Lab-on-Chip LC as a PAT Tool for Process

Monitoring

Scott GilbertCrystal Vision Microsystems LLCCPAC Visiting Scholar

CPAC Summer Institute July 15-17, 2008

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Requirements for an effective on-line HPLC analyzer

Small footprint, self-contained miniaturized HPLC unit for plant deploymentMinimally invasive – sub-ml sample sizeNear-real time analysis – 1 to 2 minutesZero sample cross talkEase of maintenance – minimize moving partsRobust

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Concept of a Modular LC Process Analyzer based on microfluidic Lab-on-Chip

NeSSI Generation III dream analyzer

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microLC NeSSI Configuration

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NeSSI microLC System

Full view of experimental modular LC prototype mounted on a Parker-Hannifin Intraflow™ pegboard with pressure control for fluid reservoirs. Sample circulation lines are connected to block.

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Details of NeSSI LC Sensor

Sampling technique takes advantage of pressure in sample loop

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Functional Integration of μ-fluidic LC Chip for On-line Sample Pretreatment

3 in

Electrical contact pads

mixer

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Monolithic continuous beds in microchannels -very fast baseline separations

Source: C. Ericson et al. Anal. Chem. 2000 72, 81-87.

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Sampling / Injection

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Chip under flow with two streams: fluorescent fluorescein dye tracer (green) and mobile phase (colorless) [video clip]

Detail of chromatographic injection of fluorescent dye tracer (video clip)

mixer

column

mobile phase

fluorescein dye

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Plug generation by flow-injection

20mm

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On-line sampling set-up

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Initial performance

Dilution performance at constant analyte concentrationSampling changing concentration of analyte at constant dilution

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Characteristics of μ−mixer for on-line dilution

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Simulation of reaction monitoring - standard addition of aliquots to reaction vessel

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Standard addition monitoring response data

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Integrated on-chip mixers and extractors for on-line sample conditioning

Performs functions:dilutionfiltrationpH conditioning

waste

diluentstreamsample stream

return micromixer

H-filter

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Considerations for on-line sampling of bioreactors

Big Issue is sample pretreatment of high solids slurries

Pre-dilution using micromixersPre-filtration using membrane filters (clogging?)On-chip liquid-liquid extraction using H-filterCleaning of sample lines

Can we use NeSSI as a sampling platform?Continuous flow can maintain cleanliness of Coating or growth of biomass possibility

We need your input!

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Future work at CPAC

New work in collaboration with Rob Synovec’s group

Chromatographic performance is being addressed presently Focus on small molecules initially

Eventually we will address the sampling issuesCollaboration will involve groups of Renata Bura and Clem Furlong for optimizing system

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Thank you for your attention!