Although mechanochemical synthesis offers a sustainable way to produce solid forms of pharmaceutical compounds, the molecular-level mechanisms that govern solvent-mediated transformations remain largely unexplored. In this study, we present an in situ solid-state nuclear magnetic resonance (NMR) approach to directly monitor the evolution of liquid-assisted grinding reactions under magic-angle spinning conditions. Using a modified CLASSIC NMR protocol, we tracked the cocrystallization of two model systems, theophylline-benzamide and metronidazole-gallic acid, in the presence of solvents with different levels of polarity. This method allows us to observe both the solid and liquid phases within the reaction environment simultaneously, revealing transient intermediates, hydrate formation, and solvent-dependent polymorphic outcomes. Comparisons with time-resolved in situ X-ray diffraction confirm the complementary nature of NMR in capturing mechanistic details that are otherwise inaccessible to a diffraction-based analysis. This work establishes solid-state NMR as a powerful and accessible in situ tool for investigating the effects of solvents in mechanochemical synthesis, thereby advancing our molecular understanding of polymorphic control and reaction pathways.
Abstract
Journal Article
eng
42044204
Gołkowska, Anna M., et al. "Unveiling Solvent-Mediated Mechanochemical Cocrystallization Pathways By in Situ CLASSIC NMR Spectroscopy." Molecular Pharmaceutics, 2026.
Gołkowska AM, Nowak M, Fábián L, et al. Unveiling Solvent-Mediated Mechanochemical Cocrystallization Pathways by In Situ CLASSIC NMR Spectroscopy. Mol Pharm. 2026.
Gołkowska, A. M., Nowak, M., Fábián, L., Iuga, D., Emmerling, F., Nartowski, K. P., Karolewicz, B., & Khimyak, Y. Z. (2026). Unveiling Solvent-Mediated Mechanochemical Cocrystallization Pathways by In Situ CLASSIC NMR Spectroscopy. Molecular Pharmaceutics. https://doi.org/10.1021/acs.molpharmaceut.5c01909
Gołkowska AM, et al. Unveiling Solvent-Mediated Mechanochemical Cocrystallization Pathways By in Situ CLASSIC NMR Spectroscopy. Mol Pharm. 2026 Apr 27; PubMed PMID: 42044204.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR
T1 - Unveiling Solvent-Mediated Mechanochemical Cocrystallization Pathways by In Situ CLASSIC NMR Spectroscopy.
AU - Gołkowska,Anna M,
AU - Nowak,Maciej,
AU - Fábián,László,
AU - Iuga,Dinu,
AU - Emmerling,Franziska,
AU - Nartowski,Karol P,
AU - Karolewicz,Bożena,
AU - Khimyak,Yaroslav Z,
Y1 - 2026/04/27/
PY - 2026/4/27/pubmed
PY - 2026/4/27/medline
PY - 2026/4/27/entrez
KW - NMR spectroscopy
KW - liquid-assisted grinding
KW - mechanochemistry
KW - pharmaceutical cocrystals
KW - polymorphism
KW - solvents effect
JF - Molecular pharmaceutics
JO - Mol Pharm
N2 - Although mechanochemical synthesis offers a sustainable way to produce solid forms of pharmaceutical compounds, the molecular-level mechanisms that govern solvent-mediated transformations remain largely unexplored. In this study, we present an in situ solid-state nuclear magnetic resonance (NMR) approach to directly monitor the evolution of liquid-assisted grinding reactions under magic-angle spinning conditions. Using a modified CLASSIC NMR protocol, we tracked the cocrystallization of two model systems, theophylline-benzamide and metronidazole-gallic acid, in the presence of solvents with different levels of polarity. This method allows us to observe both the solid and liquid phases within the reaction environment simultaneously, revealing transient intermediates, hydrate formation, and solvent-dependent polymorphic outcomes. Comparisons with time-resolved in situ X-ray diffraction confirm the complementary nature of NMR in capturing mechanistic details that are otherwise inaccessible to a diffraction-based analysis. This work establishes solid-state NMR as a powerful and accessible in situ tool for investigating the effects of solvents in mechanochemical synthesis, thereby advancing our molecular understanding of polymorphic control and reaction pathways.
SN - 1543-8392
UR - https://www.unboundmedicine.com/prime/citation/42044204/Unveiling_Solvent-Mediated_Mechanochemical_Cocrystallization_Pathways_by_In_Situ_CLASSIC_NMR_Spectroscopy.
DB - PRIME
DP - Unbound Medicine
ER -
