Discrepancy between thermodynamic and kinetic stabilities of the tert-butanol hydrates and its implication for obtaining pharmaceutical powders by freeze-drying.

The tert-butanol (TBA)-water system is studied in relation to increasing the efficiency of obtaining pharmaceutical powders by freeze-drying. Trehalose was used as a model target product. We report the X-ray diffraction and thermal analysis data which add surprising new information to the phase diagram of this previously repeatedly studied system. The freezing protocol has a strong impact on the specific surface area of the trehalose freeze-dried cakes and on the primary drying time. This is related to a discrepancy between the kinetic and thermodynamic stabilities of several TBA hydrates: di-hydrate (H1), heptahydrate (H2), and decahydrate (H3).

A large anisotropic plasticity of L-leucinium hydrogen maleate preserved at cryogenic temperatures.

L-Leucinium hydrogen maleate crystals are very plastic at ambient conditions. Here it is shown that this plasticity is preserved at least down to 77 K. The structural changes in the temperature range 293-100 K were followed in order to rationalize the large anisotropic plasticity in this compound. To the best of our knowledge, this is the first reported example of an organic compound remaining so plastic at cryogenic conditions.

Crystal structure of a 1:1 salt of 4-amino-benzoic acid (vitamin B10) with pyrazinoic acid.

The title 1:1 salt, C7H8NO2 +·C5H3N2O2 - (systematic name: 4-carb-oxy-anilinium pyrazine-2-carboxyl-ate), was synthesized successfully by slow evaporation of a saturated solution from water-ethanol (1:1 v/v) mixture and characterized by X-ray diffraction (SCXRD, PXRD) and calorimetry (DSC). The crystal structure of the salt was solved and refined at 150 and 293 K. The salt crystallizes with one mol-ecule of 4-amino-benzoic acid (PABA) and one mol-ecule of pyrazinoic acid (POA) in the asymmetric unit. In the crystal, the PABA and POA mol-ecules are associated via COOH⋯Narom heterosynthons, which are connected by N-H⋯O hydrogen bonds, creating zigzag chains. The chains are further linked by N-H⋯O hydrogen bonds and π-π stacking inter-actions along the b axis [centroid-to-centroid distances = 3.7377 (13) and 3.8034 (13) Šat 150 and 293 K, respectively] to form a layered three-dimensional structure.

Crystal structure of 4-benzyl-carbamoyl-1-methyl-pyridin-1-ium iodide: an efficient multimodal anti-viral drug.

In the title compound, [MeC5H4NCONHCH2C6H5]I or C14H15N2O+·I-, a cation and an anion form an ionic pair linked by a strong N-H⋯I hydrogen bond. In the crystal, ionic pairs linked by weak C-H⋯I hydrogen bonds form infinite ribbons along the crystallographic a axis. Polymorphism screening varying crystallization solvents (water, acetone 90%-water, ethanol 90%-water, 2-propanol 90%-water, DMF, DMSO, methanol, aceto-nitrile) and conditions (solution temperature, heating and cooling protocols) did not reveal any other polymorphs than the one reported in this work.

Large porous particles for respiratory drug delivery. Glycine-based formulations.

Large porous particles are becoming increasingly popular as carriers for pulmonary drug delivery with both local and systemic applications. These particles have high geometric diameters (5-30µm) but low bulk density (~0.1g/cm3 or less) such that the aerodynamic diameter remains low (1-5µm). In this study salbutamol and budesonide serve as model inhalable drugs with poor water solubility. A novel method is proposed for the production of dry powder inhaler formulations with enhanced aerosol performance (e.g. for salbutamol-glycine formulation the fine particle fraction (FPF≤4.7µm) value is 67.0±1.3%) from substances that are poorly soluble in water. To overcome the problems related to extremely poor aqueous solubility of the APIs, not individual solvents are used for spray freeze-drying of API solutions, but organic-water mixtures, which can form clathrate hydrates at low temperatures and release APIs or their complexes as fine powders, which form large porous particles after the clathrates are removed by sublimation. Zwitterionic glycine has been used as an additive to API directly in solutions prior to spray freeze-drying, in order to prevent aggregation of powders, to enhance their dispersibility and improve air-flow properties. The clathrate-forming spray freeze-drying process in the multi-component system was optimized using low-temperature powder X-ray diffraction and thermal analysis.

