The role of feed pretreatment and thermal stress in the development of griseofulvin/amino acid CAMS by Hot-Melt Extrusion: Structure relaxation and release/permeability evaluation

Development of co-amorphous systems (CAMS) of griseofulvin (GRI) with three amino acids (AAs) − L-lysine (GRI/LYS), L-methionine (GRI/MET), and L-valine (GRI/VAL) was investigated using the established methods of feed solvent pretreatment hot melt extrusion (mHME), ball milling (BM; dry and liquid-assisted), quench cooling (QC), and solvent evaporation (SE). The role of solvent treatment and thermal stress in mHME was elucidated. CAMS formation was evaluated using crystallography (XRPD) and modulated differential scanning colorimetry (DSC). Successful CAMS development was possible only with mHME emphasizing the importance of thermal stress. Hydrogen bonding was identified spectroscopically (ATR-FTIR) in the mHME and SE products by the disappearance of the 1658 cm⁻¹ FTIR carbonyl peak indicating the important role of AcOH in feed pretreatment. Structural relaxation time of the developed CAMS was studied using thermal activity monitoring (TAM). Johari–Goldstein (β) secondary relaxation temperature was estimated using dynamic mechanical analysis (DMA). The structural relaxation time (τ_D^β), and the secondary relaxation temperature (Tg_β) of the developed CAMS increased in the order GRI/LYS < GRI/MET < GRI/VAL. Significant correlations exist between Tg_β and τ_D^β (R² = 0.9922), and between Tg_β and the Hansen solubility parameters (R² = 0.9965). The results of the in vitro dissolution/permeability test using the MicroFLUX™ system, in which the donor and receiver compartments are separated by a lipophilic membrane/hydrophilic filter barrier showed that GRI/VAL and GRI/MET CAMS gave significantly higher release and permeability compared to amorphous drug alone, due to the superior dissolution and sustained supersaturation.