Solvation and surface effects on polymorph stabilities at the nanoscale

We explore the effects of particle size and solvent environment on the thermodynamic stability of two pairs of polymorphs subjected to ball-mill neat grinding (NG) and liquid assisted grinding (LAG). Two systems were studied: (i) forms I and II of a 1 : 1 theophylline : benzamide cocrystal and (ii) forms A and B of an aromatic disulfide compound. For both systems, the most stable-bulk polymorph converted to the metastable-bulk polymorph upon NG. LAG experiments yielded different outcomes depending on the amount of solvent used. This was further investigated by performing carefully controlled LAG experiments with increasing $\mu$L amounts of solvents of different nature. With these experiments, we were able to monitor form A to B and form I to II conversions as a function of solvent concentration and derive polymorph equilibrium curves. The concentration required for a switch in polymorphic outcome was found to be dependent on solvent nature. We propose that these experiments demonstrate a switch in thermodynamic stability of the polymorphs in the milling jar. Form B, the stable-bulk polymorph, has less stable surfaces than form A, thus becoming metastable at the nanoscale when surface effects become important. $\textit{Ex situ}$ diffraction and electron microscopy data confirm crystal sizes in the order of tens of nanometers after the ball mill grinding experiments reach equilibrium. DFT-d computations of the polymorph particles stabilities support these findings and were used to calculate cross-over sizes of forms A and B as a function of solvent. Attachment energies and surface stabilities of the various crystalline faces exposed were found to be very sensitive to the solvent environment. Our findings suggest that surface effects are significant in polymorphism at the nanoscale and that the outcomes of equilibrium ball-mill NG and LAG experiments are in general controlled by thermodynamics.Engineering and Physical Sciences Research Counci

Functional materials discovery using energy–structure–function maps

Molecular crystals cannot be designed in the same manner as macroscopic objects, because they do not assemble according to simple, intuitive rules. Their structures result from the balance of many weak interactions, rather than from the strong and predictable bonding patterns found in metal–organic frameworks and covalent organic frameworks. Hence, design strategies that assume a topology or other structural blueprint will often fail. Here we combine computational crystal structure prediction and property prediction to build energy–structure–function maps that describe the possible structures and properties that are available to a candidate molecule. Using these maps, we identify a highly porous solid, which has the lowest density reported for a molecular crystal so far. Both the structure of the crystal and its physical properties, such as methane storage capacity and guest-molecule selectivity, are predicted using the molecular structure as the only input. More generally, energy–structure–function maps could be used to guide the experimental discovery of materials with any target function that can be calculated from predicted crystal structures, such as electronic structure or mechanical properties

Kryptoracemates

Racemic crystals normally crystallise in centrosymmetric spacegroups containing equal numbers of enantiomers. More rarely, racemates may crystallise in non-centrosymmetric space-groups having glide symmetry or, even more rarely, in space-groups devoid of a centre of inversion, having no rotary-inversion axes nor glide plane. The latter class of crystals form the subject of the present bibliographic review – a survey of kryptoracemic behaviour. The term kryptoracemic alludes to the presence of a hidden or non-crystallographic centre of inversion between two molecules that might otherwise be expected to crystallise in an achiral space-group, often about a centre of inversion. Herein, examples of molecules with stereogenic centres crystallising in one of the 65 Sohncke space-groups are described. Genuine kryptoracemates, i.e. crystals comprising only enantiomorphous pairs are described followed by an overview of non-genuine kryptoracemates whereby the crystal also contains other species such as solvent and/or counterions. A full range, i.e. one to six, stereogenic centres are noted in genuine kryptoracemates. Examples will also be described whereby there are more that one enantiomeric pair of molecules in the crystallographic asymmetric unit. A more diverse range of examples are available for non-genuine kryptoracemates. There are unbalanced species where in addition to the enantiomeric pair of molecules, there is another enantiomeric molecule present. There are examples of genuine co-crystals, solvated species and of salts. Finally, special examples will be highlighted where the counterions are chiral and where they are disparate, both circumstances promoting kryptoracemic behaviour