[Modeling of hemodynamic changes in the aneurysm of the middle cerebral artery depending on the pathology of the parent artery].

OBJECTIVE: To examine the influence of the parent artery pathology on the local hemodynamics on the level of aneurysm. MATERIAL AND METHODS: Mathematical models of the arteriovenous malformation (AVM) were built on the CT-angiography data of real patients. To simulate the thrombosis, the parent artery and its branches were sequentially turned off in the model 1. In the model 2, the simulation of embolization of AVM was achieved by cutting off the exactly section of the parent artery that was involved in the arteriovenous formation. RESULTS AND CONCLUSION: Model 1 showed that the flow redistribution did not significantly impact on the risk of rupture after the parent artery was turned off and blood pressure was increased in both aneurysms by 3 mm Hg. Model 2, in which the aneurysms were combined with a direct arteriovenous drainage with low peripheral resistance, showed that turning off the parent artery and pathological drainage led to the serious reduction in the venous drainage flow and it's increasing in the parent artery by about 60% that significantly increased the risk of rupture.

Unusual hydrogen bonding in L-cysteine hydrogen fluoride.

L-Cysteine hydrogen fluoride, or bis(L-cysteinium) difluoride-L-cysteine-hydrogen fluoride (1/1/1), 2C3H8NO2S(+)·2F(-)·C3H7NO2S·HF or L-Cys(+)(L-Cys···L-Cys(+))F(-)(F(-)...H-F), provides the first example of a structure with cations of the 'triglycine sulfate' type, i.e. A(+)(A···A(+)) (where A and A(+) are the zwitterionic and cationic states of an amino acid, respectively), without a doubly charged counter-ion. The salt crystallizes in the monoclinic system with the space group P2(1). The dimeric (L-Cys···L-Cys(+)) cation and the dimeric (F(-)···H-F) anion are formed via strong O-H···O or F-H···F hydrogen bonds, respectively, with very short O···O [2.4438 (19) Å] and F···F distances [2.2676 (17) Å]. The F···F distance is significantly shorter than in solid hydrogen fluoride. Additionally, there is another very short hydrogen bond, of O-H···F type, formed by a L-cysteinium cation and a fluoride ion. The corresponding O···F distance of 2.3412 (19) Šseems to be the shortest among O-H···F and F-H···O hydrogen bonds known to date. The single-crystal X-ray diffraction study was complemented by IR spectroscopy. Of special interest was the spectral region of vibrations related to the above-mentioned hydrogen bonds.

L-Methioninium picrate.

Single crystals of l-methioninium picrate were obtained by evaporation of aqueous solution containing equimolar quantities of each component. l-Methioninium picrate crystallizes in the monoclinic system (space group P21, Z=2). The asymmetric unit contains one l-methioninium cation and one picrate anion. The carboxyl group of the cation forms an O-H⋯O hydrogen bond with the phenoxy oxygen atom and has an O⋯O distance of 2.669(3)Å. The protonated amino group of the l-methioninium cation forms N-H⋯O hydrogen bonds with the phenoxy oxygen atom of the picrate anion and the carbonyl oxygen atom of the symmetry related cation. The infrared and Raman spectra are recorded and discussed.

Sarcosine and betaine crystals upon cooling: structural motifs unstable at high pressure become stable at low temperatures.

