Simple Robotics for Synthesis

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(No Transcript)
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A Simple Approach to Liquid Handling Robotics in
Parallel Synthesis
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Parallel Synthesis

• What is it? - A way to make molecules faster.
• Why do it? - More efficient, less work/compound
• Ask more Questions, get more Answers
• When do you use it? Lead Generation, Lead
  Optimization, Process Development - Chemistry
  Driven

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Parallel Synthesis

• Parallel Synthesis Doing Synthetic Organic
  Chemistry, including setup, reaction, workup,
  purification and analysis, in Parallel.

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Considerations fora Chemistry Robot

• Chemistry reactions often take a long time so
  they shouldn't take place on the robot
• Automation should address the more tedious tasks
• Workup extractions, filtrations, chromatography
• Analysis TLC, analytical sample prep for NMR,
  LC/MS etc.
• Reagent Addition and Reformatting
• Synthetic Chemistry automation needs are very
  different from Biology or Diagnostic needs.
• Perform many different tasks occasionally (15
  minutes ea.)
• Need quick setup
• Need robust platform - Solvent resistant

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Operational Complexity
We want

• vs.

This
Not This
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Guiding Principles forChemistry Automation

• Keep it Simple
• Make it look familiar easy to learn
• Limit the number of formats and use standard
  formats
• microplate footprint
• Use one-to-one mappings, A1 (source) goes to A1
  (destination)
• Run reactions at equi-molar scale so you use
  constant volumes across the reactions
• Find a generalized process that matches what a
  chemist needs to do with what a liquid handling
  robot does best.

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SynthArrayReactors

• Solution Phase Chemistry Reactors
• Microplate Footprint 96, 24 6 well formats
• Reactor Vessels held at top - visibility

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Guiding Principles forChemistry Automation

• What do chemist do?
• They move solutions around.
• What do robots do?
• They pick up solutions in one place
• and put them back down in another.
• So, if you keep a one to one mapping (steps) and
  you keep limited formats (x, y positions), all
  you need to tell a robot is the z positions, the
  volume to transfer and which wells to operate on.

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Setting the ZPosition

• Liquid detection is not reliable in organic
  reaction mixtures!!
• The desired Z position is highly variable from
  run to run
• Aliquots
• Extractions
• Filtrations
• Our solution Set the Z's at runtime by hand and
  eye

z1
Drive the tip to the desired position
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Decisions for a Chemistry Robot

• Use Tecan Robots Used in HTS
• Write software in a lower level environment (nice
  GUI)
• Hard for the programmer but done once (or seldom)
• Easy for chemists but used often
• Design where the Chemist only needs to specify
• Job to be done - Deck Layout (24 or 96, transfer,
  etc.)
• Heights of Source (z1) and Destination (z2)
• Volume to move
• Which wells to move
• A few optional parameters that might prove useful

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ImplementationMiniPrep 75/1

• Approach
• used on
• Tecan's
• 5000 series
• Integrator
• Genesis
• Toolbox
• MiniPrep
• Express

Source
Destinations
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ImplementationMiniPrep 75/1
2 Syringes give better accuracy over a larger
volume range
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Mini-Prep 75The Software
1. Worktable Chooser
2. Z-Height 3. volume controls
4. Well Chooser controls
5. Other controls
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1
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Worktable Layout
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8
5
3
6
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Destinations
Sources
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Available Layouts
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Z and VolumeControl
2. Buttons drive tip to desired Z position
1. Choose rack 5 to set Z position Sends tip to
position A1of Rack 5
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fine
course
5
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Syringe Speed Slider
3. Type in Dispense Volume
Z position
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Mini-Prep 75Selection Control

• Select Wells to Transfer
• Click and Drag to Select
• Hold Control Key for Multiple Selects or
  Deselects
• Green shows Selected Wells
• Blue shows Selected Wells after operation

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MiniPrep 75Misc. Controls
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One Generic Method- Liq.-Liq. Extraction

• Deck Layout
• 24 well to 24 well
• Source vertical position z1
• Destination vertical position z2
• Volume to transfer
• Wells to transfer

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Mini-Prep 75 Z and Volume Control
Input volume equal or greater than the volume to
be transferred
Tip moved to Z position
Miniscus
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One Generic Method SPE Extraction

• Deck Layout
• 24 well to 24 well
• Source vertical position z1
• Destination vertical position z2
• Volume to transfer
• Wells to transfer

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One Generic Method Chromatography

• Deck Layout
• 24 well to 24 well
• Source vertical position z1
• Destination vertical position z2
• Volume to transfer
• Wells to transfer

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One Generic Method TLC spotting

• Deck Layout
• 24 well to TLC plate
• Source vertical position z1
• Vertical position z2 is fixed
• Volume to transfer
• Wells to transfer

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TLC 24 Well
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TLC 24 Well
Spotting TLC plate from 24 well reactor
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One Generic MethodAnalytical Sample Prep

• Deck Layout
• 24 well to 96 well
• Source vertical position z1
• Destinations vertical position z2 z3
• Volume to transfer plus added wash
• Wells to transfer

Destination 2
Destination 1
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Prep Tubes to 24 wells
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Prep Tubes to 24 wells
Gilson Rack adapter
Transfer from Prep tubes to FlexStore vials
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Mini-Prep 75Summary
1. Worktable Chooser
2. Z-Height 3. volume controls
4. Well Chooser controls
5. Other controls
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1
4
Worktable Layout
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8
5
3
6
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Destinations
Sources
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Robot Summary

• Compact, affordable liquid handling robot
• Capable of
• Extractions
• Filtratations
• Analytical Sample Prep
• TLC spotting
• Prep reconstitution
• Reagent addition and more
• Very easy to learn and use (dynamic Z and vol.
  control)
• 45 second setup time is typical
• Fast 15 sec/well
• Flexible and extensible

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Acknowledgments

• Technical Contributions
• Tom Graham Programming Equipment Design
• Tecan 5202 and Genesis (Integrator and Toolbox)
• Matt Clapham Programming
• Genesis and MiniPrep (Toolbox and Express)
• Kent Carrow S D Machine and Tool, Inc.
  Durham, NC
• Spiritual Contributions
• Former Lilly RTP/Sphinx Lead Generation Group