Reticular synthesis of porous molecular 1D nanotubes and 3D networks

Synthetic control over pore size and pore connectivity is the crowning achievement for porous metal–organic frameworks (MOFs). The same level of control has not been achieved for molecular crystals, which are not defined by strong, directional intermolecular coordination bonds. Hence, molecular crystallization is inherently less controllable than framework crystallization, and there are fewer examples of ‘reticular synthesis’, in which multiple building blocks can be assembled according to a common assembly motif. Here we apply a chiral recognition strategy to a new family of tubular covalent cages to create both 1D porous nanotubes and 3D diamondoid pillared porous networks. The diamondoid networks are analogous to MOFs prepared from tetrahedral metal nodes and linear ditopic organic linkers. The crystal structures can be rationalized by computational lattice-energy searches, which provide an in silico screening method to evaluate candidate molecular building blocks. These results are a blueprint for applying the ‘node and strut’ principles of reticular synthesis to molecular crystals

Transforming Computed Energy Landscapes into Experimental Realities: The Role of Structural Rugosity

We exploit the possible link between structural surface roughness and difficulty of crystallisation. Polymorphs with smooth surfaces may nucleate and crystallise more readily than polymorphs with rough surfaces. The concept is applied to crystal structure prediction landscapes and reveals a promising complementary way of ranking putative crystal structures

Switching polymorph stabilities with impurities provides a thermodynamic route to benzamide form III

Almost 200 years ago, benzamide was reported as polymorphic with two of its forms (II and III) found to be difficult to crystallise. In a recent study, it was shown that benzamide form I can easily convert into benzamide form III using mechanochemistry in the presence of nicotinamide. Here we show, experimentally and computationally, that this transformation is the result of a thermodynamic switch between these two polymorphic forms driven by the formation of solid solutions with small amounts of nicotinamide. The presence of nicotinamide in the crystallisation environment promotes the robust and exclusive crystallisation of the elusive form III. These results represent a promising route to the synthesis and utilisation of elusive polymorphs of pharmaceutical interest. The formation of solid solutions can result in changes of relative stabilities of crystal polymorphs. Here, the elusive form III of benzamide is stabilized through solid solution formation with nicotinamide. It is shown, experimentally and computationally, how such thermodynamic switching allows for consistent and facile crystallization of the otherwise elusive benzamide form III

Can solvated intermediates inform us about nucleation pathways? The case of β-pABA

Classical nucleation theory teaches the idea that molecular clusters form and grow in solution and that depending on prevailing conditions there is a chance for some to grow large enough to overcome the interfacial energy penalty and become mature crystals. However, from such a kinetic analysis, nothing is learnt of the nature of the composition or the molecular packing in such clusters. As a means of addressing this shortcoming consideration has, in the past, been given to the idea that in certain systems crystallography may offer additional, structural, insights. From this approach the notions of ‘nucleation pathway’ or ‘nucleation transition state’ have become useful concepts around which to formulate hypotheses as to how clusters may yield specific molecular packing, resulting for example, in the observation of crystal polymorphs. Here we offer an in-depth crystallographic analysis related to the nucleation of the α and β polymorphs of para-aminobenzoic acid in an attempt to reveal the pathways leading to the two forms. Using a combination of CSD analyses, crystal structure prediction and targeted crystallizations we explore plausible solution pathways to these polymorphs and discuss our results in the light of known kinetic data for the nucleation and growth of this material

When Crystals Do Not Grow: The Growth Dead Zone

The experimental observation that certain crystal faces do not grow, despite being in contact with supersaturated solution, is a widely reported phenomenon. This concept of a growth "dead zone" has been known for many years, but its origin remains an unresolved problem in crystal growth. Sometimes it seems to be an inherent feature of the solution growth process, while at others it appears that an impurity is an essential element for its appearance. Here we review existing data and provide new experimental evidence to confirm the widespread existence of the dead zone across a range of molecular materials. Available crystal growth kinetics are confronted with mechanistic models. Examination of the packing arrangements of appropriate crystal faces suggests that this behavior is linked to molecular-scale surface roughness