The crystal structures of N-methyl derivatives of the simplest amino acid glycine, namely sarcosine (C3H7NO2) and betaine (C5H11NO2), were studied upon cooling by single-crystal X-ray diffraction and single-crystal polarized Raman spectroscopy. The effects of decreasing temperature and increasing hydrostatic pressure on the crystal structures were compared. In particular, we have studied the behavior upon cooling of those structural motifs in the crystals, which are involved in structural rearrangement during pressure-induced phase transitions. In contrast to their high sensitivity to hydrostatic compression, the crystals of both sarcosine and betaine are stable to cooling down to 5 K. Similarly to most α-amino acids, the crystal structures of the two compounds are most rigid upon cooling in the direction of the main structural motif, namely head-to-tail chains (linked via the strongest N-H···O hydrogen bonds and dipole-dipole interactions in the case of sarcosine, or exclusively by dipole-dipole interactions in the case of betaine). The anisotropy of linear strain in betaine does not differ much upon cooling and on hydrostatic compression, whereas this is not the case for sarcosine. Although the interactions between certain structural motifs in sarcosine and betaine weaken as a result of phase transitions induced by pressure, the same interactions strengthen when volume reduction results from cooling.

Glycine phases formed from frozen aqueous solutions: revisited.

Glycine phases formed when aqueous solutions were frozen and subsequently heated under different conditions were studied by Raman scattering, x-ray diffraction, and differential scanning calorimetry (DSC) techniques. Crystallization of ice I(h) was observed in all the cases. On cooling at the rates of 0.5 K∕min and 5 K∕min, glassy glycine was formed as an intermediate phase which lived about 1 min or less only, and then transformed into ß-polymorph of glycine. Quench cooling of glycine solutions (15% w∕w) in liquid nitrogen resulted in the formation of a mixture of crystalline water ice I(h) and a glassy glycine, which could be preserved at cryogenic temperatures (80 K) for an indefinitely long time. This mixture remained also quite stable for some time after heating above the cryogenic temperature. Subsequent heating under various conditions resulted in the transformation of the glycine glass into an unknown crystalline phase (glycine "X-phase") at 209-216 K, which at 218-226 K transformed into ß-polymorph of glycine. The "X-phase" was characterized by Raman spectroscopy; it could be obtained in noticeable amounts using a special preparation technique and tentatively characterized by x-ray powder diffraction (P2, a = 6.648 Å, b = 25.867 Å, c = 5.610 Å, ß = 113.12[ordinal indicator, masculine]); the formation of "X-phase" from the glycine glassy phase and its transformation into ß-polymorph were followed by DSC. Raman scattering technique with its power for unambiguous identification of the crystalline and glassy polymorphs without limitation on the crystallite size helped us to follow the phase transformations during quenching, heating, and annealing. The experimental findings are considered in relation to the problem of control of glycine polymorphism on crystallization.

Different effects of α- and γ-glycine on the aberrant activity of pyramidal neurons of hippocampal slices.

Experiments in vitro on hippocampal slices of mouse have shown that solutions prepared from polymorphic modifications α- and γ-glycine have different effect on the aberrant activity of neurons. In the presence of α-glycine the excitability of these neurons decreased more slowly, prolonging its modulating effect on NMDA type glutamate receptors. This effect agrees with higher biological activity of α-polymorphic modifications (as compared with that of the α-form) that previously observed with respect to behavior of mice from the line with genetic diathesis to catalepsy, which were used as a biological model for investigation of some pathological behavior forms.

Raman study of low-frequency modes in three glycine polymorphs.

The temperature dependence of selected low-wavenumber (< 200 cm(-1)) Raman bands was studied for the different crystalline phases (α-, ß-, γ-) of glycine--the simplest possible "building block" of a biomolecule. The temperature dependence of the frequencies of vibrational modes deviates from the theoretical expectation based on the assumption of cubic anharmonicity. Although relatively small, this deviation was observed above 250 K for all the three polymorphs. This finding was discussed in relation to the "dynamical transition" phenomenon, observed in variety of biomolecules in the range 200-250 K. The similarity of the temperatures suggests, that the origin of the dynamical transition phenomenon can be related to intrinsic conformational states of biomolecules, while water serves rather as a plasticizer or a structure organizer.

Pressure-induced phase transitions in L-alanine, revisited.

