Microcalorimetry

Broadly speaking, calorimetry is the measurement of heat transferred into or out of a system due to some transition in the sample, whether it be a chemical reaction, binding or other change of state, such as a phase transition. As the name suggests, microcalorimetry involves similar measurements, but at a micro-scale, not only in terms of the amount of heat generated, but also the actual physical size of the sample, often on the order of about 1 mL of solution or less. Using small samples offers both challenges and benefits. It can be challenging to be sensitive to the small changes involved, and also to guard against stray thermal influences in the environment. At the same time, some modes involve controlling the temperature of the sample, and it is much easier to rapidly change or control the temperature of a small sample. While any type of transition in a sample could be examined with microcalorimetry, the field has a strong focus on the interactions of life science molecules, particularly in the context of pharmaceutical and biopharmaceutical products and their interaction with proteins and other molecules of interest, in order to study binding affinity, enzyme kinetics, conformational effects, molecular stability and other thermodynamic properties.

Several specific methods for standard calorimetry have also been adapted for microscale calorimetry. Some systems can support multiple modes of microcalorimetry, while others are more special purpose for a single testing mode. Probably the most common mode is isothermal titration calorimetry (ITC). The heart of this type of measurement is in the heat flow, which is achieved by measuring the differences between the thermal response of the sample cell and a reference cell of identical size and shape. The cells are simple chambers made from materials designed to withstand both corrosion and temperature extremes. While the reference cell contains only water or a standard solution, the sample cell also contains one of the two solution of interest. The cells share a common temperature bath, and a thermocouple provides a very sensitive means of noting any differences in temperature between the two cells.

Once the cells are prepared, the titration system injects a solution containing the second molecule into the cell, either continuously or in controlled volumes at set times. When the molecules react, heat can be either produced or absorbed by the reaction, affecting the temperature of the sample cell. A precise heating system drives the sample cell in order to maintain it at the same temperature as the reference cell. Over the course of the experiment—usually on the order of hours—the instrument’s primary measurement is the power supplied to keep the temperature the same. Through integration and standard thermodynamic identities, this information can be converted into heat of reaction, enthalpy change and other information about the kinetics of the reaction as a function of time or the relative molarity of the two compounds.

Another possible calorimetry mode used in microcalorimetry is differential scanning calorimetry (DSC). Rather than studying the interactions of two molecules as in ITC, this technique is more suited to studying the behavior of a single molecule or material under changing temperature conditions. The temperature of the sample is scanned through a range by applying a constant power or heat flux to the sample, and the thermal response of the sample (compared to the reference cell) is measured. This can be used to study phase transitions and other properties of the sample.

Pharmaceutical and biotherapeutic applications are the most common for microcalorimetry. The interactions between potential therapeutic compounds and proteins of interest, as well as the stability of the compounds themselves, can be studied with these methods, providing some complementary information to other techniques, such as SPR. In principle, other types of samples can also be studied, but these applications involving chemicals, catalysts, battery materials and other advanced materials science applications are in the minority.

Relatively few vendors compete in the microcalorimetry market. Malvern Panalytical (Spectris) is the leading vendor in the marketplace, having acquired the MicroCal line from GE Healthcare in 2014 (see IBO 6/15/14). The company offers both microDSC and microITC in a few different configurations for specific applications primarily within biopharma and the research community. TA Instruments (Waters) is the next most significant vendor, again addressing the market with a broad portfolio of instruments, including some with multiple cells for greater throughput. Setaram, the French thermal analysis specialists, are the next largest vendor, offering a high-pressure microcalorimeter for the study of gas hydrates. Another notable market participant is Rigaku, which supplies microDSC as a highly complementary technique to its XRD business. Other suppliers include Symcel and Thermo Hazard Technology, which has a microcalorimeter designed for cell biology applications.

Microcalorimetry at a Glance:

Leading Suppliers

  • Malvern Panalytical (Spectris)
  • TA Instruments (Waters)
  • Setaram

Largest Markets

  • Pharmaceuticals
  • Biotechnology
  • Academia

Instrument Cost

  • $15,000–$100,000
< | >