This Dalton Perspective deals with solvent-free reactions taking place within solids or between solids or involving a solid and a vapour. The focus is on reactions involving organometallic and coordination compounds and occurring via reassembling of non-covalent bonding, e.g. hydrogen bonds, and/or formation of ligand-metal coordination bonds. It is argued that reactions activated by mechanical mixing of solid reactants as well as those obtained by exposing a crystalline solid to a vapour can be exploited to "make crystals", which is the quintessence of crystal engineering. It is demonstrated through a number of examples that solvent-free methods, such as co-grinding, kneading, milling of molecular solids, or reactions of solid with vapours represent viable alternative, when not unique, routes for the preparation of novel molecular and supramolecular solids as well as for the preparation of polymorphic or solvate modifications of a same species. The structural characterization of the products requires the preparation of single crystals suitable for X-ray diffraction, a goal often achieved by seeding.
A novel series of melanin concentrating hormone receptor 1 (MCHr1) antagonists were the starting point for a drug discovery program that culminated in the discovery of 103 (AZD1979). The lead optimization program was conducted with a focus on reducing lipophilicity and understanding the physicochemical properties governing CNS exposure and undesired off-target pharmacology such as hERG interactions. An integrated approach was taken where the key assay was ex vivo receptor occupancy in mice. The candidate compound 103 displayed appropriate lipophilicity for a CNS indication and showed excellent permeability with no efflux. Preclinical GLP toxicology and safety pharmacology studies were without major findings and 103 was taken into clinical trials.
A series of macrocycles inspired by natural products were synthesized to investigate how side-chains may shield amide bonds and influence cell permeability. NMR spectroscopy and X-ray crystallography revealed that the phenyl group of phenylalanine, but not the side-chains of homologous or aliphatic amino acids, shields the adjacent amide bond through an intramolecular NH-π interaction. This resulted in increased cell permeability, suggesting that NH-π interactions may be used in the design of molecular chameleons.
The
micronization process of new compounds is usually performed
based on an empirical basis with a limited understanding of input
material properties and potential challenges. This study focuses on
the understanding of the fracture behavior of small organic molecular
crystals, by using particle shape and surface energy analysis techniques
as well as molecular modeling tools. These methodologies enable us
to generate new data and new ways of working that can provide crucial
information for future pharmaceutical development. The shape, surface
energy, and mechanical properties for four different drug substances
were studied. This study showed that the crystal shape and the intermolecular
interactions influence the dominant fracture mechanism. An in-depth
knowledge of these together with the mechanical properties gives an
insight of the fracture mechanism of small organic molecular crystals.
In a second part, Partial Least Squares regression was applied to
the data sets to model the size reduction ratio and d
90 of the micronized materials. Models were derived using
multiple parameters.
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