Laser Diode Thermal Desorption (ldtd) An Alternative To The Lc For High-throughput Quantitation: Some Early Case Studies

Don Gray, Senior Scientist
October, 29, 2009

Why LDTD at BASi?

  • Speed: 40 minutes / plate
  • Resources: no column or mobile phase
  • Familiar sample preparation
  • No carryover
  • Barcoded plates/Integration with LIMS
  • Easily interchangeable with standard source


  • Not universal: Sulfoxides, Proteins, Peptides don’t work
  • Thermal Lability a possible issue
  • Isobaric Compounds are out
  • Destructive analysis

LDTD Ionization Source

  • Sample is dried onto the bottom of a well from a standard 96-well plate with a metal sheet insertion.
  • Thermal desorption induced by a laser at 980 nm (no photonsample interactions).
  • Gaseous neutral species transferred by a carrier gas.
  • Ionization occurs into the corona discharge region.

Theoretical Aspects of the Ionization

The ionization process that occurs in the LDTD source is an Atmospheric pressure chemical (APC) type of ionization without the presence of solvent (no mobile phase or enhancement matrix.)

Key Features

  • Low volume sample analysis (1 to 10 µL).
  • 96-well plates are designed to be compatible with conventional sample preparation systems.
  • No extra sample pre-treatment needed.
  • The absence of enhance matrix and mobile phase lower the noise signal.
  • Elimination of cross contamination / carryover due to LC.
  • Wells are individually isolated during the thermal desorption.
  • The thermal desorption process takes seconds.

A1: Empty A2: 2μL droplet


Extraction Method

  • 100 µL sample + 50 µL of IS + 600 µL of acidified water
  • Tomtec automated extraction procedure
  • Solid phase extraction with Phenomenex® Strata™ X (30mg/well)
  • Pioglitazone-d4 internal standard
  • Evaporated samples reconstituted in 250 µL of a water/acetonitrile/acetate buffer mixture
  • Method range is 25.0- 2500 ng/mL in human serum


Extraction Method

  • Sample + internal standard + buffer + ethyl acetate
  • Seal, mix, and centrifuge
  • Transfer ethyl acetate and blow down
  • Reconstitute (60% aqueous, no buffer)
  • Split extract
  • Dilute LDTD aliquot 1:1 with methanol
  • Spot 2 µL onto LazWell plate and allow to evaporate
  • Analyze
  • Method range is 5 to 5000 ng/mL

Carbamazepine LC-MS Transitions


Carbamazepine LDTD Transitions


Carbamazepine metabolites


Carbamazepine LDTD Transitions



Carbamazepine Day 1


Carbamazepine Day 2


Carbamazepine Day 3

Carbamazepine Conclusions

  • Not quite there using HPLC extraction
  • Want more signal.
    • Recon with smaller volume, different composition
    • Skipping the evaporation/recon, plate organic directly
    • Better optimize system
  • Stable labeled internal standards are good

Moving Forward

  • Investigate the ‘peak in the blank’
  • MIST Guidance - conjugated metabolites, N-oxides
  • Optimize extraction for LDTD
  • Generic extraction
  • Validate methods for non-proprietary drugs
  • Analyze incurred (pre-clinical) samples

Thanks To

  • Patrice Tremblay - Phytronix
  • Hasantha Jayaratna
  • Michael Pugh
  • Tim Shoaf
  • Ben Slentz
  • Management at BASi