Cocrystals "Divorce and Marriage": When a Binary System Meets an Active Multifunctional Synthon in a Ball Mill.

A well-defined and stable "AB" binary system in the presence of "C" a crystalline synthon ground in a ball mill undergoes selective transformation in the solid state according to the equation AB+C→AC+B. When the amount of C is increased two times then the equation AB+2C→AC+BC is valid. The other variants are more complex. The pathway BC+A is allowed and leads to the AC and B products. The pathway AC+B is not preferred, and no transformation is observed. These non-obvious correlations were observed for cocrystal of barbituric acid (BA):thiobarbituric acid (TBA) recently reported by Shemchuk et al. (Chem. Commun. 2016, 52, 11815-11818) in the presence of 1-hydroxy-4,5-dimethyl-imidazole 3-oxide (HIMO). This synthon shows high affinity for the BA0.5 TBA0.5 cocrystal as well for its individual components, BA and TBA. Single-quantum, double-quantum (SQ-DQ) 2D 1 H very fast MAS NMR with a spinning rate of 60 kHz was employed as a basic and most diagnostic tool for the study of cocrystals transformations. Analysis of the experimental data was supported by theoretical calculations, including computation of the stabilization energy, Estab , defined as the energy difference between the energy of a co-crystal and the sum of the energies of particular components in the respective stoichiometric ratios. Two mechanisms of synthon replacement have been proposed. Pathway 1 assumes a concerted mechanism of substitution. In this approach, synthon attack is synchronized in time with the departure of one of the components of the binary system. Pathway 2 implies a non-concerted process, with an intermediate stage in which three separate components are present. Evidence suggesting a preference for Pathway 2 is shown.

Lipid vesicle-loaded meso-substituted chlorins of high in vitro antimicrobial photodynamic activity.

Photodynamic inactivation potential against bacteria of four chlorin derivatives with phenyl or fluorophenyl substituents was evaluated. The quantum yield values of singlet oxygen formation were in the range of 0.16-0.86. Compounds were characterized by high quantum yields of fluorescence (0.15-0.44) and moderate photostability in DMF solutions. Irradiation of chlorins in DMSO resulted in their phototransformation and then photodecomposition. Photodynamic inactivation of bacteria was performed after the compounds had been loaded into lipid vesicles. The following log reductions of growth values were obtained: Enterococcus faecalis >5.44; Staphylococcus aureus 2.74-5.34; Escherichia coli 0.01-2.14. No activity of meso-substituted chlorins was noticed against Pseudomonas aeruginosa and fungi Candida albicans and Trichophyton mentagrophytes.

Insights into the tautomerism in meso-substituted corroles: a variable-temperature 1H, 13C, 15N, and 19F†NMR spectroscopy study.

Tris(pentafluorophenyl)corrole and its (15)N-enriched isotopomer were studied in [D8]toluene solution by 1D and 2D variable-temperature NMR techniques to establish the mechanisms of tautomerization of the NH protons inside the interior of the corrole macrocycle. Three such rate processes could be identified of which two modulate the spectral line shapes at temperatures above 205 K and the third is NMR-inaccessible as it is very fast. The latter involves the proton engaged in an unsymmetrical proton sponge unit formed by two pyrrole nitrogen atoms. Temperature and concentration dependences of the two remaining processes were determined. One of them is purely intramolecular and the other is intermolecular at low temperatures, with growing contribution of an intramolecular mechanism at elevated temperatures. The proposed microscopic mechanisms of all these processes are semi-quantitatively confirmed by quantum chemical calculations using density functional theory.

Application of 1-Hydroxy-4,5-Dimethyl-Imidazole 3-Oxide as Coformer in Formation of Pharmaceutical Cocrystals.

Two, well defined binary crystals with 1-Hydroxy-4,5-Dimethyl-Imidazole 3-Oxide (HIMO) as coformer and thiobarbituric acid (TBA) as well barbituric acid (BA) as Active Pharmaceutical Ingredients (APIs) were obtained by cocrystallization (from methanol) or mechanochemically by grinding. The progress of cocrystal formation in a ball mill was monitored by means of high-resolution, solid state NMR spectroscopy. The 13C CP/MAS, 15N CP/MAS and 1H Very Fast (VF) MAS NMR procedures were employed to inspect the tautomeric forms of the APIs, structure elucidation of the coformer and the obtained cocrystals. Single crystal X-ray studies allowed us to define the molecular structure and crystal packing for the coformer as well as the TBA/HIMO and BA/HIMO cocrystals. The intermolecular hydrogen bonding, π-π interactions and CH-π contacts responsible for higher order organization of supramolecular structures were determined. Biological studies of HIMO and the obtained cocrystals suggest that these complexes are not cytotoxic and can potentially be considered as therapeutic materials.

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 for this peculiar behavior are investigated, employing a joint experimental and theoretical approach. This includes the design of cocrystals with coformers having a 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. The 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.

New synthetic pathway leading to oxospirochlorins.

In this work we propose a completely new approach for the synthesis of spirochlorin derivatives based on the use of an imino-keto intermediate formed in situ from 2-amino-5,10,15,20-tetraphenylporphyrins and inverse electron demand Diels-Alder (iEDDA) cycloaddition with 3,6-di-2-pyridyl-1,2,4,5-tetrazine. The mechanism of reaction was analyzed employing theoretical methods by comparing the difference in energy of Frontier Molecular Orbitals (FMO) for appropriate reagents. Ground-state molecular electrostatic (ESP) potential maps were employed as additional tools allowing explanation of the reactivity of substrates. The new class of spirochlorin compounds was fully characterized by means of mass spectrometry, IR, liquid and solid state NMR and X-ray crystallography. Correlation between molecular structure and optical properties for the obtained title compounds is discussed.

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 three derivatives of 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-d 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.