A novel perovskite based catalyst with high selectivity and activity for partial oxidation of methane for fuel cell applications.

Solid oxide fuel cells (SOFCs) have the potential to revolutionise the present fuel economy due to their higher fuel conversion efficiency compared with standard heat engines and the possibility of utilizing the heat produced in a combined heat and power system. One of the reasons they have yet to fulfil this potential is that the conventional anode material of choice, a nickel/yttria-stabilised zirconia cermet, requires a high temperature production process and under operating conditions is susceptible to carbon and sulphur poisoning. Perovskite-based materials have been proposed as potential anode materials for SOFCs due to their potentially high electronic conductivity and catalytic properties. One of the problems in realizing this potential has been their low catalytic activity towards methane reforming compared to conventional nickel based cermet materials. A nickel doped strontium zirconate material produced by low temperature hydrothermal synthesis is described which has high activity for methane reforming and high selectivity towards partial oxidation of methane as opposed to total oxidation products. Initial studies show a very low level of carbon formation which does not increase over time.

Inhaled synthetic surfactant abolishes the early allergen-induced response in asthma.

Allergen-induced inhibition of pulmonary surfactant in asthma may promote airway oedema and consequently potentiate the severity of the asthmatic response. A randomised, single-blind, cross-over study of an inhaled synthetic phospholipid dry-powder surfactant (Pumactant) was conducted in atopic, asthmatic subjects with previously documented early and late asthmatic responses (EAR and LAR) to an inhaled allergen. This was conducted to evaluate the role of exogenous surfactant administration on EAR and LAR. A total of seven subjects had complete evaluable data and received the full dose of Pumactant. Asthmatic subjects inhaled two separate doses of 400 mg Pumactant prior to an allergen exposure. The first dose was administered 8 h in advance and the second dose 30 min in advance. The dosage occurred through a purpose-built administration device. This was followed by a standard bronchial-provocation test, and forced expiratory volume in one second (FEV1) was measured at regular intervals over a 10-h period. Pumactant was well tolerated and, surprisingly, abolished the EAR but not the LAR in all seven subjects. The mean area under the curve between 0-2 h (EAR) following bronchial provocation test was 0.08 for the Pumactant treatment group (PT) and 13.29 for the no treatment (NT) group. The maximum drop in FEV1 for EAR was 4.19% and 23.98% in the PT and the NT group, respectively. The demonstration of inhibition of the early asthmatic response by exogenous surfactant, provides the first evidence that pulmonary surfactant dysfunction may also contribute to the very early asthmatic response to allergen. Exogenous surfactant administration could serve as a useful adjunct in controlling the early allergen-induced symptoms in patients with allergic asthma.

Powder compaction properties of sodium starch glycolate disintegrants.

The compaction behavior of three "as supplied" commercially available grades of sodium starch glycolate (SSG), Explotab, Primojel, and Vivastar P, was investigated at compression speeds of 0.17 and 30 mm/sec. The results suggested that the three "as supplied" materials exhibit different compression and compaction behavior. Primojel and Explotab exhibited similar compactibility, whereas Vivastar P produced compacts of poor integrity. This behavior was not mirrored in the compressibility of the powders, where Vivastar P and Explotab exhibited similar performance. The materials were studied using x-ray diffraction, scanning electron microscopy, Carr's compressibility index, and swelling volume. In terms of material characteristics, all the products exhibited similar swelling in water. Primojel and Explotab retained most of the crystallographic order from the parent potato starch and exhibited comparable particle surface topographies. Vivastar P contained the lowest moisture level. However, it is not clear if the poor compactibility of Vivastar P is due to differences in moisture content, the reduced surface topography, or subtle differences in the SSG polymer structures (substitution, cross-linking, and crystallinity). Overall, even though the three commercial grades of sodium starch glycolate are successfully used as disintegrants, they do exhibit differences in their "as supplied" powder mechanical properties: Primojel and Explotab exhibit similar compactibility, whereas Vivastar P is poorly compactable but exhibits similar compressibility to Explotab. These observations may have implications when formulating poorly compactable or moisture-sensitive drugs.

The influence of relative humidity on particulate interactions in carrier-based dry powder inhaler formulations.

