Concomitant polymorphs of 2-imino-2H-chromene-3-carboxylic acid amide: experimental and quantum chemical study.

2-Iminocoumarin-3-carboxamide (2-imino-2 H-chromene-3-carboxylic acid) is a perspective compound for use in the pharmaceutical industry. This compound crystallized from several solvents as two concomitant polymorphic forms. The monoclinic polymorph, crystallized initially, is formed due to strong N-H...O hydrogen bonds, weak C-H...O and C-H...N(π) hydrogen bonds, and stacking interactions of `head-to-head' type. The triclinic polymorphic form obtained due to slow evaporation of the same solution is formed due to only strong intermolecular interactions, N-H...O hydrogen bonds of two types, and stacking interactions of two types. Analysis of pairwise interaction energies showed that the monoclinic structure is columnar while the triclinic one is layered. Calculations in a periodic approximation of their lattice energies confirmed that the monoclinic polymorphic crystals are metastable as compared to the stable triclinic polymorph. Further quantum chemical modeling of possible structure deformations proved that both concomitant polymorphs can not be transformed into a new polymorphic form under external influence.

Polymorphic transition due to grinding: the case of 3-[1-(tert-butoxycarbonyl)azetidin-3-yl]-1,2-oxazole-4-carboxylic acid.

A polymorphic transition as a result of grinding was found for 3-[1-(tert-butoxycarbonyl)azetidin-3-yl]-1,2-oxazole-4-carboxylic acid. The thorough study of polymorphic structures before and after crystal structure transformation has revealed some pre-conditions for a polymorphic transition and regularities of changes in molecular and crystal structure. In metastable polymorph 1a, the conformationally flexible molecule adopts a conformation with the higher energy and forms a less preferable linear supramolecular synthon. Additional energy imparted to a crystal structure during the grinding process proved to be enough to overcome low energy barriers for the nitrogen inversion and rotation of the oxazole ring around the sp3-sp2 single bond. As a result, polymorph 1b with a molecule adopting conformation with lower energy and forming a more preferable centrosymmetric supramolecular synthon was obtained. The study of pairwise interaction energies in the two polymorphs has shown that metastable polymorph 1a is organized by molecular building units and has a columnar-layered structure. A centrosymmetric dimer should be recognized as a complex building unit in more stable polymorph 1b, which has a layered structure.

1-Allyl-4-hydroxy-2,2-dioxo-N-(4-methoxyphenyl)-1H-2λ6,1-benzothiazine-3-carboxamide: polymorphic transition due to grinding with the loss of the biological activity.

A study of two polymorphic forms of 1-allyl-4-hydroxy-2,2-dioxo-N-(4-methoxyphenyl)-1-2λ6,1-benzothiazine-3-carboxamide (a structural analogue of piroxicam) has revealed some regularities in the crystal structure formation due to different evaporation rates from the tested solvents. The monoclinic polymorph crystallized from ethyl acetate is formed due to a large number of very weak C-H...O and C-H...π interactions as well as one strong stacking interaction. The triclinic polymorph crystallized from N,N-dimethylformamide is formed due to a small number of weak specific interactions and a maximal number of strong stacking interactions. The stacked dimer is a complex building unit in both polymorphic structures. Further analysis showed that the monoclinic structure is layered while the triclinic one is columnar. The two polymorphic structures also differ in their biological activity (antidiuretic and analgesic). The monoclinic polymorph possesses very high biological activity while the triclinic polymorph is almost inactive. The polymorphic transition of the biologically active metastable monoclinic structure into the inactive stable triclinic one within four weeks of grinding is caused by orientational factors rather than conformational ones and is accompanied by a change in the redistribution of interaction energies in the crystal from anisotropic to more isotropic. Thus, a slow polymorphic transition after grinding results in a loss of the biological activity.

Salts of 4-[(benzyl-amino)-carbon-yl]-1-methyl-pyridinium and iodide anions with different cation:iodine stoichiometric ratios.

The two iodide salts, 4-[(benzyl-amino)-carbon-yl]-1-methyl-pyridinium iodide-iodine (2/1), C14H15N2O+·I-·0.5I2, I, and 4-[(benzyl-amino)-carbon-yl]-1-methyl-pyridinium triiodide, C14H15N2O+·I3 -, II, with different cation:iodine atoms ratios were studied. Salt I contains one cation, one iodide anion and half of the neutral I2 mol-ecule in the asymmetric unit (cation:iodine atoms ratio is 1:2). Salt II contains two cations, one triiodide anion (I 3 -) and two half triiodide anions (cation:iodine atoms ratio is 1:3). The NH group forms N-H⋯I hydrogen bonds with the I- anion in the crystal of I or N-H⋯O hydrogen bonds in II where only triiodide anions are present.