Supercritical-CO2 Foam Extrusion of Hydroxypropyl Methyl Cellulose Acetate Succinate/Itraconazole Amorphous Solid Dispersions: Processing-Structure-Property Relations.

This study investigates the effects of supercritical CO2 as a foaming agent on structure and physical properties of hot melt extruded hydroxypropyl methylcellulose acetate succinate (HPMCAS)-itraconazole (ITZ) amorphous solid dispersions (ASDs) with the aim of improving the milling efficiency and tabletability of these ASDs. Two different grades of AFFINISOLTM HPMCAS, the standard grade (Std) and the High Productivity grade (HP) were used. The HP-grade has a lower molecular weight, melt viscosity and wider processing temperature range. Extrudates with different ITZ concentrations (0%, 20% and 40%) and CO2 injection pressure of 100 and 200 bar were prepared. The cellular microstructure of the foams showed that HP-grade HPMCAS had better affinity with the CO2 resulting in better distribution of CO2. The results of DSC and X-ray diffraction analysis revealed that the supercritical CO2 did not affect the amorphous state of the API in the extrudates. Milling efficiency of the ASDs was significantly improved up to around 90% increase in the mass recovery. The tabletability of the milled extrudates showed a considerable increase in tablet tensile strength. In addition, foaming considerably improved the supersaturation of HP-grade ASD while showing minimal improvement in dissolution behavior of the Std-grade material.

Scale-Up and In-line Monitoring During Continuous Melt Extrusion of an Amorphous Solid Dispersion.

Chemical degradation of drug substances remains a major drawback of extrusion. Larger-scale extrusion equipment has advantages over smaller equipment due to deeper flight elements and added flexibility in terms of screw design, unit operations, and residence time. In a previous study, we extruded a meloxicam-copovidone amorphous solid dispersion (ASD) on a Nano-16 extruder and achieved 96.7% purity. The purpose of this study is to introduce a strategy for scaling the process to an extruder with dissimilar geometry and to investigate the impact on the purity of the ASD. The formulation previously optimized on the Nano-16, 10:90 meloxicam and copovidone, was used for scale-up. Our approach to scale-up to the ZSE-18, utilized specific mechanical energy input and degree of fill from the Nano-16. Vacuum was added to prevent hydrolysis of meloxicam. Downstream feeding and micronization of meloxicam were introduced to reduce the residence time. In-line monitoring of the solubilization of meloxicam was monitored with a UV probe positioned at the die. We were able to achieve the same purity of meloxicam with the Micro-18 as we achieved with Nano-16. When process conditions alone were not sufficient, meglumine was added to further stabilize meloxicam. In addition to the chemical stability advantage that meglumine provided, we also observed solubility enhancement which allowed for an increase in drug loading to 20% while maintaining 100% purity.

Investigation of process temperature and screw speed on properties of a pharmaceutical solid dispersion using corotating and counter-rotating twin-screw extruders.

OBJECTIVE: The use of corotating twin screw hot-melt extruders to prepare amorphous drug/polymer systems has become commonplace. As small molecule drug candidates exiting discovery pipelines trend towards higher MW and become more structurally complicated, the acceptable operating space shifts below the drug melting point. The objective of this research is to investigate the extrusion process space, which should be selected to ensure that the drug is solubilized in the polymer with minimal thermal exposure, is critical in ensuring the performance, stability and purity of the solid dispersion. METHODS: The properties of a model solid dispersion were investigated using both corotating and counter-rotating hot-melt twin-screw extruders operated at various temperatures and screw speeds. The solid state and dissolution performance of the resulting solid dispersions was investigated and evaluated in context of thermodynamic predictions from Flory-Huggins Theory. In addition, the residence time distributions were measured using a tracer, modelled and characterized. KEY FINDINGS: The amorphous content in the resulting solid dispersions was dependent on the combination of screw speed, temperature and operating mode. CONCLUSIONS: The counter-rotating extruder was observed to form amorphous solid dispersions at a slightly lower temperature and with a narrower residence time distribution, which also exhibited a more desirable shape.