Dielectric behaviour of montmorillonite/cyanoethylated cellulose nanocomposites.

A dielectric nanocomposite based oncyanoethylatedcellulose (CRS) and MMT nanoclay was successfully prepared with different weight percentages (5%, 10% and 15%) of MMT. MMT nanoplatets obtained via sonication of MMT nanoclay in acetone for a prolonged period was used in the preparation of CRS-MMT nanocomposites. CRS-MMT thin films on SiO2/Si wafers are used to form metal-insulator-metal (MIM) type capacitors. At 1kHz CRS-MMT nanocomposites exhibited high dielectric constants (εr) of 71, 55 and 42 with low leakage current densities (10-6-10-7A/cm2) for nanocomposites with 5%, 10% and 15% weight of MMT respectively, higher than values of pure CRS (21), Na-MMT(10). Reduction of εr with higher MMT loading can be attributed to a network formation as evidenced via strong bonding interactions between CRS and MMT leading to a lower molecular mobility. The leakage is studied using conductive atomic force microscopy (C-AFM) indicates that leakage pathways are associated with MMT nanoplatelets embedded in the CRS polymer matrix.

Rationalization of the Color Properties of Fluorescein in the Solid State: A Combined Computational and Experimental Study.

Fluorescein is known to exist in three tautomeric forms defined as quinoid, zwitterionic, and lactoid. In the solid state, the quinoid and zwitterionic forms give rise to red and yellow materials, respectively. The lactoid form has not been crystallized pure, although its cocrystal and solvate forms exhibit colors ranging from yellow to green. An explanation for the observed colors of the crystals is found using a combination of UV/Vis spectroscopy and plane-wave DFT calculations. The role of cocrystal coformers in modifying crystal color is also established. Several new crystal structures are determined using a combination of X-ray and electron diffraction, solid-state NMR spectroscopy, and crystal structure prediction (CSP). The protocol presented herein may be used to predict color properties of materials prior to their synthesis.

Nanocomposites of TiO2/cyanoethylated cellulose with ultra high dielectric constants.

A novel dielectric nanocomposite containing a high permittivity polymer, cyanoethylated cellulose (CRS) and TiO2 nanoparticles was successfully prepared with different weight percentages (10%, 20% and 30%) of TiO2. The intermolecular interactions and morphology within the polymer nanocomposites were analysed. TiO2/CRS nanofilms on SiO2/Si wafers were used to form metal-insulator-metal type capacitors. Capacitances and loss factors in the frequency range of 1 kHz-1 MHz were measured. At 1 kHz CRS-TiO2 nanocomposites exhibited ultra high dielectric constants of 118, 176 and 207 for nanocomposites with 10%, 20% and 30% weight of TiO2 respectively, significantly higher than reported values of pure CRS (21), TiO2 (41) and other dielectric polymer-TiO2 nanocomposite films. Furthermore, all three CRS-TiO2 nanocomposites show a loss factor <0.3 at 1 kHz and low leakage current densities (10(-6)-10(-7) A cm(-2)). Leakage was studied using conductive atomic force microscopy and it was observed that the leakage is associated with TiO2 nanoparticles embedded in the CRS polymer matrix. A new class of ultra high dielectric constant hybrids using nanoscale inorganic dielectrics dispersed in a high permittivity polymer suitable for energy management applications is reported.

Sonocrystallization yields monoclinic paracetamol with significantly improved compaction behavior.

Ultrasound-assisted crystallization (sonocrystallization) was used to prepare a mixture of nano- and micrometer-sized crystals of the monoclinic form of paracetamol-a widely used analgesic known for its particularly problematic mechanical behavior under compression (i.e. poor tabletability). The nano- and micrometer-sized crystals yielded a powder which exhibits elastic moduli and bulk cohesions that are significantly higher than those observed in samples consisting of macrometer-sized crystals, thus leading to enhanced tabletability without the use of excipients, particle coating, salt, or cocrystal formation. Experimental compaction and finite element analysis were utilized to rationalize the significantly improved compaction behavior of the monoclinic form of paracetamol.

Introductory lecture: Mechanochemistry, a versatile synthesis strategy for new materials.

Mechanochemistry deals with reactions induced by the input of mechanical energy - for example by impacts within a vibratory ball mill. The technique has a long history with significant contributions from Ostwald, Carey Lea and, notably, Faraday. Mechanochemistry has subsequently seen application in a variety of areas of materials science including mechanical alloying in metallurgy, the synthesis of complex organic molecules and, more recently, the discovery and development of new solid forms of active pharmaceutical ingredients. This paper overviews the broad areas of application of mechanochemistry, some key features which make it a particularly attractive approach to materials synthesis and some mechanistic aspects highlighted within the literature. A significant part, however, will focus on recent applications in the area of pharmaceuticals and its important role in exploring the rich variety of solid forms available for small, drug-like, molecules.

