Liquid-assisted grinding

S. Karki, T. Frisic, W. Jones, W.D.S. Motherwell, Screening for pharmaceutical cocrystal hydrates via neat and liquid-assisted grinding, Mol. Pharm. 4 (2007) 347-354. 

Copyright (2010) Wiley. Used with permission from Frigid T, Reid DG, Halasz /, Stein RS, Dinnebier RE, Duer MJ. Ion- and liquid-assisted grinding improved mechanochemical synthesis of metal Organic frameworks reveals salt inclusion and anion templating. Angew Chem Int Ed... 

Copyright (2015) Wiley. Used with permission from Hasa D, Schneider Rauber G, Voinovich D, Jones W. Cocrystal formation through mechanochemistry from neat and liquid-assisted grinding to polymer-assisted grinding. Angew Chem Int Ed 2015 54 7371-5. 

Application of powder X-ray diffraction for the analysis of polymorphic purity of A/-(4-nitrophenyl)-A/-morpholinothiourea (37) samples prepared by conventional solution synthesis in dichloromethane and mechanochemical liquid-assisted grinding approach. At low concentration, polycrystalline powder of form I precipitates out, while of form II precipitates from more concentrated soiution and mechanochemical synthesis. 

Friscic T, Trask AV, Jones W, Motherwell WDS. Screening for inclusion compounds and systematic construction of three-component solids by liquid-assisted grinding. Angew Chem Int Ed 2006 45 7546-50. 

Fernandes JA, Sardo M, Mafra L, Cboquesillo-Lazarte D, Mascioccbi N. X-ray and NMR crystallography studies of novel theophylline cocrystals prepared by liquid assisted grinding. Cryst Growth Des 2015 15 3674-83. 

Tireli M, Juribasid Kulcsar M, Cindro N, Gracin D, Biliskov N, Borovina M, Curie M, Halasz I, Uzarevid K. Mechanochemical reactions studied by in situ Raman spectroscopy base catalysis in liquid-assisted grinding. Chem Commun 2015 51 8058-61. 

Shearouse WC, Mack J. Diastereoselective liquid assisted grinding cracking functional resins to advance chromatography-free synthesis. Green Chem 2012 14 2771-5. 

ICP-MS Inductively coupled plasma mass spectrometry ILAG Ion- and liquid-assisted grinding INA Isonicotinic acid... 

IR spectrocopy Infrared spectroscopy KIE Kinetic isotope effect LAG Liquid-assisted grinding MA Maleic anhydride... 

A first example of double photoreaction in the solid state was reported by us from co-crystals obtained by direct grinding of trans-l,2-h s 2-pyridyl)ethylene (2,2 -bpe) with fumaric acid (HaFu) and mesaconic acid (H2Mes) in 1 1 molar ratio via liquid-assisted grinding H2Fu-2,2 -bpe... 

Figure 5 Synthesis of 1-3 using liquid-assisted grinding (LAG). Coordinated water molecules are shown in light gray, O in black, C in gray, and Zn in dark gray. H atoms and the DMF molecules included in the channels of 2 are omitted for clarity. DMF, iV,A-dimethylformamide. (Reproduced from Ref. 33. Wiley-VCH, 2010.)...

As shown by the results described above, the use of dry reactants is not the most productive method when dealing with molecular crystals. Often better results are obtained by adding a tiny amount of a given solvent to the mixture kneading, also called solvent drop grinding or liquid-assisted grinding). " " As a matter of fact, the use of a small quantity of solvent can accelerate or... 

Novel techniques for the creation of co-crystals and solvates such as neat and liquid assisted grinding have challenged the ability of crystal structure prediction to predict stoichiometry from first principles. Recent work has addressed the problem of predicting solvate stoichiometry of acetic acid (the solvent) with various molecules including carbamazepine (CBZ) and its 10,11-dihydro derivative (DHCBZ), urea and theobromine(see Figure 4.8). 

However, grinding in the presence of a small amount of a liquid phase (liquid-assisted grinding or LAG) was found to be highly efficient for the synthesis of co-crystals, resulting in rapid and quantitative formation of cocrystals, typically within 20 minutes. A suitable illustration of the greater efficiency of LAG for co-crystal screening is the proof-of-principle study of the... 

However, for some specific compounds tested this was not the case. Specifically, liquid-assisted grinding experiments involving four steroids as target molecules and 24 small planar molecules as co-crystal formers showed surprising results (Figure 5.7). The shapes and polarities of the steroids... 

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