A solid-state-dependent correlation between drug-polymer hot melt extrudate mechanical behavior and milled extrudate...

The mechanical behavior of drug-polymer hot melt extrudates, whether amorphous or partially crystalline, was found to predict the tensile strength of tablets directly compressed from the milled extrudates, with the most predictive test depending on the extrudate solid state. Griseofulvin (GF), a poorly water-soluble BCS class II drug prone to crystallization, was selected as the model drug. Two polymers were compared, Hydroxypropyl Cellulose SL (HPC) and Kollidon VA 64 (PVPVA), to uncover the influence of drug-polymer interactions and identify (anti)plasticization phenomena. Extrudates were prepared spanning fully amorphous to partially crystalline states, as defined by XRPD, by varying HME processing temperature and drug loading. Mechanical behavior was assessed by nanoindentation (modulus and hardness) and three-point bend testing (flexural modulus and breaking force). The milled extrudates were directly compressed without extragranular material to assess tabletability, compressibility, and compactability. Increasing GF concentration in HPC extrudates increased modulus and breaking force via antiplasticization until 20 wt% GF followed by plasticization, while PVPVA extrudates exhibited bulk plasticization. The most predictive test depended on solid state: flexural modulus correlated with tablet tensile strength for amorphous extrudates (R² = 0.903), while nanoindentation modulus correlated for crystalline extrudates (R² = 0.910), providing a material-sparing screening methodology. Notably, this work uncovers a thermodynamic-mechanical paradox: the marginally miscible GF/HPC system antiplasticized while the strongly miscible GF/PVPVA system plasticized in bulk, contrary to what the Flory-Huggins interaction parameter and Tg would predict. This paradox is explained by polymer chain architecture and free-volume (hole-filling) effects rather than thermodynamic interaction strength alone.