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In Situ Salt Formation during Melt Extrusion for Improved Chemical Stability and Dissolution Performance of a
Abbe Haser1, Tu Cao1, Joseph W Lubach2
1Division of Pharmaceutics, College of Pharmacy , The University of Texas at Austin , 2409 University Avenue , A1920, Austin , Texas 78712 , United States.
Molecular Pharmaceutics
|February 8, 2018
Summary
Adding meglumine to meloxicam amorphous solid dispersions (ASDs) prevents drug degradation during melt extrusion. This novel approach enhances drug stability and improves dissolution performance, offering a promising solution for poorly soluble compounds.
Area of Science:
- Pharmaceutical Sciences
- Materials Science
- Drug Delivery
Background:
- Poorly soluble compounds pose challenges in drug development, particularly concerning degradation during melt extrusion.
- Melt extrusion is a key process for creating amorphous solid dispersions (ASDs), but thermal lability of drug substances is a significant hurdle.
- Previous work indicated meglumine incorporation stabilizes meloxicam during extrusion, surpassing process optimization alone.
Purpose of the Study:
- To elucidate the mechanism of chemical stabilization of meloxicam by meglumine during melt extrusion.
- To evaluate the impact of meglumine on the physical stability and dissolution performance of meloxicam-Kollidon VA64 ASDs.
- To assess the long-term stability of meglumine-containing ASDs under accelerated storage conditions.
Main Methods:
- Melt extrusion of meloxicam-Kollidon VA64 blends with and without meglumine at a 1:1 molar ratio.
- High-Performance Liquid Chromatography (HPLC) for assessing meloxicam purity post-extrusion.
- Solid-state Nuclear Magnetic Resonance (NMR) spectroscopy to investigate drug-excipient interactions.
- Non-sink dissolution testing to evaluate drug release and supersaturation.
- Accelerated stability studies at 40 °C/75% Relative Humidity (RH) for six months.
Main Results:
- Meglumine at a 1:1 molar ratio with meloxicam ensured 100% purity of meloxicam after melt extrusion.
- Solid-state NMR confirmed proton transfer, indicating in situ salt formation between meloxicam and meglumine.
- The meglumine-containing ASD maintained meloxicam supersaturation (approximately 50-fold) for over 7.25 hours during dissolution.
- The ASD without meglumine precipitated within 2.25 hours post-pH shift.
- No significant chemical degradation, recrystallization, or moisture uptake was observed in meglumine-containing ASDs after six months of accelerated storage.
Conclusions:
- In situ salt formation between meloxicam and meglumine is the mechanism for chemical stabilization during melt extrusion.
- Meglumine incorporation significantly enhances the physical stability and dissolution performance of meloxicam ASDs.
- This strategy provides a robust method for stabilizing thermally labile drugs, improving their therapeutic potential.
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