Two new bismuth salts with succinic acid: synthesis, structural, spectroscopic and thermal characterization.

Two novel bismuth succinate hydrates, namely, poly[[diaqua(µ3-butane-1,4-dicarboxylato)hemi(µ-butane-1,4-dicarboxylato)bismuth] monohydrate], {[Bi(C4H4O4)1.5(H2O)2]·H2O}n (1), and poly[[µ-aqua-aqua(µ3-butane-1,4-dicarboxylato)(µ-butane-1,4-dicarboxylato)-µ-oxido-dibismuth] monohydrate], {[Bi2(C4H4O4)2O(H2O)2]·H2O}n (2), have been synthesized. Their crystal structures were determined by single-crystal X-ray diffraction and the compounds were characterized by IR and Raman spectroscopy, powder X-ray diffraction and thermal analysis. The crystal structure analysis revealed that the compounds are coordination polymers, with 1 having a two-dimensional layered structure and 2 displaying a three-dimensional (3D) framework. Fully deprotonated succinate anions (C4H4O42-) in two different conformations (trans and gauche) are included in their composition. The Bi3+ cations are surrounded by O atoms from the carboxylate groups of succinate anions and aqua ligands. BiO9 coordination polyhedra in 1 are connected in pairs by edges. These pairs are bound together by bridging succinate ligands to form layers. Bismuth coordination polyhedra of two different types (BiO9 and BiO7) in 2 are connected by edges to form infinite ribbons. Ribbons of polyhedra with bridging succinate ligands form a 3D polymeric structure.

Completing the picture of tolazamide polymorphism under extreme conditions: a low-temperature study.

We present the results of an experimental and computational study of structural changes in two polymorphs of tolazamide {systematic name: 1-[(azepan-1-ylamino)carbonyl]-4-methylbenzenesulfonamide}, C14H21N3O3S, on cooling to 100 K and reverse heating. No phase transitions occurred in this temperature range. The anisotropy of the thermal expansion was different for the two polymorphs and differed from that reported previously for the hydrostatic compression. The changes in different intermolecular contacts responsible for the strain anisotropy were analysed. Relative shortening of the contacts was related directly to their initial length and reversely to the steric density around them. Increasing steric density is likely to be the driving force for the conformational ordering of the azepane ring under compression.

Isoenergetic Polymorphism: The Puzzle of Tolazamide as a Case Study.

In the present case study of tolazamide we illustrate how many seemingly contradictory results that have been obtained from experimental observations and theoretical calculations can finally start forming a consistent picture: a "puzzle put together". For many years, tolazamide was considered to have no polymorphs. This made this drug substance unique among the large family of sulfonylureas, which was known to be significantly more prone to polymorphism than many other organic compounds. The present work employs a broad and in-depth analysis that includes the use of optical microscopy, single-crystal and powder X-ray diffraction, IR and Raman spectroscopies, DSC, semiempirical PIXEL calculations and DFT of three polymorphs of tolazamide. This case study shows how the polymorphs of a molecular crystal can be overlooked even if discovered serendipitously on one of numerous crystallizations, and how very different molecular packings can be practically isoenergetic but still crystallize quite selectively and transform one into another irreversibly upon heating.

A high-pressure polymorph of chlorpropamide formed on hydrostatic compression of the α-form in saturated ethanol solution.

The crystal structure of the high-pressure polymorph (α') of an antidiabetic drug, chlorpropamide [4-chloro-N-(propylaminocarbonyl)benzenesulfonamide, C(10)H(13)ClN(2)O(3)S], which is formed at ~2.8 GPa from the α-polymorph (P2(1)2(1)2(1)) on hydrostatic compression in saturated ethanol solution, has been determined. As a result of the phase transition, the a, c and α parameters change jumpwise, whereas the changes in b parameter are continuous through the phase transition point. The high-pressure form is monoclinic (P2(1)11) and has Z' equal to 2, the two independent molecules differing in their conformations. The hydrogen bonds expand slightly in the high-pressure polymorph after the transition, and this expansion is interrelated with the changes in molecular conformations enabling a denser packing. The transition is reversible, but the crystal quality deteriorates as a result of multiple compression-decompression cycles, and a pseudomerohedral twinning accompanies the transformation.

