T. P. Shakhtshneider

Effect of High Pressure on the Polymorphs of Paracetamol

Effect of hydrostatic pressure on the two (I – monoclinic and II – orthorhombic) polymorphs of paracetamol was studied by X-ray diffraction in the diamond anvil cell at pressures up to 4.5 GPa (for the monoclinic form) and up to 5.5 GPa (for the orthorhombic form). The two groups of phenomena were studied: (i) the anisotropic structural distortion of the same polymorph, (ii) transitions between the polymorphs induced by pressure.The anisotropy of structural distortion of polymorphs I and II was well reproducible from sample to sample, also from powder samples to single crystals. The bulk compressibility of the two forms was shown to be practically the same. However, a noticeable qualitative difference in the anisotropy of structural distortion was observed: with increasing pressure the structure of polymorph II contracted in all the directions showing isotropic compression in the planes of hydrogen-bonded molecular layers, whereas the layers in the structure of the polymorph I expanded in some directions. Maximum compression in both polymorphs I and II was observed in the directions normal to the molecular layers.The transitions between the polymorphs induced by pressure were poorly reproducible and depended strongly on the sample and on the procedure of increasing/decreasing pressure. No phase transitions were induced in the single crystals of the monoclinic polymorph at pressures at least up to 4GPa, although a partial transformation of polymorph I into polymorph II was observed at increased pressure in powder samples. Polymorph II transformed partly into the polymorph I during grinding. The transformation could be hindered if grinding was carried out in CCl4.

How good are the crystallisation methods for co-crystals? A comparative study of piroxicam

Co-crystallisation of two components into one crystal form can enhance the solid-state properties of drug compounds. A plethora of crystallisation methods has been applied to co-crystallisation and the reported study compares the three most common ones (crystallisation from the melt, from solution and solvent-drop grinding) with respect to their applicability and necessity for a co-crystal screening. Piroxicam, a non-steroidal anti-inflammatory drug, was chosen as a model system and submitted to an extensive co-crystal screening using twenty different acids as co-crystal formers, six crystallisation techniques and five solvents. A total of 46 co-crystal forms were obtained, 38 of which are novel. Solvent-drop grinding showed the highest absolute number of experiments resulting in co-crystals, while crystallisation from the melt yielded the highest number of co-crystal formation when crystalline material was obtained. Evaporation resulted in a high number of crystalline products but many of those were binary and ternary mixtures of crystal forms. Cooling and precipitation techniques gave only poor results. Acetone and THF showed the highest number of crystalline products while chloroform gave the highest relative yield of co-crystals. Ethanol and acetonitrile showed extensive hydrate formation. No influence of the co-crystal former on the co-crystal formation could be detected.

Are meloxicam dimers really the structure-forming units in the ‘meloxicam–carboxylic acid’ co-crystals family? Relation between crystal structures and dissolution behaviour

We compare the packing of meloxicam in all the meloxicam-containing crystal structures known up to now, with a special emphasis on meloxicam and its co-crystals with carboxylic acids, two of which, with adipic and terephthalic acids, have not been reported before. We argue that it is not the meloxicam dimers, as was claimed in Cheney et al., Cryst. Growth Des. 2010, 10, 4401–4413, but a fragment containing two molecules of meloxicam linked via a carboxylic acid molecule that is the primary structure-forming element in all the known 2 : 1 meloxicam : carboxylic acid co-crystals. Meloxicam molecules form H-bonded dimers in the crystals of meloxicam, but these dimers are no longer present in any of the known meloxicam co-crystals. The molecules of meloxicam in some of its co-crystal structures can be occasionally close to each other as a consequence of a certain steric relation defined by the size of the carboxylic acid molecules. However, these molecular pairs termed “dimers” by Cheney et al. are different from the dimers in the crystals of meloxicam and can be held together by weak H-bonds only (if any), therefore they can hardly be considered as a structure-forming unit. An improved dissolution of meloxicam co-crystals as compared to poorly soluble meloxicam is supposed to be related to the presence of meloxicam dimers linked by relatively strong H-bonds in the crystals of meloxicam and to the absence of these dimers in its co-crystals.

Anisotropy of crystal structure distortion in organic molecular crystals of drugs induced by hydrostatic compression

Variation of the unit cell parameters of paracetamol and phenacetin as a function of hydrostatic pressure was studied by X-ray diffractometry in diamond anvils. At elevated pressure (4 GPa), the crystal structures undergo anisotropic distortion. The greatest compression was observed in the directions in which the molecules are linked by van der Waals forces alone. Compressibility of the structures in the direction of hydrogen bonds depends on the presence of other types of interaction and on molecular arrangement in the crystals. In the case of paracetamol, integrated compression of the structure led to its stretching in definite crystallographic directions.