An atomic force microscope (AFM) colloid probe technique has been used to investigate the effect of relative humidity (RH) on the adhesion properties of pharmaceutical powder surfaces. The adhesion between a model substrate, alpha-lactose monohydrate, and model particulate drugs, salbutamol sulphate and budesonide, was investigated between RHs of 15 and 75%. The surface topography of the model alpha-lactose monohydrate was produced by controlling the supersaturation conditions during crystal growth to produce sub-nanometre scale roughness. The adhesion interactions between lactose and drug probes of salbutamol sulphate and budesonide were shown to be significantly increased with each incremental rise in humidity. Capillary forces were significantly more dominant for the adhesion in the budesonide-lactose system up to 60% RH but were more dominant for salbutamol sulphate-lactose above 60% RH. These studies suggested that non-surface-specific capillary forces play a dominant role in the adhesion between drug and carrier, which may significantly reduce the deaggregation and dispersion properties of a dry powder formulation.

Chemical characterisation of sodium starch glycolate particles.

The internal and surface chemical compositions of three sodium starch glycolate (SSG) products, Explotab, Primojel and Vivastar P were studied using scanning electron microscopy (SEM), energy dispersive X-ray analysis (EDX), time of flight secondary ion mass spectrometry (TOF-SIMS) and 23Na nuclear magnetic resonance spectroscopy (NMR). The surfaces of Explotab and Primojel contained very distinct features containing Na and Cl, however, Primojel also contained features which contained Na which may reflect the presence of Na glycolate and/or Na citrates. Vivastar P contained relatively few surface Cl containing features. Analysis of cross-sections of the particles showed that Na appeared to be uniformly distributed throughout the particles of all the products. Additionally, there was a significant concentration of Cl in the periphery of Explotab and Primojel. In the case of Vivastar P, significant levels of Na and Cl were detected in the internal regions of the particles which, together with 23Na NMR, suggests that NaCl is uniformly distributed within Vivastar P. 23Na NMR also suggested that the ratio of organic Na to NaCl was considerably lower in Vivastar P than Primojel and Explotab. Overall, even though all these three products satisfy the pharmacopeial descriptions of SSG, these studies suggest that Primojel and Explotab exhibit different chemical compositions to Vivastar P. Since the three products studied are reported to be prepared from potato starch, the apparent differences in chemical composition probably reflect the different manufacturing processes used, however, batch to batch variations may account for some of the subtle differences.

Directional bonding in compacted microcrystalline cellulose.

The mechanical properties of compacts of microcrystalline cellulose (MCC) and silicified microcrystalline cellulose (SMCC) were evaluated by tensile testing, diametric compression testing, and compression testing. For tensile and compression testing, cubic specimens were carefully machined from MCC and SMCC compacts, and the tensile and compression strengths were evaluated both normal and parallel to the compaction direction. The cubic tensile strengths were compared to values obtained from the diametric compression test. The results obtained using the diametric compression test suggested compacts of SMCC exhibit greater strength than those of MCC. In addition, the cubes machined from compacts of MCC and SMCC exhibited directional strength; the direction normal to the compaction direction display ed the greater tensile strength, and the parallel direction had greater compression strength. The diametric compression test afforded strength values with reduced spread compared to the values collected from the cubic tensile test, suggesting that the errors involved in collecting diametric compression test data of compacts are less than those for the cubic tensile test. Analysis of the cubes using X-ray diffraction (XRD) suggested that they display directional structural anisotropy, with the direction normal to the compaction direction being more crystalline than the parallel direction. However, it is not clear whether the difference in the directional strength is solely a consequence of the increased crystallinity or a culmination of crystallographic and mechanical keying effects.

Spray-dried insulin particles retain biological activity in rapid in-vitro assay.

The purpose of this study was to rapidly determine, without the use of extensive animal studies, whether biological activity is retained after spray drying insulin with two excipients, lactose and xanthan gum. This was achieved by the detection of protein kinase B (PKB), which is activated by phosphorylation in response to insulin binding to cellular receptors. A myeloid cell line was cultured and stimulated with the reconstituted insulin powders. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) was then utilised to allow in-vitro detection of phosphorylated PKB using an anti-phospho-PKB antibody. A single band specific to phosphorylated PKB was found on the Western blots, indicating that the active conformation of insulin was retained when spray dried in combination with lactose and with xanthan gum over the spray-drying inlet temperature range of 110-170 degrees C. Evidence of inactivation/denaturation was observed when insulin was spray dried at an inlet temperature of 200 degrees C. The assay may be of use as a more rapid and economic means to screen insulin formulations for inhalation and other purposes as opposed to conventional monitoring of blood glucose levels in animals.

The formulation of powder inhalation systems containing a high mass of nedocromil sodium trihydrate.

