Crystal structure of an anhydrous form of trehalose: structure of water channels of trehalose polymorphism

alpha, alpha-Trehalose (trehalose) is a nonreducing disaccharide of glucose and is accumulated at high concentrations in some anhydrobiotic organisms, which can survive without water for long periods and rapidly resume active metabolism upon hydration. Although it has been proposed that the intriguing mechanism of bioprotection in anhydrobiosis is conferred by a water channel, details of such a channel have yet to be revealed. We determined the crystal structure of a trehalose anhydrate to further understand the relationship between the structure of water channels and the trehalose polymorph. The space group was identical to that of the dihydrate and the lattice constants were also very similar. Among the five intermolecular hydrogen bonds between the trehalose molecules, four were preserved in the anhydrate. If dehydration of the dihydrate is slow and/or gentle enough to preserve the hydrogen bonds, transformation from the dihydrate to the anhydrate may occur. There are two different holes, hole-1 and hole-2, along one crystal axis. Hole-1 is constructed by trehalose molecules with a screw diad at its center, while hole-2 has a smaller diameter and is without a symmetry operator. Because of the screw axis at the center of hole-1, hollows are present at the side of the hole with diameters roughly equal to that of hole-1. Hole-1 and side pockets followed by hollows correspond to the positions of two water molecules of the dihydrate. The side hollows of the water channel are also observed in the water-filled hole of the dihydrate. Consequently, hole-1 is considered to be a one-dimensional water channel with side pockets. We also calculated molecular and crystal energies to examine the rapid water uptake of the anhydrate. It was demonstrated that the intermolecular interactions in the anhydrate were weaker than in the other anhydrous form, and probably also than those in amorphous trehalose. The anhydrate provides water capture for another solid form and gives protection from water uptake. These structural properties of the anhydrate may elucidate bioprotection in anhydrobiosis.     

Surprises in a ‘Simple' System: 2,4‐Diaminobenzenesulfonic Acid

The search for the polymorphic forms of 2,4‐diaminobenzenesulfonic acid (DBSA), known to exist since 1880, has revealed a surprisingly rich solid‐state system for such a simple molecule. A monohydrate, a dimoiric hydrate, an anhydrate and two polymorphic forms of the hydrochloride of this material have thus far been prepared. Their characterization by microscopic and thermal methods, FT‐IR spectroscopy, and single‐crystal structure determination are described.     

Thermal investigation on polymorphism in sodium saccharine

The thermal behavior of sodium saccharin polymorphic forms was investigated using thermogravimetry and differential scanning calorimetry, while structural changes during the dehydration processes were monitored by X-ray powder diffraction. In solid state, sodium saccharine may exhibit three forms: anhydrate, 2/3 hydrate (triclinic), and 15/8 hydrate (monoclinic) ones. In this investigation, it was established that monoclinic and triclinic forms compose an entantiotropically related polymorphs system. At 82 °C, the 15/8 hydrated monoclinic form is converted to 2/3 hydrated triclinic form, which showed to be the more thermodynamically stable form at room temperature. Spontaneous solidification leads to the formation of triclinic cell setting, and additionally, spontaneous hydration of the anhydrous form leads to formation of 2/3 hydrated triclinic form.     

Packing interactions in hydrated and anhydrous forms of the antibiotic Ciprofloxacin: a solid-state NMR, X-ray diffraction, and computer simulation study

We present an experimental NMR, X-ray diffraction (XRD), and computational study of the supramolecular assemblies of two crystalline forms of Ciprofloxacin: one anhydrate and one hydrate forming water wormholes. The resonance assignment of up to 51 and 54 distinct (13)C and (1)H resonances for the hydrate is reported. The effect of crystal packing, identified by XRD, on the (1)H and (13)C chemical shifts including weak interionic H-bonds, is quantified; (1)H chemical shift changes up to ～-3.5 ppm for CH···π contacts and ～+2 ppm (CH···O((-))); ～+4.7 ppm (((+))NH···O((-))) for H-bonds. Water intake induces chemical shift changes up to 2 and 5 ppm for (1)H and (13)C nuclei, respectively. Such chemical shifts are found to be sensitive detectors of hydration/dehydration in highly insoluble hydrates.     