Cocrystal dissociation in the presence of water: a general approach for identifying stable cocrystal forms.

In previous studies, cocrystals have been shown to be susceptible to dissociation at high humidity because of differences in the solubilities of the two coformer molecules, especially when these molecules can form hydrates. Contrastingly, however, the propensity of the pharmaceutically active compound caffeine to hydrate formation is reduced by cocrystallization with oxalic acid. Here, the stability of the oxalic acid cocrystal of caffeine is investigated from a thermodynamic perspective through the use of aqueous slurries of caffeine hydrate and oxalic acid dihydrate. Conversion to the anhydrous caffeine-oxalic acid cocrystal occurred under these conditions confirming that this form is thermodynamically stable in an aqueous environment. The slurry methodology was further developed as a general approach to screening for cocrystals that are not susceptible to dissociation at high humidity. In this manner, cocrystals of the hydrate-forming molecules theophylline, carbamazepine, and piroxicam that are stable at high humidity, indefinitely avoiding hydrate formation, were identified.

An investigation of the causes of cocrystal dissociation at high humidity.

The dissociation at high humidity of cocrystals formed between caffeine and theophylline with a series of dicarboxylic acids is investigated and found to be driven by the partial dissolution of the acid, rather than by the formation of caffeine/theophylline hydrate. It is shown that partial dissociation occurs under all humidity conditions, and that cocrystals of compounds which do not form hydrates also dissociate by this mechanism. The observations made in this study indicate that cocrystal instability at high humidity will be a widespread issue, especially for cocrystals where the two coformers have widely differing aqueous solubilities, as is likely for systems where cocrystallisation is being used as means of improving the aqueous solubility, or dissolution rate, of a compound.

Polymorphs, hydrates and solvates of a co-crystal of caffeine with anthranilic acid.

A polymorph screen on a new 1:1 co-crystal of caffeine, C8H10N4O2, with anthranilic acid, C7H7NO2, has revealed a rich diversity of crystal forms (two polymorphs, two hydrates and seven solvates, including two sets of isostructural solvates). These forms were prepared by liquid-assisted grinding and solution crystallization, and the crystal structures of nine of these forms have been solved using either single-crystal or powder X-ray data. The structures contain O-H...N and N-H...O hydrogen bonds through which caffeine and anthranilic acid molecules assemble to form zigzag-type chains. These chains can interact in an anti-parallel and offset manner to form cage- or channel-type skeletons within which solvent molecules can be located, giving rise to the diversity of forms observed for this co-crystal. In contrast, an equivalent series of liquid-assisted grinding and solution crystallization experiments with the closely related system of theobromine, C7H8N4O2, and anthranilic acid resulted in the formation of only one 1:1 co-crystal form.

Methanesulfonic acid salt forms of carbamazepine and 10,11-dihydrocarbamazepine.

New methanesulfonic acid salt forms of the anticonvulsant and analgesic active pharmaceutical ingredient carbamazepine and its closely related structural analogue 10,11-dihydrocarbamazepine have been prepared and characterized by single-crystal X-ray diffraction at 120 and 100 K, respectively {namely [(5H-dibenzo[b,f]azepin-5-yl)(hydroxy)methylidene]azanium methanesulfonate, C15H13N2O(+)·CH3SO3(-), and [(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)(hydroxy)methylidene]azanium methanesulfonate, C15H15N2O(+)·CH3SO3(-)}. In light of the structural information obtained, the crystal structure of the carbamazepine trifluoroacetic acid monosolvate [dibenzo[b,f]azepine-5-carboxamide-trifluoroacetic acid (1/1), C15H12N2O·CF3COOH] was redetermined at 100 and 270 K, and from this data it was concluded that the protonation state for this solvate species is best described as in an `intermediate state' with the acidic proton located almost at the mid-point between the acid and base.

Use of in situ atomic force microscopy to follow phase changes at crystal surfaces in real time.

AFM of cocrystals: Atomic force microscopy can be used to observe phase changes at crystal surfaces where the transformation is accompanied by a change in the spacing between layers of molecules. The conversion of a metastable polymorph of the caffeine-glutaric acid cocrystal into the thermodynamically stable form was analyzed continuously in situ using intermittent-contact-mode atomic force microscopy.

Polymorph identification and crystal structure determination by a combined crystal structure prediction and transmission electron microscopy approach.

Electron diffraction offers advantages over X-ray based methods for crystal structure determination because it can be applied to sub-micron sized crystallites, and picogram quantities of material. For molecular organic species, however, crystal structure determination with electron diffraction is hindered by rapid crystal deterioration in the electron beam, limiting the amount of diffraction data that can be collected, and by the effect of dynamical scattering on reflection intensities. Automated electron diffraction tomography provides one possible solution. We demonstrate here, however, an alternative approach in which a set of putative crystal structures of the compound of interest is generated by crystal structure prediction methods and electron diffraction is used to determine which of these putative structures is experimentally observed. This approach enables the advantages of electron diffraction to be exploited, while avoiding the need to obtain large amounts of diffraction data or accurate reflection intensities. We demonstrate the application of the methodology to the pharmaceutical compounds paracetamol, scyllo-inositol and theophylline.

