(742g) Hyperthermia-Induced in Situ Amorphization of a Poorly Water-Soluble Drug

Superparamagnetic iron oxide nanoparticles (SPION) can generate heat upon exposure to an alternating magnetic field (AMF). This has been extensively studied for their potential to modulate drug release from enabling formulations. In this study, SPION are used for on demand drug amorphization of poorly water-soluble drugs in tablet compacts. On demand amorphization dissolves the drug in a polymer to form an amorphous solid dispersion with improved drug solubility at elevated temperatures inside the solid dosage form. The in situ approach circumvents physical stability issues often encountered during manufacturing and storage of amorphous solid dispersions as amorphization is only carried out prior to administration in the tablet compacts. Previously, in situ drug amorphization has been achieved by microwave irradiation, however with the drawback that the dosage form has to contain high amounts of water. Here, SPION were used to induce in situ amorphization of celecoxib, a model poorly water-soluble compound, within tablet compacts.

SPION were produced by flame spray pyrolysis, a scalable nanomanufacturing technique. A Design of Experiments (DoE) approach was applied to investigate the effect of SPION composition (Zn_0.5Fe_2.5O₄ and Mn_0.5Fe_2.5O₄), SPION content (10 – 20 wt%), drug load (30 – 50 wt%), and exposure time in the AMF (3 - 15 min) on residual drug crystallinity in the tablets. In vitro dissolution testing was carried out with fully amorphous tablets.

A set of 34 experiments were performed and the model was optimized using a partial least squares method. The temperature of SPION-loaded compacts increased upon AMF exposure. The maximum temperature achieved was correlated to the degree of drug amorphization, and was highly dependent on the SPION composition and content in the tablets. Full amorphization was achieved with 20 wt% Mn_0.5Fe_2.5O₄ and 30 wt% celecoxib in the tablets that reached the maximum temperature of 165.2 °C after an AMF exposure time of 15 min.

This study demonstrates, for the first time, the potential to use SPION for on demand amorphization of poorly water-soluble drugs thereby overcoming physical stability issues of amorphous solid dispersions.