The effect of pressure on L-alanine has been studied by X-ray powder diffraction (up to 12.3 GPa), single-crystal X-ray diffraction, Raman spectroscopy and optical microscopy (up to approximately 6 GPa). No structural phase transitions have been observed. At approximately 2 GPa the cell parameters a and b become accidentally equal to each other, but without a change in space-group symmetry. Neither of two transitions reported by others (to a tetragonal phase at approximately 2 GPa and to a monoclinic phase at approximately 9 GPa) was observed. The changes in cell parameters were continuous up to the highest measured pressures and the cells remained orthorhombic. Some important changes in the intermolecular interactions occur, which also manifest themselves in the Raman spectra. Two new orthorhombic phases could be crystallized from a MeOH/EtOH/H(2)O pressure-transmitting mixture in the pressure range 0.8-4.7 GPa, but only if the sample was kept at these pressures for at least 1-2 d. The new phases converted back to L-alanine on decompression. Judging from the Raman spectra and cell parameters, the new phases are most probably not L-alanine but its solvates.

Difference in the dynamic properties of chiral and racemic crystals of serine studied by Raman spectroscopy at 3-295 K.

Single-crystal polarized Raman spectra (60-4000 cm(-1) at 3 < or = T < or = 295 K) were measured for chiral L- and racemic DL-serine, alpha-amino-beta-hydroxypropionic acid, (NH3)+CH(CH2OH)(COO)-. The Raman spectra of dl-serine do not show any striking changes with temperature or on storage. In contrast to that, the dynamical properties of L-serine change at about 140 K. These changes can be interpreted as the reorientation of the side chain -CH2OH fragments of the zwitterions with respect to the backbone C-C bonds, resulting in the positional disorder of the O-H...O intermolecular H-bonds. The redistribution in the intensities of the Raman spectra of the crystals of L-serine stored for a long time (about a year) indicates the changes in the orientation of the molecular fragments in the direction normal to the axes of the head-to-tail chains. The difference in the thermodynamic functions of L- and DL-serine reported previously [Drebushchak, V. A.; Kovalevskaya, Yu. A.; Paukov, I. E.; Boldyreva, E. V. J. Therm. Anal. Calorim. 2007, 89 (2), 649-654] is explained by the difference in the spectra of external vibrations of the crystals.

A urea complex of copper(II) hypophosphite at 293, 100 and 15 K.

The crystal structure of poly[copper(II)-di-mu-hypophosphito-mu-urea], [Cu(H2PO2)2(CH4N2O)]n, has been determined at 293, 100 and 15 K. The geometry of the hypophosphite anion is very close to ideal, with point symmetry mm2. Each Cu atom lies on an inversion centre and is coordinated to six O atoms from four hypophosphite anions and two urea molecules, forming a tetragonal bipyramid. The unique urea molecule lies on a twofold axis. Each hypophosphite anion in the structure is coordinated to two Cu atoms. The hypophosphite anions, urea molecules and Cu(II) cations form polymeric ribbons. The Cu(II) cations in the ribbon are linked together by two hypophosphite anions and a urea molecule, which is coordinated to Cu via an O atom. The ribbons are linked to each other by N-H...O hydrogen bonds and form polymeric layers.

Anisotropic crystal structure distortion of the monoclinic polymorph of acetaminophen at high hydrostatic pressures.

The anisotropy of structural distortion of the monoclinic polymorph of acetaminophen induced by hydrostatic pressure up to 4.0 GPa was studied by single-crystal X-ray diffraction in a Merrill-Bassett diamond anvil cell (DAC). The space group (P2(1)/n) and the general structural pattern remained unchanged with pressure. Despite the overall decrease in the molar volume with pressure, the structure expanded in particular crystallographic directions. One of the linear cell parameters (c) passed through a minimum as the pressure increased. The intramolecular bond lengths changed only slightly with pressure, but the changes in the dihedral and torsion angles were very large. The compressibility of the intermolecular hydrogen bonds NH...O and OH...O was measured. NH...O bonds were shown to be slightly more compressible than OH...O bonds. The anisotropy of structural distortion was analysed in detail in relation to the pressure-induced changes in the molecular conformations, to the compression of the hydrogen-bond network, and to the changes in the orientation of molecules with respect to each other in the pleated sheets in the structure. Dirichlet domains were calculated in order to analyse the relative shifts of the centroids of the hydrogen-bonded cycles and of the centroids of the benzene rings with pressure.