On Educational psychology: A cognitive view.

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.

Chalcogen bonding is a type of noncovalent interaction in which a covalently bonded chalcogen atom (O, S, Se or Te) acts as an electrophilic species towards a nucleophilic (negative) region(s) in another or in the same molecule. In general, this interaction is strengthened by the presence of an electron-withdrawing group on the electron-acceptor chalcogen atom and upon moving down in the periodic table of elements, from O to Te. Following a short discussion of the phenomenon of chalcogen bonding, this Perspective presents some demonstrative experimental observations in which this bonding is crucial for synthetic transformations, crystal engineering, catalysis and design of materials as synthons/tectons.

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Chalcogen bonding in synthesis, catalysis and design of materials

Pharmaceutical solvates, hydrates and amorphous forms: A special emphasis on cocrystals

Cocrystals have gained much interest in recent years owing to their potential to improve the physicochemical properties of the parent compounds. It was once thought that cocrystals could be a means to prevent polymorphism but many recent examples of cocrystal polymorphism have been discovered and reported. Similar to single component crystals, polymorphs of cocrystals can display significantly different properties. In this contribution, we present a survey of polymorphic cocrystals. The different types of polymorphs, namely synthon, conformational, packing, and tautomeric, are identified and discussed with representative examples. In addition, polymorphs of cocrystals that showed distinct physicochemical properties are highlighted.

Polymorphism in cocrystals: a review and assessment of its significance

The sulfamethizole antibiotic drug has rich hydrogen bond functionalities (donors: amine NH2 and imine NH; acceptors: sulfonyl O, thiazolidine N and S, and imidine N), which makes it a functionally diverse molecule to form cocrystals. A cocrystal screen of sulfamethizole (SMT) with COOH, NH2, pyridine, and CONH2 functional group containing coformers, e.g., p-aminobenzoic acid (PABA), vanillic acid (VLA), p-aminobenzamide (ABA), 4,4-bipyridine (BIP), suberic acid (SBA), oxalic acid (OA), and adipic acid (ADP), resulted in six cocrystals and one salt, namely, SMT–ADP (1:0.5), SMT–PABA (1:1), SMT–VLA (1:1), SMT–ABA (1:1), SMT–BIP (1:1), SMT–SBA (1:0.5), and SMT–OA (1:1). The novel crystalline adducts were synthesized by liquid-assisted cogrinding and isothermal solvent crystallization. In addition to single-crystal X-ray diffraction, the phase composition of the powder samples was confirmed by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). Hydrogen bonding interactions between t...

Novel Synthons in Sulfamethizole Cocrystals: Structure–Property Relations and Solubility

The effect of carboxylic acids on glycine polymorphism, salt and co-crystal formation was compared for slow evaporation of solutions at ambient conditions, spray drying, “fast” and “slow” anti-solvent crystallisation and dry co-grinding. Different phases were found to crystallise from the same starting components, depending on the preparative technique. Small amounts of most carboxylic acids (glutaric acid being the only exception) promoted crystallisation of the γ-polymorph in solution and as a result of co-grinding. When added in equimolar quantities, the same carboxylic acids formed salts with glycine (addition of glutaric acid resulted in co-crystal formation) on slow evaporation of solutions and on co-grinding. Neither succinic nor L-malic acids produced glycine salts, but instead promoted formation of γ-glycine when present in any amount. Anti-solvent crystallisation and spray drying of solutions containing small or large amounts of carboxylic acids produced a variety of glycine polymorphs as both pure phases and their mixtures, whereas only oxalic acid yielded salts. The ability to synthesise glycinium semi-oxalate form II by spray drying was demonstrated.

The effect of carboxylic acids on glycine polymorphism, salt and co-crystal formation. A comparison of different crystallisation techniques