Pressure-induced phase transitions in organic molecular crystals: a combination of X-ray single-crystal and powder diffraction, Raman and IR-spectroscopy

The contribution summarizes the results of recent studies of phase transitions induced by high pressure in a number of molecular organic crystals, such as polymorphs of paracetamol, chlorpropamide, polymorphs of glycine, L- and DL-serine, β-alanine. The main attention is paid to the following topics: (1) Reversible / irreversible transformations; (2) Different behavior of single crystals / powders; (3) The role of pressure-transmitting liquid; (4) The role of the kinetic factors: phase transitions on decompression, or after a long storage at a selected pressure; (5) Isosymmetric phase transitions; (6) The role of the changes in the hydrogen bond networks / intramolecular conformational changes in the phase transitions; (7) Superstructures / nanostructures formed as a result of pressure-induced phase transitions.

Thermoanalytical investigation of drug-excipient interaction. Part I. Piroxicam, cellulose and chitosan as starting materials

SummaryCellulose, chitosan and piroxicam were investigated by TG and DSC at heating up to 215°C, and by X-ray powder diffraction before and after the heating. Dehydration of cellulose and chitosan comes to the end near 160°C. Thermal decomposition of chitosan starts at the final stage of its dehydration, and the mass losses after these two reactions overlap with one another. Enthalpy of dehydration is 47.1±2.4 kJ mol-1of water for cellulose and 46.2±2.0 kJ mol-1for chitosan. Thermal decomposition of chitosan is an exothermic process. Crystal structure of cellulose after heating remains unchanged, but that of chitosan contracts. Piroxicam melts at 200.7°C with the enthalpy of melting 35 kJ mol-1. Heat capacity of the liquid phase is greater than that of the solid phase by approximately 100 J mol-1 K-1. Cooled back to ambient temperature, piroxicam remains glassy for a long time, crystallizing slowly back into the starting polymorph.

Mechanochemical preparation of drug carrier solid dispersions

The method of mechanical activation was used to obtain solid-state dispersions of some drugs in polyvinylpyrrolidone, polyethylene glycol and talc as carriers. Solid dispersions obtained by mechanical activation were found to have higher apparent solubilities and dissolution rates than mechanically activated drugs or their physical or eutectic mixtures with carriers used. It was shown by IR-spectroscopy and fluorescence measurements that mechanical treatment gave rise to an interaction between components which was apparently responsible for the solubilization effects observed.

Effect of Mechanochemical Treatment on Physicochemical and Antitumor Properties of Betulin Diacetate Mixtures with Arabinogalactan

It was shown using gel-permeation chromatography that arabinogalactan in a SPEX 8000 ball mill changed its molecular-weight distribution (MWD) after mechanochemical treatment. The presence of betulin diacetate assisted the reduction of the MWD after dissolution of the mechanically activated mixture in water and evaporation of the solvent. Complexes of betulin diacetate with arabinogalactan were also obtained as thin films that were readily soluble in water. Mechanical composites of arabinogalactan with betulin diacetate were capable of inducing cell elimination processes mediated by disruption of ionic homeostasis in Ehrlich ascites carcinoma cells.

Mechanochemical Synthesis of Nanocomposites of Drugs with Inorganic Oxides

The nanocomposites of piroxicam and indomethacin with fine porous inorganic oxides, alumina, silica, and magnesia, were obtained by high energy ball milling. Except for the piroxicam–alumina system, the composites revealed higher dissolution rate and solubility of the drugs as compared to the initial ones. The changes in the IR spectra suggested the interaction of the components during ball milling. It was assumed that the formation of new bonds at the contacts of particles in the composite resulted in stabilization of drugs in a metastable state inhibiting their transition into the initial crystalline form.

Supramolecular architecture of betulin diacetate complexes with arabinogalactan from Larix sibirica.

Supramolecular ensembles of arabinogalactan (AG) and its complexes with betulin diacetate (BDA) were studied in water and dimethyl sulfoxide (DMSO) using ablation, induced by submillimeter radiation from the free electron laser. Solutions of 1wt% AG resulted in formation of aerosol particles with a maximum size of 60-70nm. In contrast, with DMSO as the solvent, the majority of particles were significantly smaller. Nevertheless, the addition of water shifted the particle size distribution to a larger size, suggesting the cross-linking of AG chains due to hydrogen bonding through water molecules. The ensembles of molecules were larger in solutions of the AG-BDA complex as compared to pure AG aqueous solution, and the distribution was narrow. The role of side chain interactions in the formation of AG-BDA complexes in aqueous solutions was confirmed by NMR.