A liquid-in-glass thermometer with sub-microKelvin resolution, and its application for calorimetry

Abstract

Labeling methods with optical readout are widely used to implement high throughput screens for drug discovery. However, labeling requires assay customization and does not allow examination of the reactants in their native state. The most direct and universal non-labeling method is calorimetry, but current calorimetric techniques are limited in resolution and throughput for pharmaceutical applications. In this thesis, a novel single-reaction microcalorimeter with optical readout, based on liquid expansion, was designed and built. The instrument was first constructed as a miniature liquid-in-glass thermometer in which the meniscus level was read by a Michelson interferometer. Contact angle hysteresis was limited by a wetting film and the low meniscus velocity. The sub-microKelvin resolution achieved was the lowest known for any thermometer above cryogenic temperatures. The thermometer was modified for use as a batch analysis microcalorimeter. Special attention was paid to minimize evaporation of the 1 /L reaction drops. Resolution of approximately 10 pJ was achieved for an acid dilution.