The results of the synthesis in the “L-serine–oxalic acid–water” system were compared for co-grinding of powder samples with water added in four different ways: as crystal water to either or both of the reactants or as a drop of water in the liquid phase. The products formed on co-grinding were compared with each other and with those that crystallised from solutions on slow evaporation under ambient conditions, on spray drying and on antisolvent crystallisation. Co-grinding of dry anhydrous reagents gave only trace amounts of the product phase (anhydrous 1 : 1 serinium oxalate) apparently due to the interaction with trace amounts of water in the air. In the presence of crystal water or water added in the liquid phase, the polymorphs of [L-serH]2[ox]·2H2O (as pure forms or in a mixture) were formed. Neat co-grinding of anhydrous oxalic acid with L-serine monohydrate or of anhydrous L-serine with oxalic acid dihydrate gave polymorph II (kinetic form). Co-grinding of L-serine monohydrate with oxalic acid dihydrate as well as liquid-assisted grinding with a sufficient amount of liquid water added gave polymorph I (thermodynamic form) and polymorph 2 (with a very low transformation degree) if too little water was added. The seemingly solid-state reaction proceeded in fact in the liquid phase at a contact between the solid particles and did not depend on the crystal structures of the initial components. The role of mechanical treatment in inducing the synthesis is merely bringing the reacting species into contact, improving their mixing, and facilitating the dehydration of crystal hydrates. The reaction could be observed also on storage of mixtures, via the intermediate aqueous solution formed at the contacts between particles, resulting in the same intermediate product as obtained by spray drying, whereas antisolvent crystallisation and slow evaporation gave the same polymorph as was eventually observed on LAG or on prolonged storage of a solid mixture.

The role of a liquid in “dry” co-grinding: a case study of the effect of water on mechanochemical synthesis in a “L-serine–oxalic acid” system

The problem of obtaining multi-component crystals as co-crystals (with neutral molecules) rather than as salts (with charged cations and anions) attracts much attention. This is not merely a scientific challenge, but is often important for issues related to intellectual property in the pharmaceutical industry. Until now, examples have been documented where control over co-crystal–salt state has been achieved by modifying either the chemical components (co-formers) or temperature. Serendipitously we recently obtained, for the first time, a co-crystal and a salt of the same chemical composition – β-alanine and DL-tartaric acid – crystallizing stochastically at the same temperature from the same solution (E. A. Losev and E. V. Boldyreva, Acta Crystallogr., Sect. C: Struct. Chem., 2018, 74, 177–185, 10.1107/S2053229617017909). Here we report the possibility of obtaining reproducibly crystals of either of the two forms, the stable co-crystal (II) or a metastable salt (III), depending on the crystallization protocol. These observations are rationalized in terms of control over nucleation and the nuclei growth of the two phases, Ostwald's rule of stages and “disappearing polymorphs”. We report the results of using slow evaporation, fast and slow anti-solvent crystallization, and co-grinding with a variable amount of added water, as well as of “slurry experiments”. The thermodynamically stable co-crystal (II) can be obtained as a pure phase through liquid-assisted grinding, and upon crystallization from solution if seeds of it are already present in solution. The metastable molecular salt (III) is formed as a pure phase upon “dry” co-grinding without any water added specially (although in a humid atmosphere), upon fast anti-solvent crystallization, or during slow anti-solvent crystallization experiments before any seeds of the co-crystal (II) become available. After the co-crystal (II) has been formed once, even introducing a seed of the molecular salt (III) does not help to crystallize the salt from solution. The salt (III) is thus a typical “disappearing polymorph”. For comparison, we describe the co-crystallization of DL-tartaric acid with other amino acids of the same homological series. This gives the same products under all of the tested crystallization conditions – salts for the larger γ- and α-aminobutyric acids (GABA (IV) and AABA (V), respectively), and a co-crystal for the smaller glycine (I). The findings shed light on the mechanism of the alternative precipitation of co-crystals or salts of zwitterionic compounds from their aqueous solutions.

A salt or a co-crystal – when crystallization protocol matters

Glycine–glutaric acid co-crystals undergo a first-order reversible phase transition at a very low pressure (0.1 GPa) to give the low-temperature phase described recently. This fact was confirmed by single crystal X-ray diffraction and Raman spectroscopy.

Evgeniy A. Losev

Papers

Novel Synthons in Sulfamethizole Cocrystals: Structure–Property Relations and Solubility

The effect of carboxylic acids on glycine polymorphism, salt and co-crystal formation. A comparison of different crystallisation techniques

The role of a liquid in “dry” co-grinding: a case study of the effect of water on mechanochemical synthesis in a “L-serine–oxalic acid” system

A salt or a co-crystal – when crystallization protocol matters

Polymorphism of “glycine–glutaric acid” co-crystals: the same phase at low temperatures and high pressures