Quantifying Micromolar Crystallinity in Pharmaceutical Materials Utilizing ¹⁹F Solid-State NMR.

Area of Science:

• Pharmaceutical analysis
• Solid-state chemistry
• Materials science

Background:

• Quantifying low-level components in solid-state analysis is challenging for conventional techniques.
• Identifying and quantifying the physical form of drug substances is critical for pharmaceutical quality control.
• Recrystallization in amorphous solid dispersions can negatively impact drug product stability and bioavailability.

Purpose of the Study:

• To develop and demonstrate fluorine-19 solid-state nuclear magnetic resonance (¹⁹F ssNMR) methods for quantifying minor crystalline contents in amorphous pharmaceuticals.
• To establish the sensitivity and reliability of ¹⁹F ssNMR for detecting trace crystalline phase changes.

Main Methods:

• Development and application of ¹⁹F direct polarization and ¹H-¹⁹F cross-polarization ssNMR techniques.
• Implementation and comparison of ¹H-¹⁹F multiple cross-polarization (MultiCP) with conventional methods.
• Utilization of a relaxation-filtered ¹⁹F ssNMR method to suppress amorphous signals and enhance crystalline detection.

Main Results:

• ¹⁹F ssNMR methods can quantify 0.1% w/w crystalline compound I in its amorphous formulation.
• ¹H-¹⁹F MultiCP was implemented for the first time and compared to standard cross-polarization.
• A relaxation-filtered ¹⁹F ssNMR method detected as low as 0.04% w/w crystalline components (6 μmol in a 100 mg tablet).

Conclusions:

• The developed ¹⁹F ssNMR methods offer high sensitivity and confidence for quantifying trace crystalline amounts in amorphous pharmaceuticals.
• This technique facilitates the detection of phase changes in solid-state drug formulations.
• The findings support improved formulation development and quality control in the pharmaceutical industry.