Evaluation of the Use of E_a (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 E a 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% R 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 (E a ) were 27.9 and 16.6 kcal/mol for the methanol and TBA solvates, respectively. In the "isokinetic" range, E a values of 36.9 and 15.5 kcal/mol, respectively, were obtained. Additionally, the E a of desolvation of the TBA solvate was significantly reduced in the presence of seeds, whereas that of methanolate was unaffected by the presence of seeds. The methanolate had a significantly higher activation energy barrier to desolvation compared to the TBA solvate.

Building solids inside nano-space: from confined amorphous through confined solvate to confined ‘metastable’ polymorph

“…Thus, IMC form V, often incorrectly called d or form IV, can be obtained via slow desolvation of the methanol solvate at room or elevated temperatures or under vacuum. 23,47 Based on our experience, a slow desolvation process at room temperature may take up to 3 months, but leads to pure form V, while much faster desolvation at elevated temperatures often leads to a mixture of polymorphs (V, g, a).…”

“…IMC form V shows small needles which melt between 130-131 1C followed by a recrystallisation directly into g-IMC or a mixture of both a and g-IMC. 47 All DSC data of the reference samples are summarised in Fig. 1B.…”

“…25 This form was reported to recrystallise subsequently into more stable polymorphs. 23,47 The amorphous drug loaded within the MCF host at the concentration of 30 and 50 wt% crystallises into a mixture of IMC phases after addition of methanol, which are partly loaded outside the pores. The DSC thermograms of both composites with the highest loadings show the melting peaks of bulk g-IMC.…”

Screening of Binary Solvent Mixtures and Solvate Formation of Indomethacin

“…It was possible to completely remove the solvent bound to the crystal structure by increasing the drying time to one week. Desolvation of IMC methanolate cannot be readily achieved due to the high activation energy of desolvation [35]. Complete removal of solvent is important because of the residual solvent limits set by the International Committee on Harmonization [36].…”

Polymorphism and Solvatomorphism 2009

“…The solid-state desolvation of the indomethacin solvatomorphs with tbutyl alcohol and methanol was studied using isothermal thermogravimetric analysis conducted on solvates seeded with differing seed crystals of the nonsolvated forms. 143 It was concluded that solid-state desolvation predominantly proceeded by a nucleationlimited mechanism (as described by the Avrami-Erofeev kinetics equation), and that the activation energy for desolvation of the t-butyl alcohol solvate was significantly reduced in the presence of seeds, whereas the activation energy for desolvation that of methanolate was unaffected by the presence of seeds.…”