Time-resolved mechanochemical cocrystallisation studies have so-far focused solely on neat and liquid-assisted grinding. Here, we report the investigation of polymer-assisted grinding reactions using in situ X-ray powder diffraction, revealing that reaction rate is almost double compared to neat grinding and independent of the molecular weight and amount of the polymer additive used.
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http://dx.doi.org/10.1039/d0cc03460f | DOI Listing |
Phys Chem Chem Phys
March 2024
School of Chemistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
The solid-state reaction of the active pharmaceutical ingredient theophylline with citric acid is a well-established example of a mechanochemical reaction, leading to a model pharmaceutical cocrystal. Here, classical force field molecular dynamics was employed to investigate the molecular mixing and structural distortion that take place on the mechanically driven indentation of a citric acid nanoparticle on a slab of crystalline theophylline. Through non-equilibrium molecular dynamics simulations, a 6 nm diameter nanoparticle of citric acid was introduced onto an open (001) surface of a theophylline crystal, varying both the angle of incidence of the nanoparticle between 15° and 90° and the indentation speed between 1 m s and 16 m s.
View Article and Find Full Text PDFChem Sci
November 2023
Department of Chemistry, McGill University 801 Sherbrooke St. W. H3A 0B8 Montreal Canada
In pursuit of accessible and interpretable methods for direct and real-time observation of mechanochemical reactions, we demonstrate a tandem spectroscopic method for monitoring of ball-milling transformations combining fluorescence emission and Raman spectroscopy, accompanied by high-level molecular and periodic density-functional theory (DFT) calculations, including periodic time-dependent (TD-DFT) modelling of solid-state fluorescence spectra. This proof-of-principle report presents this readily accessible dual-spectroscopy technique as capable of observing changes to the supramolecular structure of the model pharmaceutical system indometacin during mechanochemical polymorph transformation and cocrystallisation. The observed time-resolved spectroscopic and kinetic data are supported by X-ray diffraction and solid-state nuclear magnetic resonance spectroscopy measurements.
View Article and Find Full Text PDFMechanochemistry provides an efficient, but still poorly understood route to synthesize and screen for polymorphs of organic solids. We present a hitherto unexplored effect of the milling assembly on the polymorphic outcome of mechanochemical cocrystallisation, tentatively related to the efficiency of mechanical energy transfer to the milled sample. Previous work on mechanochemical cocrystallisation has established that introducing liquid or polymer additives to milling systems can be used to direct polymorphic behavior, leading to extensive studies how the amount and nature of grinding additive affect reaction outcome and polymorphism.
View Article and Find Full Text PDFPhys Chem Chem Phys
September 2020
G.A. Krestov Institute of Solution Chemistry RAS, 153045 Ivanovo, Russia.
In the search for new co-crystal forms, many studies only consider one method of co-crystallisation which may lead to incorrect results. In this work, we demonstrate the efficiency of applying multiple experimental and virtual screening methods for a more comprehensive search for co-crystals of acetazolamide. A new co-crystal of acetazolamide with 4-aminobenzoic acid ([ACZ + PABA] (1 : 1)) was discovered, although previously, it had been found in the blind spot of the liquid-assisted grinding (LAG) screening method.
View Article and Find Full Text PDFChem Commun (Camb)
August 2020
Department of Chemical and Pharmaceutical Sciences, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy.
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