Amorphous agomelatine stabilization in the presence of pyrogenic silica: Molecular mobility and intermolecular interaction studies

Abstract

In the present work molecular mobility and intermolecular interactions were evaluated as two distinct mechanisms for amorphous agomelatine (AGM) stabilization in the presence of pyrogenic silica. Specifically, amorphous AGM properties related to molecular mobility in terms of relaxation time were calculated based on the Kohlrausch-Williams-Watts (KWW) and Adam-Gibbs (AG) equations, while the kinetic fragility index was calculated based on temperature-modulated differential scanning calorimetry (TM-DSC). Results showed that independently of the approach followed (KWW or AG) AGM's molecular mobility was reduced in the presence of silica (KWW calculated stretched relaxation time constant, τ^β, was 83.61 and 44.78 for AGM and AGM/silica dispersions; respectively, while AG-based initial relaxation time, τ⁰, at storage temperatures 40-50 K below AGM's Tg was increased from six to eight days in the presence of silica); while kinetic fragility index values for amorphous AGM were reduced from 116.05 to 110.24 in the presence of silica. Additionally, MD simulations verified experimentally via attenuated total reflectance (ATR) FTIR spectroscopy, revealed the presence of significant intermolecular interactions between AGM and silica which act as an additional mechanism for amorphous AGM stabilization.

Keywords: Agomelatine; Amorphization; Fragility; Molecular dynamics simulations; Molecular mobility; Pyrogenic silica; Relaxation time.