Glycinium semi-malonate and a glutaric acid-glycine cocrystal: new structures with short O-H...O hydrogen bonds.

Glycinium semi-malonate, C(2)H(6)NO(2)(+)·C(3)H(3)O(4)(-), (I), and glutaric acid-glycine (1/1), C(2)H(5)NO(2)·C(5)H(8)O(4), (II), are new examples of two-component crystal structures containing glycine and carboxylic acids. (II) is the first example of a glycine cocrystal which cannot be classified as a salt, as glutaric acid remains completely protonated. In the structure of (I), there are chains formed exclusively by glycinium cations, or exclusively by malonate anions, and these chains are linked with each other. Two types of very short O-H...O hydrogen bonds are present in the structure of (I), one linking glycinium cations with malonate anions, and the other linking malonate anions with each other. In contrast to (I), no direct linkages between molecules of the same type can be found in (II); all the hydrogen-bonded chains are heteromolecular, with molecules of neutral glutaric acid alternating with glycine zwitterions, linked by two types of short O-H...O hydrogen bonds.

A new method of producing monoclinic paracetamol suitable for direct compression.

PURPOSE: To develop a technique of obtaining monoclinic polymorph of paracetamol suitable for direct compression without excipients. METHODS: Preparation of spongy monoclinic paracetamol was based on quench-cooling of paracetamol solutions in water-acetone mixtures sprayed into a vessel with liquid nitrogen followed by removal of solvents by freeze-drying. X-ray powder diffraction was used to study annealing of quench-cooled solutions in "paracetamol-acetone-water" and "acetone-water" systems and to find optimum conditions for obtaining fine particles of pure monoclinic paracetamol. Samples were characterized by electron microscopy; compression properties were measured. RESULTS: The preparation technique gave fine monoclinic paracetamol powder containing agglomerates (30-200 µm) composed of flat particles (linear sizes 1-10 µm, the thickness 60-150 nm). The spongy sample was suitable for direct compression without excipients, stable on storage, and mechanically robust. Mechanically stable tablets pressed from the spongy sample were better soluble in water than commercially available tablets of paracetamol with excipients. CONCLUSIONS: The proposed method gave spongy monoclinic paracetamol samples with improved properties. For inexpensive paracetamol, the method may not yield economic advantage. However, the same method based on freeze-drying solutions in mixed aqueous-organic solvents can be used to prepare new improved forms of other molecular solids for pharmaceutical applications.

Solid-state transformations in the ß-form of chlorpropamide on cooling to 100 K.

A single-crystal X-ray diffraction study of the effect of cooling down to 100 K on the ß-form of chlorpropamide, 4-chloro-N-(propylaminocarbonyl)benzenesulfonamide, has revealed reversible phase transitions at ∼257 K and between 150 and 125 K: ß (Pbcn, Z' = 1) ⇔ ß(II) (P2/c, Z' = 2) ⇔ ß(III) (P2/n, a' = 2a, Z' = 4); the sequence corresponds to cooling. Despite changes in the space group and number of symmetry-independent molecules, the volume per molecule changes continuously in the temperature range 100-300 K. The phase transition at ∼257 K is accompanied by non-merohedral twinning, which is preserved on further cooling and through the second phase transition, but the original single crystal does not crack. DSC (differential scanning calorimetry) and X-ray powder diffraction investigations confirm the phase transitions. Twinning disappears on heating as the reverse transformations take place. The second phase transition is related to a change in conformation of the alkyl tail from trans to gauche in 1/4 of the molecules, regularly distributed in the space. Possible reasons for the increase in Z' upon cooling are discussed in comparison to other reported examples of processes (crystallization, phase transitions) in which organic crystals with Z' > 1 have been formed. Implications for pharmaceutical applications are discussed.

A conformational polymorphic transition in the high-temperature epsilon-form of chlorpropamide on cooling: a new epsilon'-form.

