Fuente: PubMed "apis" Chem Sci. 2026 Jul 29. doi: 10.1039/d6sc02621d. Online ahead of print.ABSTRACTPressure 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.PMID:42529253 | PMC:PMC13417174 | DOI:10.1039/d6sc02621d