In Situ Salt Formation during Melt Extrusion for Improved Chemical Stability and Dissolution Performance of a Meloxicam-Copovidone Amorphous Solid Dispersion.

As the pipeline for poorly soluble compounds continues to grow, drug degradation during melt extrusion must be addressed. We present a novel method for stabilizing a thermally labile drug substance while preserving its physical stability and even improving its dissolution performance. In a previous study, we found that incorporating meglumine during extrusion of meloxicam results in chemical stabilization that cannot be achieved using process optimization alone. The purpose of this study is to understand the mechanism behind this stabilization and its impact on the performance of a meloxicam-Kollidon VA64 amorphous solid dispersion. The meloxicam concentration was maintained at 10% (w/w) for blends with and without meglumine. The optimal meglumine blend contained an equimolar amount of meloxicam to meglumine with the remainder consisting of Kollidon VA64. Both formulations were processed with optimized extrusion conditions and analyzed by HPLC for purity. Meglumine at a 1:1 molar ratio with meloxicam results in 100% purity of meloxicam after melt extrusion. Solid-state NMR revealed a proton transfer between the meloxicam and meglumine indicating an in situ salt formation. During non-sink dissolution, the meglumine ASD enables meloxicam to maintain supersaturatation (≅50 times more than meloxicam free acid) for >7.25 h. The ASD without meglumine began precipitating 2.25 h following the pH shift. The ASDs were placed at 40 °C/75% RH for 6 months, and their stability was assessed. No significant chemical degradation, recrystallization, or significant moisture uptake was observed after six months' storage at 40 °C/75% RH.

Melt extrusion vs. spray drying: The effect of processing methods on crystalline content of naproxen-povidone formulations.

Our hypothesis is that melt extrusion is a more suitable processing method than spray drying to prepare amorphous solid dispersions of drugs with a high crystallization tendency. Naproxen-povidone K25 was used as the model system in this study. Naproxen-povidone K25 solid dispersions at 30% and 60% drug loadings were characterized by modulated DSC, powder X-ray diffraction, FT-IR, and solid-state 13C NMR to identify phase separation and drug recrystallization during processing and storage. At 30% drug loading, hydrogen bond (H-bond) sites of povidone K25 were not saturated and the glass transition (Tg) temperature of the formulation was higher. As a result, both melt-extruded and spray-dried materials were amorphous initially and remained so after storage at 40°C. At 60% drug loading, H-bond sites were saturated, and Tg was low. We were not able to prepare amorphous materials. The initial crystallinity of the formulations was 0.4%±0.2% and 5.6%±0.6%, and increased to 2.7%±0.3% and 21.6%±1.0% for melt-extruded and spray-dried materials, respectively. Spray-dried material was more susceptible to re-crystallization during processing, due to the high diffusivity of naproxen molecules in the formulation matrix and lack of kinetic stabilization from polymer solution. A larger number of crystalline nucleation sites and high surface area made the spray-dried material more susceptible to recrystallization during storage. This study demonstrated the unique advantages of melt extrusion over spray drying for the preparation of amorphous solid dispersions of naproxen at high drug level.