Micro Chemical Reactors from Research to Revenue

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Micro Chemical Reactors from Research to Revenue

• S. J. Haswell
• Department of Chemistry
• University of Hull
• Hull
• HU6 7RX

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Chemistry - The aim

• To join atoms together using chemical bonds to
  produce molecules.

• Chemical bonds will depend on the types of atoms
  present.
• Molecules will therefore have an atomic surface
  with different spatial energies and hence
  chemical properties depending on where the atoms
  are positioned.
• Formation of bonds and the positioning of atoms
  will also impart shape and strength to the
  molecule.
• A chemical reaction is all about moving about
  energy to achieve a stable state.

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The essentials of reaction chemistry

• Average activation energy 50 kJ mol-1
• Room temperature 25oC
• 10-2 M

• Activation (mixing) rate 10000 sec.
• Diffusion rate 0.000000001 sec.
• Electron jump 0.000000000000001 sec.

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The good old days 1902
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Say a little prayer, 1931
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70 years on spot the difference!
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The Philosophy

• Reaction chemistry is not limited by size, on
  the contrary, it is the limitation of the human
  worker that has influenced the design and
  practice of chemistry as we know it today.
• The miniaturisation of chemical reactions offers
  a unique insight into the control understanding
  of tomorrows chemistry.

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Typical Cell Dimensions in Microns

• Eukaryote 10 - 100
• Epithelial 20 - 100
• Mesophyll 40
• Bacterium 1 - 30
• Virus 0.02 - 0.25

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Size matters
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Micro reactors

• Defined as a series of interconnecting channels
  constructed in 2D and 3D geometries in which
  chemical reactions are mediated
• Channel dimensions
• 10-300 ?m
• Fabricated from polymers, metals, quartz, silicon
  or glass

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Operational advantages ofmicro reactors
Diffusion limited reactions in a laminar flow
regime.

• Spatial and temporal control over reagents and
  products
• Low volume system
• Reduced exposure to hazardous chemicals
• Generation of high intensity reaction
  environments
• Use of EOF and hydrodynamic pumps to move
  solvents and reagents
• Computer control and monitoring

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Reaction Control
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Spatial and temporal control
Injection of PADA into nickel nitrate under
electroosmotic and electrophoretic conditions
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Modeled vs. experimental date for PADA/Ni reaction
30 Sec
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In situ monitoring of an injection of PADA into
nickel nitrate
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Micro reactor chemistryProof of Principle
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Why miniaturise

• Do not miniaturise because you can

Miniaturise because it brings added value to a
process or system

• Time
• Safety
• Reaction selectivity
• Reaction control
• Unique products

• At point of use
• Portability
• Cost effective
• Broadens the skill base
• Novel technology
• Measurement
• Processes

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Drug Discovery The current situation
The number of target compounds made in a late
stage optimisation medicinal chemistry department
per year
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Drug Discovery The numbers game
1040 Drug-like chemotypes
105
1010
1020
1030
1015
1025
1035
10200 Compounds
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Drug discovery improving productivity using
micro reactors

• Current position using traditional methodology
• One compound produced per week per chemist.
• Biological screening for potential activity one
  week

• With micro reactor technology
• One compound produced and screened every two
  minutes.

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A point of care clinical diagnostic tool using
micro reactor technology
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Analysis of thyroxine

• Difficult to analyse free T3 with sufficient
  sensitivity
• Currently use radio immunoassay or ELISA on blood
  samples.
• Common to analyse bound T3 or T4.
• Ideally want to analyse free T3 for a more
  accurate correlation to patient symptoms.
• Saliva samples are easier to obtain from a
  patient.

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Choice of antigen label
Source of data http//www.assaydesigns.com
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Chemiluminescence
Chemiluminescence is defined as Emission of
light when molecules react causing a change in
energy level. Energy produced on return to ground
state is emitted as light.
Can occur in solid, liquid and gas phase.
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CL Labelling
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The Ab-Ag reaction
Antigen labelled with CL reagent
Labelled and unlabelled antigen has equal
affinity for antibody
Reagents are mixed
Antigen
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CL emission occurs
Antibodies attached to surface
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Incubation time

• The time for the Ab-Ag interaction.
• In larger scale process, this can take several
  hours.
• Diffusion in channels in the order of
  milliseconds
• T ? d2/D
• where T time, w channel width and D
  diffusion coefficient

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The scaling laws
Diffusion time d2/D
Surface to volume ratio is proportional to 1/d
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Microtiter plates Vs micro reactor
7 mm
100 µm
1.5 mm
10 µm
Micro titre plate
Micro reactor
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A conceptual drawing of the proposed apparatus.
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The Challenges of Novel Technologies

• Technology
• Underlying science

• Acceptance
• disruptive technology
• accessibility
• understanding
• value

• Paradigm shift

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A paradigm shift the dramatic revolution
Thomas Kuhn (1922-1996) The Structure of
Scientific Revolutions

• Science does not develop by the orderly
  accumulation of facts and theories, but by
  dramatic revolutions.

Scientific revolutions need creative thinking of
a kind that cannot grow out of the old order.
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Micro Chemical Systems Ltd.

• University spin out company.
• Set up and operational in 2001

• Design and fabrication of micro reactors.
• Supply laboratory and field instruments.
• Develop novel process.
• Industrial and educational

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Micro reactor availability
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Microreactor development kit
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Hydrodynamic and electrophoretic pumping systems
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Micro Chemical Systems Ltd.

• Customer base

• Pharmaceuticals and fine chemicals
• Vending and home based systems
• Energy and fuel cells
• Environmental and industrial monitoring
• Educational and research support tools
• Clinical diagnostics
• Biological and chemical processing
• Contract process development and synthesis

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The market

• Recent market reviews/benchmarks
• NEXUS - Market Analysis for Microsystems 2001
• Microsystems Manufacturing Association/DTI 2001
• Angle Technology Lab-on-a-chip DTI
• Global market share for micro systems
• 2003 400m
• 2005 2.5b
• Market growth 45 per year
• Revenue growth 150 per year

• Micro Chemical Systems is currently the market
  leader
• Target to grow a company worth in excess of 100m
  in 3-5 years

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Barriers to success

• Market acceptance
• Availability
• Adopting disruptive technology
• Education and knowledge
• Management and growth
• Market leader
• Cash flow investment/revenue
• Location

• Supply chains
• Networks and clusters users/suppliers
• Science and technology
• Expertises, knowledge and IP
• Management focus
• Inward/outward
• Partnerships

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Regional activity
Invest in a universities capability that
supports commercial development and goes beyond
the current model

• not company spin out but company growth.

• Dedicated equipment base
• Sustainable research and technical expertise
• Incubators with strong networking focus
• Financing that is flexible, realistic and not
  risk adverse

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Even the simple things in life can be difficult
to get right
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Never under estimate the posibility of getting it
wrong