NMR crystallography of the high-pressure form of a multi-component active pharmaceutical ingredient

Pressure and mechanical forces during pharmaceutical manufacturing can induce solid-phase transformations of active pharmaceutical ingredients (APIs), posing risks to product quality. Here, we report the structural characterization of a metastable high-pressure polymorph of the multi-component GDC-0022 tosylate salt formed under applied pressure of 250 MPa. The crystal structure of the high-pressure polymorph is determined with a combination of ¹H, ¹⁴N and ¹⁹F solid-state NMR (SSNMR) spectroscopy and crystal structure prediction (CSP). Distinct ¹H and ¹⁹F SSNMR signals, longitudinal relaxation time (T ₁) measurements, and 2D ¹⁹F spin-diffusion spectra confirm that the high- and low-pressure forms coexist as separate crystalline domains. 2D ¹⁹F{¹H} hetero-nuclear correlation (HETCOR) and ¹H double-quantum single-quantum (DQ-SQ) NMR spectra resolve key ¹H NMR signals of each phase, while ¹H{¹⁴N} J-HMQC experiments establish that the high-pressure form retains salt character, with one nitrogen atom remaining protonated. CSP combined with DFT GIPAW chemical shift calculations identifies a high-density polymorph consistent with the experimental ¹H and ¹⁹F chemical shifts. These results demonstrate that NMR crystallography can deconvolute complex polymorphic mixtures and provide a practical framework for managing pressure-induced phase transitions in drug manufacturing.