Quantification of compaction-induced crystallinity reduction of a pharmaceutical solid using ¹⁹F solid-state NMR and powder X-ray diffraction

Abstract

¹⁹F solid-state nuclear magnetic resonance (NMR) was investigated as an analytical technique to quantify the amorphous phase in a fluorine-containing pharmaceutical candidate. The crystallinity of Compound 1 was calculated using two ¹⁹F T₁ relaxation-based methods. The first method employs both the pure amorphous and the crystalline reference standards while the second method is model independent and utilizes a single standard. The ¹⁹F solid-state NMR results were confirmed with powder X-ray diffraction methods. From X-ray diffraction data, two linear calibration curves were obtained from blends of crystalline and amorphous Compound 1: one is based on the total integrated intensity of selected diffraction peaks and the other on the total intensity of the amorphous halo at 2θ positions that have no interference from crystalline diffraction peaks. The crystallinity of Compound 1 after compaction calculated by both ¹⁹F solid-state NMR methods was in excellent agreement with the results from the X-ray calibration curves. ¹⁹F solid-state NMR was shown to be a powerful technique in determining the amount of amorphous phase present in a pharmaceutical solid.

Keywords:

• Compaction-induced amorphorization
• ¹⁹F solid-state NMR
• model-independent method
• quantification of amorphous content
• XRD

Acknowledgments

We thank Yong Xie for providing the compacted tablets as well as useful discussion. We are grateful to Drs Shawn Walker and Margaret Faul for providing the active pharmaceutical ingredient. The support from the Amgen Small Molecule Pharmaceutical R&D Department is greatly appreciated.

Declaration of interest: The authors report no conflicts of interest.