Colin C. Seaton

Current directions in co-crystal growth

In this feature article we will focus on the issues relating to the crystal growth of co-crystals, with a particular emphasis on drug development. The initial focus of this perspective is on the relevant literature examples that may be able to inform our understanding with regards co-crystal crystallisation and the allied supramolecular concepts. The second part of this perspective contains selected examples from our own work, which add to the literature perspective. Topics include; nucleation templates, in situ synchrotron XRD studies, solid-state synthesis through mixing and screening strategies.

Complete Colloidal Synthesis of Cu2SnSe3 Nanocrystals with Crystal Phase and Shape Control

Here we report an investigation of systematic control of crystal phase in the ternary nanocrystal system, dicopper tin triselenide. Optimizing the synthetic parameters allows modulation between nucleation and growth in either the hexagonal or cubic phase. In addition to size controlled single crystals, the particles can be tuned to occur as 1D linear heterostructures or 3D tetrapods with growth in one phase and termination in the alternate.

Solubility Metastable Zone Width Measurement and Crystal Growth of the 1:1 Benzoic Acid/Isonicotinamide Cocrystal in Solutions of Variable Stoichiometry

The solubility and crystal growth of the 1:1 cocrystal between benzoic acid and isonicotinamide from 95% ethanol was studied through the creation of a ternary phase diagram at differing temperatures and turbidity measurements. From the solubility measurements thermodynamic properties of the system were evaluated, which indicate little solution binding of the two components supported by in situ FT-IR spectra. Cooling crystallisation from solutions of differing composition suggests differing crystal growth characteristics. An excess of benzoic acid appears to increase the metastable zone width and reduce the crystal size through interactions along the fastest growth axis, while an excess of isonicotinamide decreases the metastable zone width with increased crystal size.

Creating carboxylic acid co-crystals: The application of Hammett substitution constants

The creation of multi-component crystalline phases is currently experiencing a growth in interest in academia and industry. The designed creation of novel phases through control and manipulation of the potential intermolecular interactions is a key aim of crystal engineering. This work highlights recent attempts to develop a design methodology for the creation of co-crystals between carboxylic acids using the values of Hammett substitution constants of the acid pairs. From a combined experimental and computational study, it was observed that systems with Hammett constant differences greater than a half frequently co-crystallise. From DFT energy calculations of a selected subset of acid pairs, this was seen to be due to the increased interaction energy between the heteromolecular pairs over the homomolecular pairs. However, the formation of a multi-component crystal does not mean that the desired supramolecular synthon forms. In cases with large Hammett differences, salt formation can occur in competition due to the presence of amine groups (large negative Hammett constants) and strong acids (large positive Hammett constants) but consideration of the pKa differences in this case allows for prediction of salt or co-crystal formation.

Crystallography Aided by Atomic Core-Level Binding Energies: Proton Transfer versus Hydrogen Bonding in Organic Crystal Structures

Ionic bond or hydrogen bridge? Brønsted proton transfer to nitrogen acceptors in organic crystals causes strong N1s core-level binding energy shifts. A study of 15 organic cocrystal and salt systems shows that standard X-ray photoelectron spectroscopy (XPS) can be used as a complementary method to X-ray crystallography for distinguishing proton transfer from H-bonding in organic condensed matter.

Epitaxial growth of polymorphic systems: The case of sulfathiazole

The creation of composite crystals formed by the epitaxial interaction between differing polymorphs of sulfathiazole (forms II and IV) has been reported through the experimental growth from ethanol. The intermolecular interaction between the crystal phases was calculated by application of the differential evolution global optimisation algorithm. This indicates that the interaction between form IV and form II is greater than that between form IV and itself, but less than that between form II and itself. Thus from the initial nucleation of form IV the creation of form II through mismatching of the growth units would be favoured leading the growth of form II. This mechanism explains the structure of the observed crystals with an inner layer of form IV surrounded by a shell of form II.

Proton location in acid⋯pyridine hydrogen bonds of multi-component crystals

The design of new functional crystalline materials requires an understanding of the factors that control salt and co-crystal formation. These states often only differ in the location of the proton and are influenced by chemical and crystallographic factors. The interaction between a carboxylic acid and a pyridine is a frequently used supramolecular synthon in crystal engineering which can exist as either a co-crystal (CO2H⋯N) or salt (CO2−⋯HN+). The results of a Cambridge Structure Database search indicate that the nature of the functional groups on the pyridine play a stronger role in selection of the phase than those of the acid. However, the nature of the local hydrogen bonding of the interaction also adjusts the potential for proton transfer. This was demonstrated by ab initio modelling of the energy landscape for binary and ternary co-crystals by inclusion of varying components of the local environment.

Building multi-component crystals from cations and co-crystals: the use of chaperones

Ternary crystalline complexes consisting of both salts and ionic co-crystals have been created through the crystallisation of the binary co-crystal 3,5-dinitrobenzoic acid–4-(dimethylamino)benzoic acid with group 1 or ammonium cations. The size and charge density of the cation can be used to adjust the protonation level and local geometry of the acid pair. The selectivity and coordination geometry of the chaperone cation may be further adjusted by the inclusion of a crown ether to reduce the number and location of potential binding sites.

Solution mediated phase transformations between co-crystals

A solution mediated transformation between two co-crystal phases has been observed for the p-toluensulfonamide–triphenylphosphine oxide co-crystal system. This system has two known co-crystals with 1 : 1 and 3 : 2 stoichiometry respectively, and the ternary phase diagram (TPD) for the system has been determined in acetonitrile previously. By manipulating the solution composition in this solvent to a region of the TPD where the 1 : 1 co-crystal is stable, the 3 : 2 co-crystal could be observed to convert to the 1 : 1 co-crystal. The corresponding transformation was true for the 1 : 1 co-crystal in a region of the TPD where the 3 : 2 co-crystal is stable; the 1 : 1 co-crystal converted to the 3 : 2 co-crystal.

Multi-component crystals of 4-phenylpyridine: challenging the boundaries between co-crystal and organic salt formation with insight into solid-state proton transfer

Six new multi-component crystals between 4-phenylpyridine and substituted benzoic acids (3-nitrobenzoic acid, 3,5-dinitrobenzoic acid, gallic acid, 4-aminobenozic acid, salicylic acid and 2-aminobenzoic acid) were created and characterized crystallographically to investigate the influence of chemical and structural factors on the hydrogen location between the two components. While the expected intermolecular interactions are formed between the acid and pyridine group in most cases, the gallic acid structure is anomalous forming an unexpected salt with pyridine to hydroxyl interactions. Calculations of the hydrogen bonding motifs indicate that the level of proton transfer (e.g. salt versus co-crystal formation) is not solely a function of the dimer geometry but influenced by the local crystallographic environment. Analysis of the crystal structures indicates the strength of the hydrogen bonding into this motif alters the expected protonation state from chemical considerations.