Characterization of polymorphs of a novel quinolinone derivative, TA-270 (4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone)

The polymorphic forms and amorphous form of TA-270 (4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone), a newly developed antiallergenic compound, were characterized by powder X-ray diffractometry, thermal analysis, infrared spectroscopy and solid state 13C-NMR. The intrinsic dissolution rates of polymorphic forms were measured using the rotating disk method at 37 degrees C. The dissolution rates correlated well with the thermodynamic stability of each polymorphic form. These dissolution properties were clearly reflected in the oral bioavailability of TA-270 in rats. The transition behavior for each polymorph and for the amorphous form was studied under the high temperature and humidity conditions. The beta- and delta-forms were transformed into the alpha-form by heating. The amorphous form was also easily crystallized into alpha-form by heating, however it was relatively stable under humidified conditions. The internal molecular packing of each polymorph was estimated from IR and solid state NMR spectral analysis.     

Characterization of the non-stoichiometric and isomorphic hydration and solvation in FK041 clathrate

FK041 crystallizes as a non-stoichiometric hydrate or as solvated hydrates which were characterized as isomorphic clathrates by powder X-ray diffractometry. Moisture and organic solvent vapor sorption studies, differential scanning calorimetry and thermogravimetric analysis revealed that FK041 monohydrate forms a physically stable host crystal, which has lattice channels for guest water and/or organic solvent molecules. The hydration state varies non-stoichiometrically between dihydrate and tetrahydrate depending on the relative humidity and the mol content of the co-existing organic solvent, that is 2-propanol, ethanol, or acetone. These organic solvents are thought to replace a part of originally present water with a mol ratio of 1:3. 2-Propanol exhibited the most stable solvation, indicating that the size and shape of 2-propanol are the most preferable to the lattice channels.     

Thermal, phase transition, and thermal kinetics studies of carbamazepine

The thermal, phase transition of carbamazepine dihydrate and the solid-state transformation of carbamazepine from form III to form I were performed by Differential scanning calorimetry (DSC), Thermo gravimetry (TG–DTA), and X-ray powder diffraction.The non-thermal kinetic analysis of carbamazepine dihydrate and form III was carried out by DSC at different heating rates in dynamic nitrogen atmosphere. The model-free model, the Kissinger method, was used to give the Arrhenius parameters. Arrhenius plots from the kinetic model yielded activation energies corresponding to dehydration of dihydrate and melting of anhydrate CBZ form I were 95.28, 966.06 kJ mol^?1, the pre-exponential factors were 8.34E+11 and 1.41E+149, respectively. For the transformation of carbamazepine from form III to form I, activation energies corresponding to the melting of CBZ form III, recrystallization of form I, and melting of form I were 1160.81, 710.89, 1265.89 kJ mol^?1, the pre-exponential factors were 2.29E+144, 4.43E+91, and 1.61E+151, respectively. As a comparison, Ozawa method was used to verify the activation energy values obtained by Kissinger method. The result shows a close activation energy values between two methods.     

Effect of grinding on dehydration of crystal water of theophylline

The effect of grinding on the dehydration of crystal water of theophylline has been studied. It was observed that the water content of theophylline hydrate decreased with increased grinding time. As the grinding time proceeded, the results of differential scanning calorimetry (DSC) indicated that crystal water of ground theophylline hydrate dehydrated in three steps at ca. 58, 44, and 17 degrees C, respectively. Powder X-ray diffraction study revealed that the crystal lattice of theophylline monohydrate collapsed by grinding, and part of the theophylline molecules subsequently rearranged the collapsed lattice to form theophylline anhydrate. The result of Fourier transformed infrared spectroscopy demonstrated that the hydrogen bonds between crystal water molecules and theophylline molecules were weakened or destroyed to some extent by grinding. It was supposed that crystal water in the ground theophylline hydrate might exist at least in three molecular states of different hydrogen-bonding. From DSC study, it was suggested that the ruptured hydrogen bonds of water molecules in the ground theophylline hydrate were strengthened after storage under 96.5% relative humidity at 30 degrees C.     

