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.

The full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-pro t purposes provided that: • a full bibliographic reference is made to the original source • a link is made to the metadata record in DRO • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders. Please consult the full DRO policy for further details.

Packing Problems: High Z′ Crystal Structures and Their Relationship to Cocrystals, Inclusion Compounds, and Polymorphism

Organic molecules, such as pharmaceuticals, agro-chemicals and pigments, frequently form several crystal polymorphs with different physicochemical properties. Finding polymorphs has long been a purely experimental game of trial-and-error. Here we utilize in silico polymorph screening in combination with rationally planned crystallization experiments to study the polymorphism of the pharmaceutical compound Dalcetrapib, with 10 torsional degrees of freedom one of the most flexible molecules ever studied computationally. The experimental crystal polymorphs are found at the bottom of the calculated lattice energy landscape, and two predicted structures are identified as candidates for a missing, thermodynamically more stable polymorph. Pressure-dependent stability calculations suggested high pressure as a means to bring these polymorphs into existence. Subsequently, one of them could indeed be crystallized in the 0.02 to 0.50 GPa pressure range and was found to be metastable at ambient pressure, effectively derisking the appearance of a more stable polymorph during late-stage development of Dalcetrapib.

/pdf/combined-crystal-structure-prediction-and-high-pressure-45wza5t2zi.pdf

Combined crystal structure prediction and high-pressure crystallization in rational pharmaceutical polymorph screening

Crystal structure prediction (CSP) studies are not limited to being a search for the most thermodynamically stable crystal structure, but play a valuable role in understanding polymorphism, as shown by interdisciplinary studies where the crystal energy landscape has been explored experimentally and computationally. CSP usually produces more thermodynamically plausible crystal structures than known polymorphs. This article illustrates some reasons why: because (i) of approximations in the calculations, particularly the neglect of thermal effects (see §1.1); (ii) of the molecular rearrangement during nucleation and growth (see §1.2); (iii) the solid-state structures observed show dynamic or static disorder, stacking faults, other defects or are not crystalline and so represent more than one calculated structure (see §1.3); (iv) the structures are metastable relative to other molecular compositions (see §1.4); (v) the right crystallization experiment has not yet been performed (see §1.5) or (vi) cannot be performed (see §1.6) and the possibility (vii) that the polymorphs are not detected or structurally characterized (see §1.7). Thus, we can only aspire to a general predictive theory for polymorphism, as this appears to require a quantitative understanding of the kinetic factors involved in all possible multi-component crystallizations. For a specific molecule, analysis of the crystal energy landscape shows the potential complexity of its crystallization behaviour.

https://journals.iucr.org/b/issues/2013/04/00/bm5061/bm5061.pdf

Why don't we find more polymorphs?

https://journals.iucr.org/m/issues/2015/06/00/bi5049/bi5049.pdf

Supramolecular interactions in the solid state

Three fluorotoluene isomers, all liquids under ambient conditions, have been crystallized using two distinct in situ methods: cryo-crystallization (by decreasing the temperature below the freezing point) and through the application of high-pressure. In all three isomers, crystallization from high-pressure results in different polymorphic forms to those observed at low-temperature: cryo-crystallization and compression of the pure liquid results in the formation of two distinct polymorphs of both 3- and 4-fluorotoluene, but only one polymorph of 2-fluorotoluene. However, compression of a 1:1 mixture of 2- and 3-fluorotoluenes results in a different polymorph of 2-fluorotoluene to that seen when crystallizing the pure liquid. The effects of temperature and pressure on the crystallization process in systems that have only weak C–H···F–C hydrogen bonds are confirmed to be very different.

High-Pressure and Low-Temperature Polymorphism in C–H···F–C Hydrogen Bonded Monofluorotoluenes

Single-crystal X-ray diffraction has been used to elucidate the structure of two polymorphs of isopropyl alcohol, one grown through in situ cryo-crystallisation, the other through high-pressure crystallisation. The packing in both structures is dominated by O–H⋯O hydrogen bonds, with the high-pressure polymorph being significantly more dense than the low-temperature structure.

Low-temperature and high-pressure polymorphs of isopropyl alcohol

Crystallization of 2-fluorophenylacetylene at room temperature using high pressure yields three different polymorphs. These have distinct supramolecular assemblies despite the only variation in the crystallization protocol employed being the rate of compression.

Joe Ridout

Papers

High-Pressure and Low-Temperature Polymorphism in C–H···F–C Hydrogen Bonded Monofluorotoluenes

Low-temperature and high-pressure polymorphs of isopropyl alcohol

Polymorphism Arising from Differing Rates of Compression of Liquids