Atomic-Level Drug Substance and Polymer Interaction in Posaconazole Amorphous Solid Dispersion from Solid-State NMR.

Area of Science:

• Solid-state NMR spectroscopy
• Pharmaceutical sciences
• Materials science

Background:

• Amorphous solid dispersions (ASDs) are crucial for poorly water-soluble drugs, but their structural stability and dissolution mechanisms remain poorly understood.
• Investigating multicomponent amorphous systems at high resolution is challenging due to limitations in current structural analysis tools.

Purpose of the Study:

• To quantify molecular interactions between drugs and polymers in ASDs at an angstrom level.
• To develop and apply advanced ¹⁹F Magic Angle Spinning (MAS) NMR techniques for probing ASD microstructure.
• To investigate drug-polymer interactions in posaconazole (POSA)/hypromellose acetate succinate (HPMCAS) ASDs.

Main Methods:

• Development of a ¹⁹F-¹³C rotational-echo and double-resonance (REDOR) technique with supercycled symmetry-based recoupling.
• Utilized 2D ¹H-¹⁹F correlation experiments to observe intermolecular contacts.
• Employed numerical modeling to analyze potential hydrogen bonding interactions.

Main Results:

• Quantified drug-polymer molecular interactions at an angstrom level for the first time using ¹⁹F MAS NMR.
• Observed intermolecular hydrogen-to-fluorine contacts between HPMCAS hydroxyl groups and POSA's difluorophenyl group.
• Measured a ¹³C_OH-¹⁹F atomic distance of 4.3 Å, suggesting close proximity and potential hydrogen bonding (O-H···F or O-H···Ph).

Conclusions:

• ¹⁹F MAS NMR techniques provide high-resolution insights into the nature and strength of drug-polymer interactions in ASDs.
• The developed NMR methods offer a novel analytical protocol for characterizing the microstructure of amorphous pharmaceutical materials.
• Understanding these molecular interactions is key to optimizing ASD stability and drug dissolution.