Characterization of non-stoichiometric hydration and the dehydration behavior of sitafloxacin hydrate

Sitafloxacin (STFX) hydrate is a non-stoichiometric hydrate. The hydration state of STFX hydrate varies non-stoichiometrically depending on the relative humidity and temperature, though X-ray powder diffraction (XRPD) of STFX hydrate was not affected by storing at low and high relative humidities. The detailed properties of crystalline water of STFX hydrate were estimated in terms of hygroscopicity, thermal analysis combined with X-ray powder diffractometry, crystallography and density functional theory (DFT) calculation. STFX hydrate changed the water contents continuously and reversibly from an equivalent amount of dihydrate through that of sesquihydrate depending on the relative humidity at 25°C. Thermal analysis and X-ray powder diffraction (XRPD) simultaneous measurement also revealed that STFX hydrate dehydrated into a hydrated state equivalent to monohydrate by heating up to 100°C, whereas XRPD patterns were slightly affected. This indicated that the crystal structure of STFX hydrate was retained at the dehydration level of monohydrate. Single-crystal X-ray structural analysis showed that two STFX molecules and four water molecule sites were contained in an asymmetric unit. STFX molecules formed a channel structure where water molecules were included. At the partially dehydrated state, at least two of four water molecules were considered to be disordered in occupancy and/or coordinates. Insight into the crystal structure of STFX hydrate stored at low and high relative humidities and geometry of the hydrogen bond were helpful to estimate the origin of non-stoichiometric hydration of STFX hydrate.     

Structures of cabergoline anhydrate form II and novel cabergoline solvates

Crystal forms of N-[3-(dimethylamino)propyl]-N-(ethylcarbamoyl)-6-allyl-ergoline-8β-carboxamide (cabergoline) originating from various solvents have been examined by X-ray diffraction at 298 or 150 K. Crystal structures of cabergoline anhydrate, (form II, P2₁2₁2₁) and solvates (all P2₁2₁2₁) with tert-butyl methyl ether (form VIII), cyclohexane (form XV), toluene (form IX), p-xylene (form XVI), and 1,2,4-trimethylbenzene (form XVII) are described. Conformation of cabergoline in these forms was compared with crystal structures of forms I and VII of cabergoline (P2₁) described in the literature. Despite a high degree of molecular conformational freedom, cabergoline possesses similar conformation in forms I, II, VIII, IX, XV, XVI, and XVII. Molecular conformations, crystal packing and the effect of the solvent on the former two properties are examined.     

The sorption and desorption of water in lactitols

Summary Anhydrous lactitols (A1, α- and β-lactitol), lactitol monohydrate, lactitol dihydrate and lactitol trihydrate were kept for varying times in atmospheres of different relative humidity at 20°C in equivalent size plastic desiccators. The relative humidities (8-95%) were maintained with saturated salt solutions and drying agents (silica gel and phosphorous pentoxide). The composition of the samples was monitored by thermogravimetry, differential scanning calorimetry and X-ray powder diffraction. According to these measurements both lactitol monohydrate and lactitol dihydrate were substantially stable under the conditions used. Lactitol monohydrate converts to lactitol dihydrate at the highest relative humidity used. All phases of anhydrous lactitol convert into a form of lactitol monohydrate but not to lactitol dihydrate, even at the highest relative humidity used. At a high relative humidity lactitol trihydrate easily loses part of its crystal water and converts partly to lactitol dihydrate. At a lower relative humidity, the phase forming from trihydrate is difficult to identify.     

Hydrogen-bonded networks of 2,2′-substituted 4,4′-biimidazoles: New ligands for the assembled metal complexes

4,4′-Biimidazole derivatives having alkyl-substituents at 2- and 2′-positions were synthesized as new component molecules of supramolecular assemblies based on hydrogen-bonding interaction. The crystal structure analyses of methyl and ethyl derivatives revealed intriguing three-dimensional structures constructed by hydrogen-bonded networks. Furthermore, the methyl derivative formed a six-membered cyclic motif of hydrogen-bonded network to build up a channel structure. The ethyl derivative gave the two polymorphous, anhydrate and dihydrate, depending on conditions of the crystallization. The anhydrate constructed three-dimensional hydrogen-bonded networks by direct N–H⋯N hydrogen-bondings. In the crystal structure of the dihydrate of ethyl derivative, three-dimensional hydrogen-bonding interaction through water molecules formed a channel structure.     

Effect of pulverization on hydration kinetic behaviors of creatine anhydrate powders

The crystal orientation of creatine monohydrate varies significantly with tableting performance and pulverizing mechanism. Furthermore, the X-ray diffraction patterns of anhydrous forms of untreated creatine monohydrate and of pulverized creatine monohydrate exhibit different crystal orientations. However, hygroscopic forms of unpulverized creatine anhydrate and pulverized creatine anhydrate was exhibit the same diffraction peak pattern. The hygroscopicity of unpulverized and pulverized creatine anhydrate has been investigated by hydration kinetic methods using isothermal differential scanning calorimetry data. Testing of the hygroscopicity of unpulverized and pulverized creatine anhydrate at various levels of relative humidity (RH) at 25 °C revealed that the anhydrate was stable at less than 33% RH, but was transformed into the monohydrate at more than 52% RH. Hydration data of unpulverized and pulverized creatine anhydrate at 60% and 75% RH were calculated to determine hydration kinetics using various solid-state kinetic models. The hydration type of unpulverized and pulverized creatine anhydrate powder follows the zero-order mechanism (Polany–Winger equation) R1. The transition rate constant of pulverized creatine anhydrate, calculated from the slope of the straight line, was about 1.34–1.36 times higher than that of unpulverized creatine anhydrate.     