Nedocromil sodium trihydrate is not amenable to conventional methods of dry powder inhaler formulation, including the preparation of coarse carrier systems and aggregation of the pure drug powder. It is considered that the in vitro aerosol performance of such systems is governed by the cohesive drug-drug interactions. Therefore, alternative powder formulation strategies (novel to nedocromil sodium) were developed. By decreasing the particle size of the lactose carrier, the deaggregation and subsequent fine particle drug deposition were significantly improved. Further improvements were made by selecting and then optimizing high-shear mixing procedures. It was concluded, based on these findings and supportive microscopic studies (low-temperature and environmental scanning electron microscopy together with energy-dispersive X-ray analysis), that the FPL are producing their functional effects by intercalating within the drug self-agglomerates and physically disrupting the cohesive drug-drug interactions. The use of a smaller-sized lactose fraction in conjunction with a blending procedure capable of optimally disrupting the drug self-agglomerates allowed maximal intercalation of the excipient material within the drug self-agglomerates. The adhesive drug-FPL interactions are considered to be weak compared with the cohesive drug-drug particle interactions, cohesive interactions that would normally govern the aerosol performance of powder systems containing a high mass of nedocromil sodium trihydrate.

Use of a novel modified TSI for the evaluation of controlled-release aerosol formulations. I.

When considering the development of potential controlled-release pulmonary drug delivery systems, there is at present no standard method available for the assessment of in vitro drug release profiles necessary to understand how the drug might release following deposition in the lungs. For this purpose, the twin-stage impinger (TSI), apparatus A of the BP, has been redesigned and tested. This modified TSI was found capable of discriminating between drug release rates from conventional and different dry powder formulations consisting of model controlled-release excipients, providing information related to (a) drug diffusion properties of controlled-release dry powder blends with different excipient components and (b) the effect of varying drug concentration within a given formulation.

Pulmonary availability of isotretinoin in rats after inhalation of a powder aerosol.

Repeated oral administration of chemopreventive retinoids such as isotretinoin over extended periods of time is associated with intolerable systemic toxicity. Here isotretinoin was formulated as a powder aerosol, and its delivery to the lungs of rats was studied with the aim to explore the possibility of minimizing adverse effects associated with its oral administration. Rats received isotretinoin orally (0.5, 1 or 10 mg kg(-1)) or by inhalation (theoretical dose approximately 1 or approximately 10 mg kg(-1)) in a nose-only inhalation chamber. Isotretinoin was quantitated by high-pressure liquid chromatography in plasma and lung tissue. The ratios of mean area of concentration-vs-time curve (AUC) values in the lungs over mean AUCs in the plasma for isotretinoin following single or repeated aerosol exposure surpassed those determined for the oral route by factors of between two (single low-dose) and five (single high-dose). Similarly, the equivalent ratios for the maximal peak concentrations in lungs and plasma obtained after aerosol exposure consistently exceeded those seen after oral administration, suggesting that lungs were exposed to higher isotretinoin concentrations after aerosol inhalation than after oral administration of similar doses. Repeated high doses of isotretinoin by inhalation resulted in moderate loss of body weight, but microscopic investigation of ten tissues including lung and oesophagus did not detect any significant aerosol-induced damage. The results suggest that administration of isotretinoin via powder aerosol inhalation is probably superior to its application via the oral route in terms of achieving efficacious drug concentrations in the lungs.

Physicochemical factors governing the performance of nedocromil sodium as a dry powder aerosol.

Previous investigations have found that the in vitro aerosol performance of nedocromil sodium is poor. A study has been undertaken to gain a better understanding of the physicochemical properties of the drug particles together with the factors governing the aerosol performance of inhalation systems containing this drug. Material previously passed through a hammer mill only and particles subsequently passed through a micronizer were characterized, and the information gathered was correlated with the in vitro aerosol performance of the pure drug systems. Optimization of particle sizing procedures revealed that both sets of materials were ultrafine powders with a volume median diameter of approximately 1 microm. It is concluded that the processing stages, employed in the manufacture of these batches of fine particle nedocromil sodium trihydrate, may not in fact be primary particle size reduction stages but instead deaggregation stages and that these govern the aerosol performance. The in vitro aerosol performance of samples of the "micronized" nedocromil sodium stored over a range of relative humidities (RHs) was characterized. Storage RHs in the range 12-76% (where nedocromil sodium is stable as the trihydrate) did not have a dramatic effect on the in vitro aerosol performance of the drug. However, conversion to the heptahemihydrate (following storage of the drug at 86% RH) significantly decreased the deaggregation performance in an in vitro model.

