Exploring the Complexity of Processing-Induced Dehydration during Hot Melt Extrusion Using In-Line Raman Spectroscopy

Area of Science:

• Pharmaceutical Science
• Chemical Engineering
• Materials Science

Background:

• Hot melt extrusion (HME) is crucial for amorphous solid dispersion formulation.
• Understanding solid-state transformations during HME is vital for drug product stability and efficacy.
• In-line monitoring techniques are needed to study real-time HME processes.

Purpose of the Study:

• To investigate the impact of critical process parameters on drug solid form composition during HME.
• To develop a semi-quantitative kinetic profiling method for solid-state transformations.
• To explore dehydration pathways and the effect of released water on HME mixtures.

Main Methods:

• Utilized in-line Raman spectroscopy for real-time monitoring.
• Employed Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) modeling for kinetic analysis.
• Studied model drug compounds (nitrofurantoin and piroxicam) in polyethylene oxide melts.

Main Results:

• Successfully resolved hydrate and anhydrate solid forms without external calibration.
• Demonstrated real-time evaluation of shear and temperature effects on solid form composition.
• Elucidated competing dehydration mechanisms (solution-mediated and solid-solid) influenced by temperature and shear.
• Observed that released water impacts the rheological properties of the HME mixture.

Conclusions:

• The balance of dehydration mechanisms in HME is controlled by temperature and shear.
• In-line Raman spectroscopy with MCR-ALS provides valuable kinetic insights into HME solid-state transformations.
• Released water during dehydration is a critical factor affecting HME mixture rheology and processability.