Structural investigation and Hirshfeld surface analysis of two polymorphs of 2-(4-Methylbenzamido)-5-(4-fluoro-3-phenoxyphenyl)-1,3,4-thiadiazoles

In this report, the crystal structure of a new polymorphic form of 2-(4-Methylbenzamido)-5-(4-fluoro-3-phenoxyphenyl)-1,3,4-thiadiazole have been investigated and compared with the previously reported form. Crystallization experiments from a non-polar solvent resulted in the formation of a newly obtained polymorph of this substituted 1,3,4 thiadiazole compound. Structural differences and similarities in both the polymorphic forms were explored in terms of supramolecular building blocks present in the crystal packing and their influences on the supramolecular construct are investigated in terms of the nature and energetics of the associated interactions. In addition, Hirshfeld surface analysis and calculations on the enrichment ratio were carried out for both the forms to isolate the various types of interatomic contacts and differentiate their contribution towards the molecular assembly, as obtained from 2D fingerprint plots. Also, the interaction energies were computed for the new polymorph and compared with the reported form. The studies render quantitative insights into the role of strong H-bonds and weak intermolecular interactions acting cooperatively in the crystal. In addition, the role of both electrostatic and dispersion energies contributes to the overall stability in the crystal packing.     

Hydrogen bonding : Part 17. IR and NMR study of the lower hydrates of choline chloride

Choline chloride forms two lower hydrates — a dihydrate and a monohydrate — with quite unusual properties. The dihydrate is a highly structured liquid salt; the IR spectrum is similar to that of a crystalline framework clathrate hydrate, and there are separate ¹H-NMR signals for the cation hydroxyl and water protons. The dihydrate is a crystalline solid at reduced pressure. The crystalline monohydrate only exists at reduced pressure; at atmospheric pressure it disproportionates to liquid dihydrate and anhydrous choline chloride. The anhydrous choline chloride thus formed is a previously unreported crystal modification of choline chloride.     

Physico-chemical characterization of an active pharmaceutical ingredient

The physico-chemical properties and polymorphism of a new active pharmaceutical ingredient entity has been analyzed and the gain of knowledge during the chemical development of the substance is described. Initial crystallization revealed an anhydrous crystal form with good crystallinity and a single, sharp DSC melting peak at 171°C and a straightforward development of this crystal form seemed possible. However, during polymorphism screening, new crystalline forms were detected that were often analyzed as mixtures of crystal forms. The process of characterization and identification of the different crystalline forms and its thermodynamical relationship has been supported by a combination of experimental and computational work including determination of the three-dimensional structures of the crystal forms. The crystal structure of one polymorphic form was solved by single crystal X-ray structure analysis. Unfortunately, Mod B resisted in formation of suitable single crystals, but its structure could be solved by high resolution powder diffraction data analysis using synchrotron radiation. Calculation of the theoretical X-ray powder diffraction pattern from three dimensional crystal coordinates allowed an unambiguous identification of the different crystalline forms. Two polymorphic crystal forms of the API-CG3, named Mod A and Mod B, are enantiotropic whereas Mod B is the most stable polymorph at room temperature up to about 50°C and Mod A at temperatures above 50°C. The mechanism of the solid-solid transition can be explained by analyzing the molecular packing information gained from the single crystal structures. A third crystalline form with the highest melting peak turned out to be not a polymorphic or pseudopolymorphic crystal modification of our API-CG3 but a chemically different substance. This revised version was published online in July 2006 with corrections to the Cover Date.     