The mechanical properties of compacts of microcrystalline cellulose and silicified microcrystalline cellulose.

The mechanical properties of compacts of unlubricated microcrystalline cellulose and silicified microcrystalline cellulose were evaluated using the diametric tensile test. The results suggested that, under comparable testing conditions, compacts of silicified microcrystalline cellulose exhibited greater strength than those of microcrystalline cellulose. In addition to enhanced strength, silicified microcrystalline cellulose compacts exhibited greater stiffness and required considerably more energy for tensile failure to occur. Comparison of the data with that obtained for a dry blend of silicon dioxide/microcrystalline cellulose suggested that the functionality benefits of silicification were not due to a simple composite material model.

Tablet and capsule hydrophilic matrices based on heterodisperse polysaccharides having porosity-independent in vitro release profiles.

The purpose of the study was to investigate the release-controlling action of a swellable hydrophilic material based on heterodisperse polysaccharides (HP) in relation to the initial pore structure of the formulations. HP-based granules were produced under carefully controlled conditions and compacted into matrix tablets having equivalent tablet thickness. Quantification of pore structure using mercury porosimetry showed that the tablets had substantially different pore volumes and pore size distributions. Dissolution studies demonstrated that release of a water-soluble model compound, benzamide, from swollen matrices was affected neither by total porosity nor median pore diameter of the initial dry matrix. To extend the concept of porosity-independent release further, HP-based formulations containing either diclofenac sodium or propranolol HCl were contained within hard gelatin capsules in the form of uncompacted granules. This produced a dosage form with a high intraparticulate porosity in the dry state. Equivalent weights of the same formulations were also compacted into tablets. The in vitro release profiles from matrix tablets compacted from any of the formulations did not differ significantly from release profiles obtained when the same materials were contained uncompacted in hard gelatin capsules.

Design of a fluid energy single vessel powder processor for pharmaceutical use.

This study introduces a motionless novel single vessel powder processor designed to carry out all of the unit operations in the preparation of powders for tableting. The processor used controllable fluid dynamics to provide the energy for each unit operation. The vessel design was evaluated using a computational fluid dynamics model which indicated the flow necessary for the intended processing operations to take place. The processor performance was evaluated experimentally for two unit processes: particle size reduction and dry powder mixing. The processor was found capable of reducing the size of lactose granules from a median particle diameter of 459 microm to a median particle diameter of 182 microm within 5 min under optimal process conditions. It was found that a formulation containing lactose granules (373 microm median particle diameter) and a model drug, sodium chloride (30 microm), could be mixed to an improved degree of homogeneity in comparison with equivalent powders blended using a conventional turbulent tumbling technique. It was concluded that a processor having controllable fluid dynamics offered the potential to perform multi-task processing of powders.

Protein deposition from dry powder inhalers: fine particle multiplets as performance modifiers.

PURPOSE: To evaluate the use of carrier-based dry powder aerosols for inhalation delivery of proteins and examine the effect of fine particle excipients as potential formulation performance modifiers. METHODS: Bovine serum albumin (BSA) was co-processed with maltodextrin by spray-drying to produce model protein particles. Aerosol formulations were prepared by tumble mixing protein powders with alpha-lactose monohydrate (63-90 microns) or modified lactoses containing between 2.5 and 10% w/w fine particle lactose (FPL) or micronised polyethylene glycol 6000. Powder blends were characterised in terms of particle size distribution, morphology and powder flow. Formulation performance in Diskhaler and Rotahaler devices was investigated using a twin stage impinger operating at 60.s51 min-1. RESULTS: Inhalation performance of binary ordered mixes prepared using BSA-maltodextrin and lactose (63-90 microns) was improved by addition of FPL and micronised PEG 6000. For the addition of 5% w/w FPL the protein fine particle fraction (0.5-6.4 microns) using the Diskhaler was increased from 31.7 +/- 2.4% to 47.4 +/- 2.2%. Inclusion of FPL and micronised PEG 6000 changed the bulk properties of inhalation powders and reduced powder flow but did not affect device emptying. Unexpectedly, improvements in performance were found to be independent of the order of addition of FPL to the ternary powder formulations. SEM studies revealed that this was probably the result of a redistribution of protein particles between the coarse carrier lactose component and added FPL during mixing. CONCLUSIONS: Fine particle excipients can be used to improve the performance of carrier-based protein dry powder aerosols. Mechanistically, enhancement of performance is proposed to result from a redistribution of protein particles from coarse carrier particles to the fine particle component in the ternary mix.

