Understanding solid-state transformations during dehydration: new insights using vibrational spectroscopy and multivariate modelling

Many active pharmaceutical ingredients (APIs) have both anhydrate and hydrate forms. Due to the different physicochemical properties of solid forms, the changes in solid-state may result in therapeutic, pharmaceutical, legal and commercial problems. In order to obtain good solid dosage form quality and performance, there is a constant need to understand and control these phase transitions during manufacturing and storage. Thus it is important to detect and also quantify the possible transitions between the different forms. In recent years, vibrational spectroscopy has become an increasingly popular tool to characterise the solid-state forms and their phase transitions. It offers several advantages over other characterisation techniques including an ability to obtain molecular level information, minimal sample preparation, and the possibility of monitoring changes non-destructively in-line. Dehydration is the phase transition of hydrates which is frequently encountered during the dosage form production and storage. The aim of the present thesis was to investigate the dehydration behaviour of diverse pharmaceutical hydrates by near infrared (NIR), Raman and terahertz pulsed spectroscopic (TPS) monitoring together with multivariate data analysis. The goal was to reveal new perspectives for investigation of the dehydration at the molecular level. Solid-state transformations were monitored during dehydration of diverse hydrates on hot-stage. The results obtained from qualitative experiments were used to develop a method and perform the quantification of the solid-state forms during process induced dehydration in a fluidised bed dryer. Both in situ and in-line process monitoring and quantification was performed. This thesis demonstrated the utility of vibrational spectroscopy techniques and multivariate modelling to monitor and investigate dehydration behaviour in situ and during fluidised bed drying. All three spectroscopic methods proved complementary in the study of dehydration. NIR spectroscopy models could quantify the solid-state forms in the binary system, but were unable to quantify all the forms in the quaternary system. Raman spectroscopy models on the other hand could quantify all four solid-state forms that appeared upon isothermal dehydration. The speed of spectroscopic methods makes them applicable for monitoring dehydration and the quantification of multiple forms was performed during phase transition. Thus the solid-state structure information at the molecular level was directly obtained. TPS detected the intermolecular phonon modes and Raman spectroscopy detected mostly the changes in intramolecular vibrations. Both techniques revealed information about the crystal structure changes. NIR spectroscopy, on the other hand was more sensitive to water content and hydrogen bonding environment of water molecules. This study provides a basis for real time process monitoring using vibrational spectroscopy during pharmaceutical manufacturing.

Thin-Layer Chromatography with Ultraviolet and Mass Spectrometric Detection: From Preparative-Layer to Miniaturized Ultra-Thin-Layer Technique

The present challenge in drug discovery is to synthesize new compounds efficiently in minimal time. The trend is towards carefully designed and well-characterized compound libraries because fast and effective synthesis methods easily produce thousands of new compounds. The need for rapid and reliable analysis methods is increased at the same time. Quality assessment, including the identification and purity tests, is highly important since false (negative or positive) results, for instance in tests of biological activity or determination of early-ADME parameters in vitro (the pharmacokinetic study of drug absorption, distribution, metabolism, and excretion), must be avoided. This thesis summarizes the principles of classical planar chromatographic separation combined with ultraviolet (UV) and mass spectrometric (MS) detection, and introduces powerful, rapid, easy, low-cost, and alternative tools and techniques for qualitative and quantitative analysis of small drug or drug-like molecules. High performance thin-layer chromatography (HPTLC) was introduced and evaluated for fast semi-quantitative assessment of the purity of synthesis target compounds. HPTLC methods were compared with the liquid chromatography (LC) methods. Electrospray ionization mass spectrometry (ESI MS) and atmospheric pressure matrix-assisted laser desorption/ionization MS (AP MALDI MS) were used to identify and confirm the product zones on the plate. AP MALDI MS was rapid, and easy to carry out directly on the plate without scraping. The PLC method was used to isolate target compounds from crude synthesized products and purify them for bioactivity and preliminary ADME tests. Ultra-thin-layer chromatography (UTLC) with AP MALDI MS and desorption electrospray ionization mass spectrometry (DESI MS) was introduced and studied for the first time. Because of the thinner adsorbent layer, the monolithic UTLC plate provided 10 100 times better sensitivity in MALDI analysis than did HPTLC plates. The limits of detection (LODs) down to low picomole range were demonstrated for UTLC AP MALDI and UTLC DESI MS. In a comparison of AP and vacuum MALDI MS detection for UTLC plates, desorption from the irregular surface of the plates with the combination of an external AP MALDI ion source and an ion trap instrument provided clearly less variation in mass accuracy than the vacuum MALDI time-of-flight (TOF) instrument. The performance of the two-dimensional (2D) UTLC separation with AP MALDI MS method was studied for the first time. The influence of the urine matrix on the separation and the repeatability was evaluated with benzodiazepines as model substances in human urine. The applicability of 2D UTLC AP MALDI MS was demonstrated in the detection of metabolites in an authentic urine sample.

