Evaluation of the Use of Ea (Activation Energy) as a Quantitative Indicator of Physical Stability of Indomethacin Solvates: Methanolate and Tertiary Butyl Alcohol Solvate

Abstract

The purpose of this research is to study the use of Ea as a measure of the energy barrier to the solid-state desolvation of two indomethacin solvates: tert-butyl alcohol (TBA) solvate and methanolate. The desolvation of these solvates was studied over a range of temperatures (60−120 °C) by isothermal thermogravimetric analysis. Intimately mixing 15% α and γ seeds with the two solvates was carried out in order to assess the effect of seeding/nucleation on desolvation. The results suggest that solid-state desolvation predominantly proceeded by a nucleation-limited mechanism as described by the Avrami−Erofeev kinetics equation. On the basis of the equation, an “isokinetic” range was identified between 60−80 °C for the methanolate and 60−90 °C for the TBA solvate, and the dominant mechanism of desolvation remained unchanged. The Arrhenius activation energies (Ea) were 27.9 and 16.6 kcal/mol for the methanol and TBA solvates, respectively. In the “isokinetic” range, Ea values of 36.9 and 15.5 kcal/mol, respect...