The interplay between hydrogen bonds and stacking/T-type interactions in molecular cocrystals.

Supramolecular synthon and hydrogen bond pairing approaches have influenced the understanding of cocrystal formation for decades, but are hydrogen bonds really the dominant interaction in cocrystals? To investigate this, an extensive analysis of 1:1 two-component cocrystals in the Cambridge Structural Database was undertaken, revealing that stacking and T-type interactions are just as, if not more important than hydrogen bonds in molecular cocrystals. A total of 84% of the most common coformers in the dataset are aromatic. When analysing cocrystal dimers, only 20% consist of solely strong hydrogen bonds, with over 50% of contacts involving stacking and T-type interactions.

Rationalizing the Influence of Small-Molecule Dopants on Guanine Crystal Morphology.

Many spectacular optical phenomena in animals are produced by reflective assemblies of guanine crystals. The crystals comprise planar H-bonded layers of π-stacked molecules with a high in-plane refractive index. By preferentially expressing the highly reflective π-stacked (100) crystal face and controlling its cross-sectional shape, organisms generate a diverse array of photonic superstructures.

Crystal size, shape, and conformational changes drive both the disappearance and reappearance of ritonavir polymorphs in the mill.

Organic compounds can crystallize in different forms known as polymorphs. Discovery and control of polymorphism is crucial to the pharmaceutical industry since different polymorphs can have significantly different physical properties which impacts their utilization in drug delivery. Certain polymorphs have been reported to 'disappear' from the physical world, irreversibly converting to new ones.

Do metastable polymorphs always grow faster? Measuring and comparing growth kinetics of three polymorphs of tolfenamic acid.

The phenomenon of molecular crystal polymorphism is of central importance for all those industries that rely on crystallisation for the manufacturing of their products. Computational methods for the evaluation of thermodynamic properties of polymorphs have become incredibly accurate and prediction of crystal structures is becoming routine. The computational study and prediction of the kinetics of crystallisation impacting polymorphism, however, have received considerably less attention despite their crucial role in directing crystallisation outcomes.

Polymorphic Solid Solutions in Molecular Crystals: Tips, Tricks, and Switches.

Crystal polymorphism has been a topic of much interest for the past 20 years or so, especially since its scientific (and legal) importance to the pharmaceutical industry was realized. By contrast, the formation of solid solutions in molecular crystals has been overlooked despite its long-standing prevalence in the analogous field of inorganic crystals. Wilfully forgotten, crystalline molecular solid solutions may be very common in our world since molecular compounds are rarely produced with 100% purity, and impurities able to form solid solutions are difficult to reject via recrystallization.

Using Prenucleation Aggregation of Caffeine-Benzoic Acid as a Rapid Indication of Co-crystallization from Solutions.

Co-crystal design is a convenient way to remedy the poor biopharmaceutical properties of drugs. Most studies focus on experimental co-crystal screening or computational prediction, but hardly any work has been done toward fast, efficient, and reliable prediction of solution crystallization for co-crystal formation. Here, we study the caffeine-benzoic acid co-crystal system, due to its reported difficulty to crystallize from the solution phase.

Complex Growth of Benzamide Form I: Effect of Additives, Solution Flow, and Surface Rugosity.

Understanding crystal growth kinetics is of great importance for the development and manufacturing of crystalline molecular materials. In this work, the impact of additives on the growth kinetics of benzamide form I (BZM-I) crystals has been studied. Using our newly developed crystal growth setup for the measurement of facet-specific crystal growth rates under flow, BZM-I growth rates were measured in the presence of various additives previously reported to induce morphological changes.

The role of solvation in proton transfer reactions: implications for predicting salt/co-crystal formation using the Δp rule.

The Δp rule is commonly applied by chemists and crystal engineers as a guideline for the rational design of molecular salts and co-crystals. For multi-component crystals containing acid and base constituents, empirical evidence has shown that Δp > 4 almost always leads to salts, Δp < -1 almost always leads to co-crystals and Δp between -1 and 4 can be either. This paper reviews the theoretical background of the Δp rule and highlights the crucial role of solvation in determining the outcome of the potential proton transfer from acid to base.

The interplay of intra- and intermolecular errors in modeling conformational polymorphs.

Conformational polymorphs of organic molecular crystals represent a challenging test for quantum chemistry because they require careful balancing of the intra- and intermolecular interactions. This study examines 54 molecular conformations from 20 sets of conformational polymorphs, along with the relative lattice energies and 173 dimer interactions taken from six of the polymorph sets. These systems are studied with a variety of van der Waals-inclusive density functionals theory models; dispersion-corrected spin-component-scaled second-order Møller-Plesset perturbation theory (SCS-MP2D); and domain local pair natural orbital coupled cluster singles, doubles, and perturbative triples [DLPNO-CCSD(T)].