Community Pharmacies and the Needs of Mobile EU Citizens - A study on Finns living in Spain

Migration within the European Union (EU) has increased since the Union was established. Community pharmacies provide open access to health care services and can be the first, most frequently used or even the only contact with a nation s health care system among mobile community residents. In some of the mass-migration areas in Southern Europe, most of the customers may represent mobile citizens of foreign background. This has not always been taken into consideration in the development of community pharmacy services. Mobile patients have been on the EU's health policy agenda, but they have seldom been mentioned in the context of community pharmacies. In most of the EU member states, governments control the specific legislation concerning community pharmacies and there is no harmonised pharmaceutical policy or consistent minimal standards for community pharmacy services in the EU. The aim of this study was to understand medication use, the role of community pharmacies and the symptom mitigation process of mobile community residents. Finns living in Spain were used as an example to examine how community pharmacies in a EU member state meet the needs of mobile community residents. The data were collected by a survey in 2002 (response rate 53%, n= 533) and by five focus group discussions in 2006 (n=30). A large number (70%) of the respondents had moved to Spain for health reasons and suffered from chronic morbidity. Community pharmacies had an important role in the healthcare of mobile community residents and the respondents were mostly satisfied with these services. However, several medication safety risks related to community pharmacy practices were identified: 1) Availability of prescription medicines without prescription (e.g., antibiotics, sleeping pills, Viagra®, asthma medications, cardiovascular medicines, psoriasis medicines and analgesics); 2) Irrational use of medicines (e.g., 41% of antibiotic users had bought their antibiotics without a prescription, and the most common reasons for antibiotic self-medication were symptomatic common colds and sore throats); 3) Language barriers between patients and pharmacy professionals; 4) Lack of medication counselling; 5) Unqualified pharmacy personnel providing pharmacotherapy. A fifth of the respondents reported experiencing problems during pharmacy visits in Spain, and the lack of a common language was the source of most of these problems. The findings of this study indicate that regulations and their enforcement can play a crucial role in actually assuring the rational and safe use of medicines. These results can be used in the development of pharmaceutical and healthcare policies in the EU. It is important to define consistent minimum standards for community pharmacy services in the EU. Then, the increasing number of mobile community residents could access safe and high quality health care services, including community pharmacy services, in every member state within the EU.

An optimal design for screening trials

Yao, Begg, and Livingston (1996, Biometrics 52, 992-1001) considered the optimal group size for testing a series of potentially therapeutic agents to identify a promising one as soon as possible for given error rates. The number of patients to be tested with each agent was fixed as the group size. We consider a sequential design that allows early acceptance and rejection, and we provide an optimal strategy to minimize the sample sizes (patients) required using Markov decision processes. The minimization is under the constraints of the two types (false positive and false negative) of error probabilities, with the Lagrangian multipliers corresponding to the cost parameters for the two types of errors. Numerical studies indicate that there can be a substantial reduction in the number of patients required.

Preliminary investigations into the use of a functionalised polymer to reduce diffusion in Fricke gel dosimeters

Purpose A modification of the existing PVA-​FX hydrogel has been made to investigate the use of a functionalised polymer in a Fricke gel dosimetry system to decrease Fe3+ diffusion. Methods The chelating agent, xylenol orange, was chem. bonded to the gelling agent, polyvinyl alc. (PVA) to create xylenol orange functionalised PVA (XO-​PVA)​. A gel was created from the XO-​PVA (20​% w​/v) with ferrous sulfate (0.4 mM) and sulfuric acid (50 mM)​. Results This resulted in an optical d. dose sensitivity of 0.014 Gy-​1, an auto-​oxidn. rate of 0.0005 h-​1, and a diffusion rate of 0.129 mm2 h-​1; an 8​% redn. compared to the original PVA-​FX gel, which in practical terms adds approx. 1 h to the time span between irradn. and accurate read-​out. Conclusions Because this initial method of chem. bonding xylenol orange to polyvinyl alc. has inherently low conversion, the improvement on existing gel systems is minimal when compared to the drawbacks. More efficient methods of functionalising polyvinyl alc. with xylenol orange must be developed for this system to gain clin. relevance.