Structural changes in the high-temperature -polymorph of chlorpropamide, 4-chloro-N-(propylaminocarbonyl)benzenesulfonamide, C(10)H(13)ClN(2)O(3)S, on cooling down to 100 K and on reverse heating were followed by single-crystal X-ray diffraction. At temperatures below 200 K the phase transition into a new polymorph (termed the epsilon'-form) has been observed for the first time. The polymorphic transition preserves the space group Pna2(1), is reversible and is accompanied by discontinuous changes in the cell volume and parameters, resulting from changes in molecular conformation. As shown by IR spectroscopy and X-ray powder diffraction, the phase transition in a powder sample is inhomogeneous throughout the bulk, and the two phases co-exist in a wide temperature range. The cell parameters and the molecular conformation in the new polymorph are close to those in the previously known alpha-polymorph, but the packing of the z-shaped molecular ribbons linked by hydrogen bonds inherits that of the epsilon-form and is different from the packing in the alpha-polymorph. A structural study of the alpha-polymorph in the same temperature range has revealed no phase transitions.

Two polymorphs of chlorpropamide: the delta-form and the high-temperature epsilon-form.

The epsilon-form of chlorpropamide [systematic name: 4-chloro-N-(propylaminocarbonyl)benzenesulfonamide], C(10)H(13)ClN(2)O(3)S, has been obtained as single crystals from solution (and not as a polycrystalline sample by heating the alpha-, gamma- or delta-forms). The results of anisotropic structure refinements for the epsilon- and delta-forms are reported. The density of the delta-polymorph is the highest, and that of the epsilon-polymorph the lowest, among the five known chlorpropamide polymorphs. The main intermolecular hydrogen-bonding pattern in polymorphs delta and epsilon is the same as in polymorphs alpha, beta and gamma, but the conformations differ. The densities of the polymorphs were found to depend on the molecular conformations.

Bis(DL-cysteinium) oxalate.

In the title compound, 2C3H8NO2S+.C2O4(2-), the oxalate anion occupies an inversion centre and is coordinated to cysteine molecules of different chirality (L and D) via O-H...O and N-H...O hydrogen bonds, the resulting cysteine-oxalate stoichiometry in the crystal structure being 2:1. The oxalate anion is completely deprotonated, whereas cysteine has a positively charged -NH3+ group and a neutral protonated carboxyl group. The structure is built from infinite hydrogen-bonded triple layers, consisting of an oxalate layer in the middle with layers of L- and D-cysteine molecules on either side. The thiol groups are at the external sides of the layers and form S-H...O hydrogen bonds with the carboxyl groups of neighbouring cysteine molecules. An interesting feature of the structure is the occurrence of short S...S contacts between SH groups of molecules in neighbouring layers, which form not S-H...S but S-H...O intermolecular hydrogen bonds. Due to the effects of crystal packing and intermolecular hydrogen-bond formation, the conformation of the cysteine cation in the title structure is different from that calculated theoretically for an individual cation, as well as from those of cysteine zwitterions in crystals of pure cysteine.

An extended phase transition in crystalline L-cysteine near 70 K.

An anomaly of heat capacity near 70 K was registered in the crystalline L-cysteine (orthorhombic polymorph) by adiabatic calorimetry as a small, 3-5% height, diffuse "jump", or a wide "hump" accompanied by the substantial increase in the thermal relaxation time. The Cp(T) dependence is characteristic for a transformation extended over a wide temperature range and sensitive to the thermal prehistory of the sample, that can be interpreted as nonsimultaneous changes in the dynamics and the orientation of the numerous thiol groups in the structure. The measurements of the cell parameters and cell volume on cooling suggest that a discontinuity in their values over the transition point exists.

A new gamma-polymorph of chlorpropamide: 4-chloro-N-(propylaminocarbonyl)benzenesulfonamide.

The structure of a new polymorph of the title compound, C(10)H(13)ClN(2)O(3)S, known as the antidiabetic drug chlorpropamide, is monoclinic, in contrast with the two previously described orthorhombic alpha- and beta-forms. The molecules in the gamma-polymorph are linked into bands by hydrogen bonds similar to those in the alpha-polymorph. The conformation of the molecules in the gamma-form is close to that in the beta-polymorph.

4-Benzoyloxy-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide.

The crystal structure of the title compound, C(22)H(17)N(3)O(5)S, contains dimers linked by N-H...O hydrogen bonds about inversion centers. The dimers are packed in a herring-bone framework without classical hydrogen bonds between the structure-forming units.