Aerosol electrostatics. I: Properties of fine powders before and after aerosolization by dry powder inhalers.

PURPOSE: To evaluate the dependence of fine particle dose charge (FPD charge) generated from powder inhalers on physico-chemical properties of the inhalation powder, inhaler type, deaggregation mechanism, dose number and/or retained powder. METHODS: Electrostatic charges were determined on micronized powders and aerosolized fine particle doses withdrawn from two, high efficiency, multidose powder inhalers, Turbohaler and prototype Dryhaler. The behavior of terbutaline sulfate, budesonide, albuterol (sulfate and base), beclomethasone dipropionate and lactose was assessed before and after aerosolization. RESULTS: Both inhalers conferred triboelectric FPD charges during aerosolization in the range -400 pC through +200 pC. Specific charges (charge/unit mass) on the fine particle doses of budesonide from Dryhaler were significantly less than those from Turbohaler (p < 0.01). Electrostatic charges on the potentially respirable cloud of terbutaline sulfate generated by Bricanyl Turbohaler were positive and/or negative and unpredictable. With Pulmicort Turbohaler, FPD charges on budesonide were always positive. Dryhaler was used to determine the chemical dependence of fine particle triboelectrification during the aerosolization of pure materials. A triboelectric series was constructed from the Dryhaler results ranking the powders from positive to negative as budesonide > lactose > albuterol sulfate > terbutaline sulfate > or = albuterol > or = beclomethasone dipropionate. CONCLUSIONS: While there was no evidence of FPD charge dependence upon dose number with either inhaler, FPD charges were dependent upon the powder under investigation, as well as the construction and deaggregation mechanism of the inhaler. The specific charge on the fine particle dose of budesonide from Turbohaler corresponded to approximately 200 electronic charges per particle, a value which is known to affect both total and regional aerosol deposition in the human lung. Electrostatic charge effects may be important determinants of aerosol behavior and should not be neglected.

The influence of water on electrostatic charge retention and dissipation in pharmaceutical compacts for powder coating.

PURPOSE: The electrostatic properties of five materials commonly used in tabletting were investigated to assess their suitability for the novel technique of powder coating of pharmaceutical compacts. METHODS: Powder resistivity and compact voltage decay properties were determined under dry and wet conditions using purpose built equipment. RESULTS: The organic materials acted as insulators having resistivities > 10(13) omega m whilst dibasic calcium phosphate showed dielectric behaviour. A clear relationship between water content and resistivity was established for all materials. Electrical conduction across powder surfaces was demonstrated as the predominant mechanism by using low concentrations of magnesium stearate. In materials absorbing significant water a bulk mechanism was also present. After charge injection, decay rates were dependent on resistivity with those having the highest values exhibiting the slowest decay. The chemical nature of the materials was unimportant except at extremely high resistivities. Conditioning of the compacts with water reduced resistivities so that decay half-lives < 1 s were achieved. CONCLUSIONS: The electrical properties of the compact materials have been modified sufficiently to enable them to be considered suitable for powder coating.

An electrically modulated drug delivery device. III. Factors affecting drug stability during electrophoresis.

A number of factors affecting the stability of propranolol HCl during electrophoretic control were investigated. It was found that significant degradation of propranolol HCl and hydrolysis of water occurred when a current of 15 mA was used with platinized electrodes. This degradation was thought to be due to decomposition of propranolol HCl at the electrodes. Degradation could be significantly reduced by using uncoated platinum electrodes and currents in the range of 0 to 2.5 mA, while still allowing control of drug delivery rates. Electrode reaction processes were found at high ionic strengths and high drug concentrations but were not thought to be associated with drug decomposition.

An electrically modulated drug delivery device. II. Effect of ionic strength, drug concentration, and temperature.

The effects of various physicochemical parameters on the changes in drug delivery rate produced by an electrophoretic current are examined using a model system. It was shown that ionic strength has an inverse relationship with the change in delivery rate produced by a given current. Small changes in pH were measured during electrophoresis experiments which were considered to be insignificant. Drug reservoir concentration selection is critical in the design of an electrophoretic device and is based on achieving a balance between providing a suitable reservoir and allowing adequate electrophoretic control. Electrophoretic control is affected by temperature in a manner which can be predicted using the Arrhenius relationship. The low power requirements of the model system demonstrate the feasibility of using the principle of electrophoresis to control drug delivery rates in a therapeutic system.