

“…A microfluidic approach has the potential to meet these requirements. For example, we recently reported a microfluidic array chip for solid form screening of candidate pharmaceuticals [14], but this chip lacks X-ray transparency. The first step in protein crystallization involves screening a protein against a wide range of precipitants to identify suitable crystallization condition(s).…”

Crystallization of Amino Acids on A 21-Well Circular PMMA Platform Using Metal- Assisted and Microwave-Accelerated Evaporative Crystallization

“…Microfluidic platforms were also used to screen for pharmaceutical salts and polymorphs of heat sensitive active pharmaceutical ingredients through antisolvent crystallization, as an alternative method. [12],[13] However, evaporative crystallization based on the traditional room temperature crystallization method still takes hours to days to occur in laboratory bench scale. [14] ,[9],[15] Subsequently, there is still a need for crystallization platforms that offer rapidity and control over crystal size and morphology of amino acid crystals.…”

“…In response to the aforementioned needs, the Aslan Research Group has described and demonstrated the use of MA-MAEC for the rapid crystallization of several amino acids[9, 13, 16, 17] and a pharmaceutical compound. [18] In MA-MAEC, the combined use of plasmonic nanostructures (i.e., SNFs) and microwave heating affords for the rapid crystallization of amino acids without altering the physical properties of the crystal.…”