Development and characterization of co-amorphous griseofulvin/L-leucin by modified solvent processing hot-melt extrusion

Co-amorphous systems (CAMS) were developed between griseofulvin (GRI) and L-leucine (LEU) at 2:1 wt ratio, by application of a novel solvent assisted hot-melt extrusion (HME) method that involved wet processing/drying of the feeds prior to extrusion. CAMS formation was confirmed by powder crystallography (pXRD) and thermal analysis (DSC). Intermolecular H-bonding between the carbonyl groups of GRI and the hydroxyl and amino groups of LEU were identified by vibrational spectroscopy (ATR-FTIR). The measured glass transition temperatures (Tg) of the extrudates from feeds processed with aqueous acetic acid (AcOH) were markedly lower than that of neat amorphous GRI and values predicted from Gordon-Taylor equation, indicating plasticizing action of AcOH. Drug concentrations during dissolution of CAMS under non-sink conditions (Sink Index 0.0115) were up to x82 higher at plateau compared to crystalline drug solubility. The degree of supersaturation lasted for at least 24 h. Plasticizer (Compritol®/Kolliphor® 75/25) added before extrusion did not impact significantly on CAMS formation but altered the dissolution profile from a spring-and-parachute profile to gradual rise to maximum. These findings reinforce the application of drug/amino acid-based CAMS in formulation, particularly for high-dose drugs, for which polymers are unsuited due to the required large proportions.