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

Quantifying low-level components in solid-state analysis presents a significant challenge for most thermal, diffractometric, vibrational, and spectroscopic techniques. In pharmaceutical analysis, identifying and quantifying the physical form of the drug substance in solid dosages is a critical task to ensure the quality of drug products. For example, recrystallization of active pharmaceutical ingredients in amorphous solid dispersions can compromise the stability and bioavailability of drug products. Herein, we have developed and demonstrated fluorine-19 solid-state nuclear magnetic resonance (¹⁹F ssNMR) methods and pushed the boundary to quantify minor crystalline contents in amorphous pharmaceuticals. Calibration curves suggest that ¹⁹F direct polarization and ¹H-¹⁹F cross-polarization ssNMR can readily quantify 0.1% w/w crystalline compound I, a commercial fluorinated drug molecule developed by Merck & Co., Inc., Rahway, NJ, U.S.A., in its amorphous formulation. ¹H-¹⁹F multiple cross-polarization (MultiCP) has been implemented, for the first time, and compared with conventional cross-polarization methods. Most importantly, a relaxation-filtered ¹⁹F ssNMR method was utilized to unambiguously identify and quantify as low as 0.04% w/w crystalline components, that is, 6 μmol in a 100 mg tablet at 25% drug loading, by suppressing the signal from the amorphous counterpart. Such a low level of detection offers high confidence and sensitivity to quantify trace amounts of phase change in pharmaceutical amorphous materials in the solid state, which can facilitate formulation development as well as quality control.