Nearly twenty years ago, Dunitz and Bernstein described a selection of intriguing cases of polymorphs that disappear. The inability to obtain a crystal form that has previously been prepared is indeed a frustrating and potentially serious problem for solid‐state scientists. This Review discusses recent occurrences and examples of disappearing polymorphs (as well as the emergence of elusive crystal forms) to demonstrate the enduring relevance of this troublesome, but always captivating, phenomenon in solid‐state research. A number of these instances have been central issues in patent litigations. This Review, therefore, also highlights the complex relationship between crystal chemistry and the law.

This Tutorial Review, aimed at both the novice and the seasoned solid-state chemist, provides a succinct overview of key findings that have, over the last half century, advanced our ability to make molecular crystals with targeted structures and desired properties. The article critically evaluates the efficiency and reliability of the well-established guidelines used by experimentalists in crystal engineering, and highlights statistical and computational tools that are both advantageous to crystal design and accessible to experimental solid-state chemists.

This article outlines the benefits of using ‘Design of Experiments’ (DoE) optimisation during the development of new synthetic methodology. A particularly important factor in the development of new chemical reactions is the choice of solvent which can often drastically alter the efficiency and selectivity of a process. Whilst solvent optimisation is usually done in a non-systematic way based upon a chemist's intuition and previous laboratory experience, we illustrate how optimisation of the solvent for a reaction can be carried out by using a ‘map of solvent space’ in a DoE optimisation. A new solvent map has been developed specifically for optimisation of new chemical reactions using principle component analysis (PCA) incorporating 136 solvents with a wide range of properties. The new solvent map has been used to identify safer alternatives to toxic/hazardous solvents, and also in the optimisation of an S_NAr reaction.

We describe a conceptually novel “accelerated aging” approach for the synthesis of metal–organic materials.

Cocrystals are modular multicomponent solids with exceptional utility in synthetic chemistry and materials science. A variety of methods exist for the preparation of cocrystals, yet, some promising cocrystal phases have proven to be intractable synthetic targets. We describe a strategy for the synthesis of the pharmaceutically relevant (caffeine)·(benzoic acid) cocrystal (1), which persistently failed to form using a broad range of established techniques. State-of-the-art crystal structure prediction methods were employed to assess the possible existence of a thermodynamically stable form of 1, hence to identify appropriate heteronuclear seeds for cocrystallization. Once introduced, the designed heteronuclear seeds facilitated the formation of 1 and, significantly they (or seeds of the product cocrystal) continued to act as long-lasting laboratory “contaminants”, which encouraged cocrystal formation even when present at such low levels as to evade detection. The seeding technique described thus enables the synthesis of cocrystals regarded as unobtainable under desired conditions, and potentially signifies a new direction in the field of materials research.