Can molecular flexibility control crystallization? The case of substituted benzoic acids.

Despite the technological importance of crystallization from solutions almost nothing is known about the relationship between the kinetic process of nucleation and the molecular and crystal structures of a crystallizing solute. Nowhere is this more apparent than in our attempts to understand the behavior of increasingly large, flexible molecules developed as active components in the pharmaceutical arena. In our current contribution we develop a general protocol involving a combination of computation (conformation analysis, lattice energy), and experiment (measurement of nucleation rates), and show how significant advances can be made.

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.

Nanoindentation of Molecular Crystals: Lessons Learned from Aspirin.

Nanoindentation enables the measurement of mechanical properties from single crystals with dimensions of a few micrometers. This experimental technique, however, has only recently been applied to molecular crystals. Key differences between the application of this technique to molecular crystals and metals and other inorganics are identified.

Open questions in organic crystal polymorphism.

Polymorphs, crystals with different structure and properties but the same molecular composition, arise from the subtle interplay between thermodynamics and kinetics during crystallisation. In this opinion piece, the authors review the latest developments in the field of polymorphism and discuss standing open questions.

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.

On the entropy cost of making solvates.

We present a simple way of estimating the entropy cost of solvate formation in crystals. The entropy penalty of making solvates can be as low as <1 kJ mol or as high as >9 kJ mol and is entirely dependent on the nature of the liquid component and the temperature of solvate formation. A link is found between a low entropy cost and a higher likelihood for a solvent to make solvates.

Concerning Elusive Crystal Forms: The Case of Paracetamol.

Increasing commercial application of state of the art crystal structure prediction to aid solid form discovery of new molecular entities allows the experimentalist to target the polymorphs with desired properties. Here we remind ourselves that in this field the gap between such prediction and experimentation can be vast, the latter depending strongly on kinetic processes not accounted for in the computations. Nowhere is this gap more evident than in examples of so-called "elusive" polymorphs, forms that have been found difficult to crystallize, sometimes taking years to appear or sometimes disappearing altogether.

Conformational aspects of polymorphs and phases of 2-propyl-1-benzimidazole.

This paper reports on the polymorphism of 2-propyl-1-benzimidazole (2PrBzIm) induced by temperature change. Upon heating, an irreversible reconstructive-type phase transition at = 384 K from the ordered form (222) to a new polymorph, form (), was observed. The structural transformation between forms and involves significant changes in the crystal packing, as well as a key conformational variation around the propyl chain of the molecule.

The Curious Case of 2-Propyl-1H-benzimidazole in the Solid State: An Experimental and Theoretical Study.

2-Propyl-1H-benzimidazole (2PrBzIm) is a small molecule, commercially available, which displays a curious behavior in the solid state. 2PrBzIm, although devoid of chirality by fast rotation about a single bond of the propyl group in solution, crystallizes as a conglomerate showing chiroptical properties. An exhaustive analysis of its crystal structure and a wide range of experiments monitored by vibrational circular dichroism spectroscopy eliminated all possibilities of an artifact.

Aromatic stacking - a key step in nucleation.

Crystal nucleation from solution is of central importance in the chemical and biological sciences. Linking nucleation kinetics to the properties of solutes and solvents remains a grand-challenge in physical chemistry. Through a unique dataset of compounds able to self-assemble via both hydrogen-bonds and aromatic stacking, we are able to compare the importance of these two types of interaction in driving the nucleation process.

Crystal structure prediction: are we there yet?

This contribution comments on the advances of the latest Crystal Structure Prediction blind test and the challenges still lying ahead.

Isolation and evolution of labile sulfur allotropes via kinetic encapsulation in interactive porous networks.

The isolation and characterization of small sulfur allotropes have long remained unachievable because of their extreme lability. This study reports the first direct observation of disulfur (S2) with X-ray crystallography. Sulfur gas was kinetically trapped and frozen into the pores of two Cu-based porous coordination networks containing interactive iodide sites.

Facts and fictions about polymorphism.

We present new facts about polymorphism based on (i) crystallographic data from the Cambridge Structural Database (CSD, a database built over 50 years of community effort), (ii) 229 solid form screens conducted at Hoffmann-La Roche and Eli Lilly and Company over the course of 8+ and 15+ years respectively and (iii) a dataset of 446 polymorphic crystals with energies and properties computed with modern DFT-d methods. We found that molecular flexibility or size has no correlation with the ability of a compound to be polymorphic. Chiral molecules, however, were found to be less prone to polymorphism than their achiral counterparts and compounds able to hydrogen bond exhibit only a slightly higher propensity to polymorphism than those which do not.