The aim of this critical review is to provide a broad but digestible overview of mechanochemical synthesis, i.e. reactions conducted by grinding solid reactants together with no or minimal solvent. Although mechanochemistry has historically been a sideline approach to synthesis it may soon move into the mainstream because it is increasingly apparent that it can be practical, and even advantageous, and because of the opportunities it provides for developing more sustainable methods. Concentrating on recent advances, this article covers industrial aspects, inorganic materials, organic synthesis, cocrystallisation, pharmaceutical aspects, metal complexes (including metal–organic frameworks), supramolecular aspects and characterization methods. The historical development, mechanistic aspects, limitations and opportunities are also discussed (314 references).

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Mechanochemistry: opportunities for new and cleaner synthesis

Over the last 20 years, the number of publications outlining the advances in design strategies, growing techniques, and characterization of cocrystals has continued to increase significantly within the crystal engineering field. However, only within the last decade have cocrystals found their place in pharmaceuticals, primarily due to their ability to alter physicochemical properties without compromising the structural integrity of the active pharmaceutical ingredient (API) and thus, possibly, the bioactivity. This review article will highlight and discuss the advances made over the last 10 years pertaining to physical and chemical property improvements through pharmaceutical cocrystalline materials and, hopefully, draw closer the fields of crystal engineering and pharmaceutical sciences.

Pharmaceutical Cocrystals and Their Physicochemical Properties

Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates.

How do molecules aggregate in solution, and how do these aggregates consolidate themselves in crystals? What is the relationship between the structure of a molecule and the structure of the crystal it forms? Why do some molecules adopt more than one crystal structure? Why do some crystal structures contain solvent? How does one design a crystal structure with a specified topology of molecules, or a specified coordination of molecules and/or ions, or with a specified property? What are the relationships between crystal structures and properties for molecular crystals? These are some of the questions that are being addressed today by the crystal engineering community, a group that draws from the larger communities of organic, inorganic, and physical chemists, crystallographers, and solid state scientists. This Perspective provides a brief historical introduction to crystal engineering itself and an assessment of the importance and utility of the supramolecular synthon, which is one of the most important concepts in the practical use and implementation of crystal design. It also provides a look to the future from the viewpoint of the author, and indicates some directions in which this field might be moving.

Crystal engineering: from molecule to crystal.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jps.20578

Pharmaceutical Co-Crystals

A systematic crystal engineering study was performed on the model pharmaceutical compound caffeine to prepare a cocrystal that, unlike caffeine, is physically stable at all relative humidities (RH). Six cocrystal materials containing caffeine with one of several dicarboxylic acids are described herein. Methods of cocrystallization included solution growth, neat solid-state grinding, and grinding with solvent-drop addition. Crystal structures are reported for a total of five cocrystals containing caffeine (with oxalic acid, malonic acid, maleic acid, and glutaric acid), including two recently reported polymorphic caffeine cocrystals. In each of these structures, a predicted intermolecular hydrogen-bonding motif is observed. The stability with respect to RH is evaluated for the six cocrystal materials. The cocrystal with oxalic acid exhibits complete stability to humidity over a period of several weeks. Other cocrystals demonstrate lesser degrees of stability with respect to humidity.

Pharmaceutical Cocrystallization: Engineering a Remedy for Caffeine Hydration

Carbamazepine is known to exist in various polymorphic forms. Here we report on crystal structure prediction calculations for carbamazepine in an attempt to examine the predictability and relative stability of the various polymorphs. Hypothetical crystal structures generated in 10 of the most common space groups were compared to the observed polymorphs. Particular attention has been given to the influence of amide pyramidalization on the relative energies of the predicted structures. While the actual generation of possible crystal structures was found to be independent of the degree of deformation of the amide group, their final ranking in energy was greatly affected by pyramidalization of the amide nitrogen. This effect was examined in detail through systematic variation of the NH2 geometry for each of the low-energy crystal structures; different amide geometries were favored in the various low-energy crystal structures. The results demonstrate that energetically feasible deformation of the amide group m...

and W. D. Samuel Motherwell

Papers

Pharmaceutical Cocrystallization: Engineering a Remedy for Caffeine Hydration

Amide Pyramidalization in Carbamazepine: A Flexibility Problem in Crystal Structure Prediction?