dl‐Alaninium semi‐oxalate monohydrate

The structure of the title compound, C₃H₈NO₂⁺·C₂HO₄⁻·H₂O, is formed by two chiral counterparts (l ‐ and d ‐alaninium cations), semi‐oxalate anions and water molecules, with a 1:1:1 cation–anion–water ratio. The structure is compared with that of the previously known anhydrous dl ‐alaninium semi‐oxalate [Subha Nandhini, Krishnakumar & Natarajan (2001). Acta Cryst. E 57 , o666–o668] in order to investigate the role of water molecules in the crystal packing. The structure of the hydrate resembles that of anhydrous alaninium semi‐oxalate, with the water molecule incorporated into the general three‐dimensional network of hydrogen bonds where it forms four hydrogen bonds with neighbours disposed tetrahedrally about it. Although the main structural motifs in the hydrate and in the anhydrous form are topologically similar, the incorporation of water molecules in the network results in significant geometric distortion. There are several types of hydrogen bond in the crystal structure of the hydrate, two of which (O—H...O bonds between the semi‐oxalate anions and O—H...O hydrogen bonds between water and alaninium cations) are very short. Such hydrogen bonds between semi‐oxalate anions are also present in the anhydrous form of this compound. Short distances between semi‐oxalate anions in neighbouring chains in the hydrate alternate with longer ones, whereas in the anhydrous structure they are equidistant. Despite the similarity of these compounds, dehydration of the hydrate on storage is not of a single‐crystal to single‐crystal type, but gives a polycrystalline pseudomorph, preserving the crystal habit. This transformation proceeds through the formation of an intermediate compound, presumably a hemihydrate.     

Insights into the Crystallisation Process from Anhydrous,Hydrated and Solvated Crystal Forms of Diatrizoic Acid

Diatrizoic acid (DTA), a clinically used X‐ray contrast agent, crystallises in two hydrated, three anhydrous and nine solvated solid forms, all of which have been characterised by X‐ray crystallography. Single‐crystal neutron structures of DTA dihydrate and monosodium DTA tetrahydrate have been determined. All of the solid‐state structures have been analysed using partial atomic charges and hardness algorithm (PACHA) calculations. Even though in general all DTA crystal forms reveal similar intermolecular interactions, the overall crystal packing differs considerably from form to form. The water of the dihydrate is encapsulated between a pair of host molecules, which calculations reveal to be an extraordinarily stable motif. DTA presents functionalities that enable hydrogen and halogen bonding, and whilst an extended hydrogen‐bonding network is realised in all crystal forms, halogen bonding is not present in the hydrated crystal forms. This is due to the formation of a hydrogen‐bonding network based on individual enclosed water squares, which is not amenable to the concomitant formation of halogen bonds. The main interaction in the solvates involves the carboxylic acid, which corroborates the hypothesis that this strong interaction is the last one to be broken during the crystal desolvation and nucleation process.     

Ranking of polymorph stability for a pharmaceutical drug using the Noyes-Whitney titration template method

A further refinement to the screening process of candidate selection in early drug development is the selection of a polymorphic form on the bases of solid state stability. The Noyes-Whitney titration template method has been used routinely by others to determine the intrinsic solubility of sparingly soluble materials. This method uses potentiometric measurements whilst titrating over a pH range to determine the pH-solubility profile of a drug substance. Using a novel modification to the conventional Noyes-Whitney titration template method, this paper describes an application for the determination of the relative stability between polymorphic forms of materials. Such an assessment can be deduced from the change in Gibbs energy that accompanies the physical changes in materials when going from a solid to a solution phase and will be shown to be derived from the intrinsic solubility measurements. In addition, it will be shown that solution calorimetry was used to good effect to help in the interpretation of the solubility results.Three crystalline polymorphic modifications, a hydrate and two anhydrate forms, and an amorphous form of a pure drug substance currently in development in GSK were ranked in terms of physical stability. Stability measurements were made as a function of temperature and a phase diagram over a narrow temperature range was constructed.     

A new conformer of 1,4,7‐tris(p‐tolylsulfonyl)‐1,4,7‐triazacyclononane

A second polymorphic form (form II) of the previously reported 1,4,7‐tris(p‐tolylsulfonyl)‐1,4,7‐triazacyclononane (form I), C₂₇H₃₃N₃O₆S₃, is presented. The molecular structures of the two forms display very different conformations, thus prompting the two forms to crystallize in two different space groups and exhibit quite diverse crystal structure assemblies. Form I crystallizes in the triclinic space group P, while form II crystallizes in the monoclinic space group P2₁/n. The main differences between the two molecular structures are the conformations of the p‐tosyl groups relative to each other and to the macrocyclic ring. The resulting crystal packing displays no classical hydrogen bonds, but different supramolecular synthons give rise to different packing motifs.