rapid and Practical stability screening by microcalorimetry

When a promising new compound enters early development, studies are conducted to determine the properties of the drug under various chemical and physical conditions in order to find a formulation suitable for use in clinical trials. Measuring both the chemical and physical stability of the drug candidate is an important part of early phase development since the shelf life of the compound will ultimately depend on the stability of the compound in the formulation. Thus, information gathered in early phase stability screening tests is critical to late phase development scientists responsible for developing the final product formulation. The most common method for characterizing the stability of a new drug candidate involves preparing solutions under various “stressing” conditions such as low and high pH, and in the presence of oxidizing agents such as hydrogen peroxide (Alsante et al., 2003). Solid samples are stressed at various humidity levels and at elevated temperatures. The solutions are then analyzed by HPLC to determine degradation over time, whereas the solid samples are analyzed by powder X-ray diffraction to determine if significant physical changes occurred, and also by HPLC (following dissolution) to investigate chemical stability. Drug candidates are by design fairly stable materials. Therefore, stability testing is generally conducted at relatively high temperatures to accelerate degradation, allowing analyses to be completed in a reasonable time. While this can result in errors in relative reactivity, for example due to a change in reaction mechanism or existence of an isokinetic temperature below the stressing temperature, these stability studies are generally conducted with the practical goal of screening compounds for reactivity, and not to obtain exact reaction kinetics Microcalorimetry is the technique of choice for characterizing the stability of pharmaceutical compounds (Hansen, 1996; Selzer et al., 1998; Phipps et al., 2000; Skaria et al., 2005) due to the ability to monitor reactions at a variety of temperatures, the high sensitivity of the instruments, and the ability to monitor both chemical and physical processes. If large samples (a gram or more) are available, extremely low (less than 1% per year) degradation rates can be measured in a day or so (Angberg et al., 1995). However, even if only milligram amounts are available, current ultra-sensitive microcalorimeters can rapidly screen relative reactivity, especially if higher temperatures are employed. If the rate and heat of reaction are sufficiently large, microcalorimetry data can be obtained rapidly at a number of temperatures and be used to determine if, and at what temperatures, a change in the mechanism of the degradation reaction takes place. Importantly, microcalorimetry requires essentially no method development: solutions or solids are placed directly into the instrument and change in heat flow with time is measured. Unlike HPLC, relative reactivity data can be obtained without the need to optimize