Crystal structure determination of an elusive methanol solvate - hydrate of catechin using crystal structure prediction and NMR crystallography

Experimental screening for new crystalline forms of a flavan-3-ol derivative, catechin, yielded several new solvates and solvate–hydrates of this polyphenol, among which a new methanol-containing crystalline solid was identified. This form was found to be different from the previously described 2:1 methanol solvate of catechin. It contains one molecule of water and 0.5 molecules of methanol per catechin molecule in the asymmetric unit. To determine the crystal structure of this form, NMR crystallography and crystal structure prediction (CSP) calculations were used, as every attempt to obtain a single crystal of sufficient quality to perform single crystal X-Ray diffraction failed. To deal with a system containing five independent components in the CSP search (due to the necessity of treating whole molecules), in addition to the intramolecular flexibility of catechin with 68 viable conformers, we developed a useful short-cut, which allows for limiting the number of conformations considered in such demanding calculations. In this work, we show that it is possible to use the simulated NMR data for CSP-generated crystal structures of a simpler, yet similar system, to indicate the likely molecular conformation present in a more complex system. This approach allowed us to determine the experimental crystal structure of catechin methanol hemisolvate – monohydrate

Understanding the formation of apremilast cocrystals

Apremilast (APR), an anti-psoriatic agent, easily forms isostructural cocrystals and solvates with aromatic entities, often disobeying at the same time Kitaigorodsky’s rule as to the saturation of possible hydrogen bonding sites. In this paper the reasons standing behind this peculiar behavior are investigated, employing a joint experimental and theoretical approach. This includes the design of cocrystals with coformers having high propensity towards the formation of both aromatic – aromatic and hydrogen bonding interactions, determination of their structure, using solid state NMR spectroscopy and X-Ray crystallography, as well as calculations of stabilization energies of formation of the obtained cocrystals, followed by crystal structure prediction calculations and solubility measurements. Our findings indicate that the stabilization energies of cocrystal formation are positive in all cases, which results from strain in the APR conformation in these crystal forms. On the other hand, solubility measurements show that the Gibbs free energy of formation of the apremilast : picolinamide cocrystal is negative, suggesting that the formation of the studied cocrystals is entropy-driven. This entropic stabilization is associated with the disorder observed in almost all known cocrystals and solvates of APR

Influence of Environmental Humidity on Organization and Molecular Dynamics of Heteromacrocyclic Assemblies

1D and 2D NMR study, Car–Parrinello molecular dynamics, as well as classical molecular dynamics were employed to investigate <i>three derivatives of</i> benzodiazacoronands (achiral compounds which are able to form single crystals with a planar chirality) with intention to explain all subtle effects important during their preorganization, the step anticipating formation of crystals. The experimental study was carried out in two solvents: chloroform and DMSO either containing traces of water (commercial samples) or carefully dried over molecular sieves. Both methods revealed that environmental humidity has a dramatic influence on topology of solute–solvent interactions. Damping of the macrocycle dynamics by its diverse types of interactions with water molecules was shown by computational means. In the most spectacular experiment, we have proved that in chloroform-<i>d</i> during the low temperature measurements traces of water dramatically change the spectral pattern, leading to isochronous NMR signals of the AB spin system of benzodiazacoronand. The temperature of isochronous point (TIP) strongly depends on the benzodiazacoronand/water (BW) ratio. This observation opens a pathway to a new strategy based on variable temperature crystallizations and fitting of BW ratio with hope to optimize conditions for formation of chiral crystals