Holistic QbD approach for hot-melt extrusion process design space evaluation: Linking materials science,...

Area of Science:

• Pharmaceutical Technology
• Materials Science
• Chemical Engineering

Background:

• Hot-melt extrusion (HME) is a key technology for manufacturing amorphous solid dispersions (ASDs).
• Understanding the interplay between formulation properties, process parameters, and HME performance is crucial for robust process design.
• Copovidone and polysorbate 80 are common excipients in ASD formulations.

Purpose of the Study:

• To investigate the impact of formulation material properties (copovidone melt rheology with and without polysorbate 80) and process parameters (barrel temperature, screw speed) on HME performance.
• To establish a link between process performance and critical quality attributes, specifically residual crystallinity of telmisartan.
• To evaluate the utility of process modeling combined with reduced experimentation for Quality-by-Design (QbD) based HME process development.

Main Methods:

• Utilized experimental design coupled with process modeling to study HME of amorphous solid dispersions.
• Evaluated the rheological properties of copovidone melt, with and without polysorbate 80.
• Varied barrel temperature and screw speed while maintaining constant fill volume, using telmisartan as a model drug substance.

Main Results:

• The plasticized formulation (copovidone with polysorbate 80) exhibited a broader HME process design space concerning screw speed compared to the copovidone-only formulation.
• This broader design space was attributed to reduced melt viscosity and zero-shear rate viscosity, not primarily shear-thinning behavior.
• Residual crystallinity of telmisartan correlated with the simulated maximum melt temperature, validating the use of API-matrix solubility phase diagrams for HME process development.

Conclusions:

• Process modeling combined with reduced experimentation provides a holistic approach for evaluating QbD-based HME process design spaces.
• Polysorbate 80 acts as an effective plasticizer, enhancing the processability and expanding the operational window for HME of ASDs.
• The study confirms the importance of understanding melt rheology and temperature-dependent solubility for successful HME process development and optimization.