Dynamics of plant populations in Heteropogon contortus(black speargrass) pastures on a granite landscape in southern Queensland. 1. Dynamics of H. contortus populations

The dynamics of Heteropogon contortus (black speargrass) populations were measured in a subset of treatments contained within an extensive grazing study conducted between 1990 and 1996 in H. contortus pasture in southern Queensland. This subset included 2 landscape positions and 3 stocking rates in both native pasture and legume-oversown native pasture. Severe drought conditions throughout much of the study necessitated ongoing adjustments to the original stocking rates and, as a result, drought was the major influence on the dynamics of H. contortus populations. Plant density and basal area in the silver-leaved ironbark landscape were consistently higher than those in the narrow-leaved ironbark landscape. There was limited evidence of any impact by either light or moderate stocking rate but there was evidence of an impact at the heaviest stocking rate. There was minimal impact of legume oversowing. Relatively large fluctuations in plant density occurred during this study resulting from the death of existing plants, due mainly to drought, and seedling recruitment. Similarly, there were relatively large fluctuations in basal area caused mainly by changes in plant size. Rates for turnover of plant numbers were relatively high whereas plant turnover rates of basal areas were relatively low. Regular seedling recruitment appeared necessary to ensure the persistence of this species. Despite the high turnover, populations were maintained at reasonable levels indicating the overall resilience of H. contortus.

A Design for Testability of Undetectable Crosspoint Faults in Programmable Logic Arrays

In this paper, the validity of'single fault assumption in deriving diagnostic test sets is examined with respect to crosspoint faults in programmable logic arrays (PLA's). The control input procedure developed here can be used to convert PLA's having undetectable crosspoint faults to crosspoint-irredundant PLA's for testing purposes. All crosspoints will be testable in crosspoint-irredundant PLA's. The control inputs are used as extra variables during testing. They are maintained at logic I during normal operation. A useful heuristic for obtaining a near-minimal number of control inputs is suggested. Expressions for calculating bounds on the number of control inputs have also been obtained.

Rossijskaja Karelija i karely v imperskoi politike Rossii, 1905-1917

Russian Karelians were one of the small peasant nations of the Russian Empire that began to identify themselves as nations during the late imperial period. At that historical moment Russian Karelia fell between an economically undeveloped empire and the rapidly modernizing borderland of Finland. The economic and cultural lure of Finland drew Karelians into the Finnish camp. This attraction was seen as a challenge to Russia and influenced the straggle between Russia and Finland for the Karelians. This struggle was waged from 1905 to 1917. This work is focused on the beginning stage of the struggle, its various phases, and their results. The confrontation extended into different dimensions (economic, political, ideological, church and cultural politics) and occurred on two levels: central and regional. Countermeasures against local nationalisms developed much earlier both in Russia and in other empires for use were also used in the Russian Karelian case. Economic policies were deployed to try to make relations with Russia more alluring for Karelians and to improve their economic condition. However, these efforts produced only minimal results due to the economic weakness of the empire and a lack of finances. Fear of the economic integration of the Karelians and Finns, which would have stimulated the economy of the Karelia, also hindered these attempts. The further development of the Orthodox Church, the schools and the zemstvos in Karelia yielded fewer results than expected due to the economic underdevelopment of the region and the avoidance of the Finnish language. Policizing measures were the most successfull, as all activities in Russian Karelia by the Finns were entirely halted in practice. However, the aspiration of Russian Karelians to integrate their home districts with Finland remained a latent force that just waited for an opportunity to push to the surface again. Such a chance materialized with the Russian revolution. The Karelian question was also a part of Russian domestic political confrontation. At the and of the 1800s, the Russian nationalist right had grown strong and increasingly gained the favor of the autocracy. The right political forces exploited the Karelian question in its anti-Finnish ideology and in its general resistance to the national emancipation of the minority peoples of Russia. A separate ideology was developed, focusing on the closeness of Karelians to the "great Russian people." Simultaneously, this concept found a place in the ultramonarchist myth of the particularly close connection between the people and tsar that was prominent in the era of Nicholas II. This myth assigned the Karelians a place amongst the "simple people" faithful to the tsar.

