Dynamics of pharmaceutical amorphous solids: the study of enthalpy relaxation by isothermal microcalorimetry

Abstract

The structural relaxation time is a measure of the molecular mobility involved in enthalpy relaxation, and thus, is a measure of the dynamics of amorphous (glassy) pharmaceutical solids that determines physicochemical properties and reactivity of drugs in amorphous formulations. In this article we describe a novel method for characterization of structural relaxation using isothermal microcalorimetry, which directly measures the rate of heat release during the relaxation processes. The structural relaxation time is then obtained from a fit of the power data to the derivative version of the Kohlrausch-Williams-Watts (KWW) equation. The relaxation times of quenched and lyophilized samples of saccharides were studied using an isothermal microcalorimeter, the Thermal Activity Monitor (TAM). In addition to the KWW derivative function, a derivative equation of the modified stretched exponential function (MSE) was employed to evaluate TAM data. The later (MSE) appeared to have numerical advantages over the KWW equation. The data demonstrate, as expected, that structural relaxation times of amorphous solids depend on a number of variables, including nature of material, temperature, moisture content, thermal history, etc. Isothermal microcalorimetry with the TAM provides a very fast and reliable way to characterize the dynamics of glassy materials, which in many respects is superior to the conventional DSC approach. To the extent stability and structural relaxation dynamics in the glass are correlated, structural relaxation parameters derived by isothermal microcalorimetry may provide data useful for rational development of stable peptide and protein formulations and for the control of their processing.