Pharmaceutical Isothermal Microcalorimetry

Introduction

Solid drug compounds present a number of challenging analysis problems to pharmaceutical scientists. Once a likely drug has been found, it must be characterized to determine which form is the most stable and how much of it is crystalline and how much is not (in other words, is amorphous). In addition, it must be formulated (mixed with other solid and liquid ingredients) so that it can be formed into tablets, packaged, transported, and stored. Before being consumed by the patient, it needs to have retained as much of its initial purity as possible. After being consumed by the patient, the drug should dissolve at the rate chosen by the pharmaceutical company so it is available in the body at the right time. It is this "bio-availability" that determines the efficacy of the drug.

Pharmaceutical companies use many analytical tools for physical and chemical characterization of drugs. Examples are ultraviolet, visible, infrared, and near infrared spectroscopy (UV/VIS/IR/NIR), gas chromatography (GC), high-performance liquid chromatography (HPLC), mass spectrometry (MS), X-ray diffraction analysis (XRD), gravimetric sorption (DVS), and thermal analysis. Microcalorimetry is a form of thermal analysis, but it is far less familiar to scientists than more widely used thermal analysis techniques such as differential scanning calorimetry (DSC) or thermogravimetric analysis (TGA). Many pharmaceutical companies use Thermometric microcalorimeters (the Thermal Activity Monitor, or TAM) to solve problems which the other analytical tools available to them are not able to solve or require much more time to solve. For these researchers, it might be helpful to better explain what microcalorimetry is and how it would be useful to them.

Microcalorimetry and Thermal Analysis

Overview

Thermal analysis refers to a group of techniques in which a physical property of a substance is measured as a function of temperature while the substance is subjected to an imposed temperature alteration. For example, thermogravimetric analysis (TGA) measures how the weight of a sample changes with temperature. In general, thermal analysis instruments are designed to allow temperature of the sample to be changed rapidly.
Calorimetry refers to those measuring techniques that are used for direct determination of heat, heat production rate (or heat flow), and heat capacity as function of temperature and time. For example, differential scanning calorimetry (DSC) measures heat flow as a function of temperature, while calorimetry measures heat flow as a function of time. Calorimetry can be either run in scanning mode (changing temperature with time) or isothermally, whereas thermal analysis only refers to scanning temperature. This is confusing because some instruments can be run both ways. For example, a DSC can be run at constant temperature and a calorimeter may be run in scanning mode. In general, calorimetry instruments are designed to hold temperature of the sample as constant as possible so as to measure very small changes over long periods of time.
Microcalorimetry uses the prefix micro to indicate that these instruments measure heat flow in the microwatt range. Microcalorimetry can be either scanning or isothermal. Applications presented herein all refer to isothermal microcalorimetry.

Some description of the hardware used for thermal analysis and microcalorimetry may better delineate their differences, since a DSC and a microcalorimeter are very different.