Determination of the crystal structure of a new polymorph of theophylline.

A new approach to crystal structure determination, combining crystal structure prediction and transmission electron microscopy, was used to identify a potential new crystal phase of the pharmaceutical compound theophylline. The crystal structure was determined despite the new polymorph occurring as a minor component in a mixture with Form II of theophylline, at a concentration below the limits of detection of analytical methods routinely used for pharmaceutical characterisation. Detection and characterisation of crystallites of this new form were achieved with transmission electron microscopy, exploiting the combination of high magnification imaging and electron diffraction measurements. A plausible crystal structure was identified by indexing experimental electron-diffraction patterns from a single crystallite of the new polymorph against a reference set of putative crystal structures of theophylline generated by global lattice energy minimisation calculations.

Analysis of single particle photodegradation using photothermal infrared microspectroscopy.

The increasing use of high throughput methods, coupled with the need to develop approaches to anticipate long term stability issues, has necessitated the introduction of testing approaches whereby extremely small samples may be rapidly analysed. A novel method is described whereby the UV light-induced degradation of single particles of a model drug, nifedipine, may be rapidly and simply monitored using photothermal infrared microspectroscopy (PTMS). The technique involves the contact attachment of individual particles to a heated probe tip composed of a modified Wollaston wire which enables temperature fluctuations to be measured. Application of a focused IR beam to excite the sample allows measurement and subsequent Fourier transformation of the resultant interferogram to produce an IR spectrum which is in good agreement with that obtained from conventional IR methods. By application of a UV source to the assembly for specified time periods, we demonstrate that it is possible to monitor the appearance of peaks associated with degradation products as a function of time. The technique is critically evaluated in terms of practical issues associated with volatilization, particle size effects and orientation to the light source as well as more general issues associated with the sensitivity, resolution and quantitative interpretation of data from the PTMS technique. Overall the method has been shown to be capable of rapid measurement of photo-instability on individual particles, with important implications for development of the approach as a rapid screening or high throughput technique, although there are practical and theoretical limitations to reliable quantitative analysis at the present time.

On the polymorphism of griseofulvin: identification of two additional polymorphs.

In this paper, we present an investigation of the polymorphism of griseofulvin. In addition to the only reported crystalline form (form I), two new polymorphic forms (II and III) have been identified and characterized by differential scanning calorimetry and powder X-ray diffraction. Reasons why these two polymorphs were isolated during the present study, but not detected during the numerous previous studies on this drug, are also discussed.

A family of simple benzene 1,3,5-tricarboxamide (BTA) aromatic carboxylic acid hydrogels.

We present the characterisation of a hydrogel forming family of benzene 1,3,5-tricarboxamide (BTA) aromatic carboxylic acid derivatives. The simple, easy to synthesise compounds presented here exhibit consistent gel formation at low concentrations through the use of a pH trigger.

Solid state grinding as a tool to aid enantiomeric resolution by cocrystallisation.

The formation of diastereomeric cocrystals of malic acid and tartaric acid was investigated by liquid-assisted grinding in the solid state. We demonstrate that racemic malic acid can be converted into two distinct diastereomeric cocrystal phases by grinding with a single enantiomer of tartaric acid.

Cocrystal dissociation and molecular demixing in the solid state.

A new cocrystal containing caffeine and theophylline was found to dissociate on heating, with caffeine and theophylline molecules spontaneously demixing and recrystallizing as separate phases, in a solid-solid transition likely driven by an increase in entropy. The morphology and composition of the resulting crystals was determined by transmission electron microscopy.

Transmission electron microscopy of pharmaceutical materials.

Transmission electron microscopy (TEM) and its facility for electron diffraction has long been a key technique in materials science. Its use for characterization of pharmaceutical samples has, however, been very limited, largely due to the difficulties associated with the preparation of appropriately thin samples, as well as issues with sample damage caused by the electron beam. In this overview, we describe straightforward approaches for overcoming these issues which have enabled us to characterize a variety of pharmaceutical compounds, including theophylline, paracetamol and aspirin, and also pharmaceutical salts and cocrystals. A range of relevant information about these compounds is derived including morphology, polymorph identification, mapping of crystal habit to crystal structure and crystal defect characterization. With theophylline, we identify crystals of "impurity" polymorphic phases in samples that appear from powder X-ray diffraction to be monophasic, and observe that crystal growth behavior of samples prepared from nitromethane is significantly different to that of samples prepared from methanol. The existence of imperfections, such as dislocations, is also established and these are shown to be likely sites at which fracturing occurs when the crystals are stressed. The results demonstrate that various issues associated with pharmaceutical form development might usefully be addressed using TEM.