Reducing Browning of Fresh-cut ‘Maha’ Carambola with Chemical Additives and Low-oxygen Atmospheres

The greatest attraction to using carambola (Averrhoa carambola L.) in the fresh-cut market is the star shape that the fruit presents after a transverse cut. Carambola is well-suited for minimal processing, but cut surface browning is a main cause of deterioration. This problem is exacerbated as a result of mechanical injuries occurring during processing and is mainly induced by the leakage of phenolic compounds from the vacuole and subsequent oxidation by polyphenol oxidase (PPO) (Augustin et al., 1985). The use of browning inhibitors in processed fruits is restricted to compounds that are non-toxic, ‘wholesome’, and that do not adversely affect taste and flavour (Gil et al., 1998). In the past, browning was mainly controlled by the action of sulphites, but the use of this compound has declined due to allergic reactions in asthmatics (Weller et al., 1995). The shelf life of fresh-cut products may be extended by a combination of oxygen exclusion and the use of enzymatic browning inhibitors. The objectives of this work were to determine the effects of: (1) post-cutting chemical treatments of ascorbic, citric, oxalic acids, and EDTA-Ca; (2) atmospheric modification; and (3) combinations of the above, on the shelf life of carambola slices based on appearance, colour and polyphenol oxidase activity

Milk Production Responses to Oversowing a Portion of Tropical Grass Pasture with Summer Crop Legumes on Sub-tropical Dairy Farms

Northern Australian dairy farms have a large area of tropical dryland grass pasture available for use as summer pastures. Late summer-autumn in sub-tropical Australia is traditionally a difficult period in which to produce milk because of the decline in both quality and quantity of tropical grasses (Ehrlich et al. 1994). Options to improve autumn feed on dairy farms include introducing forage crops and conservation, increasing concentrate feeding and introducing legumes. Perennial tropical legumes have not been successful at this time of year because of their inability to sustain stocking rates above one cow/ha. This experiment, conducted on farms, was designed to test if annual crop legumes could be successfully oversown into tropical grass areas using minimal till methods to measure the subsequent impact on milk production on farms. Previous experiments using annual legumes in plots at Mutdapilly Research Station had demonstrated yields up to 10 t/ha can be achieved using annual tropical legumes with protein levels as high as 20% in the whole legume plant. Animal production for a consuming world : proceedings of 9th Congress of the Asian-Australasian Association of Animal Production Societies [AAAP] and 23rd Biennial Conference of the Australian Society of Animal Production [ASAP] and 17th Annual Symposium of the University of Sydney, Dairy Research Foundation, [DRF]. 2-7 July 2000, Sydney, Australia.

Theoretical description of time-resolved pump/probe photoemission in TaS2: a single-band DFT+DMFT(NRG) study within the quasiequilibrium approximation

In this work, we theoretically examine recent pump/probe photoemission experiments on the strongly correlated charge-density-wave insulator TaS2.We describe the general nonequilibrium many-body formulation of time-resolved photoemission in the sudden approximation, and then solve the problem using dynamical mean-field theory with the numerical renormalization group and a bare density of states calculated from density functional theory including the charge-density-wave distortion of the ion cores and spin-orbit coupling. We find a number of interesting results: (i) the bare band structure actually has more dispersion in the perpendicular direction than in the two-dimensional planes; (ii) the DMFT approach can produce upper and lower Hubbard bands that resemble those in the experiment, but the upper bands will overlap in energy with other higher energy bands; (iii) the effect of the finite width of the probe pulse is minimal on the shape of the photoemission spectra; and (iv) the quasiequilibrium approximation does not fully describe the behavior in this system.

Pheromone-mediated mass trapping and population diversion as strategies for suppressing Carpophilus spp. (Coleoptera: Nitidulidae) in Australian stone fruit orchards

1 Five experiments were conducted during 1995-99 in stone fruit orchards on the Central Coast and in inland New South Wales, Australia, on the use of synthetic aggregation pheromones and a coattractant to suppress populations of the ripening fruit pests Carpophilus spp. (Coleoptera: Nitidulidae). 2 Perimeter-based suppression traps baited with pheromone and coattractant placed at 3m intervals around small fruit blocks, caught large numbers of Carpophilus spp. Very small populations of Carpophilus spp. occurred within blocks, and fruit damage was minimal. 3 Carpophilus spp. populations in stone fruit blocks 15-370m from suppression traps were also small and non-damaging, indicating a large zone of pheromone attractivity. 4 Pheromone/coattractant-baited suppression traps appeared to divert Carpophilus spp. from nearby (130 m) ripening stone fruit. Ten metal drums containing decomposing fruit, baited with pheromone and treated with insecticide, attracted Carpophilus spp. and appeared to reduce populations and damage to ripening fruit at distances of 200-500 m. Populations and damage were significantly greater within 200m of the drums and may have been caused by ineffective poisoning or poor quality/overcrowding of fruit resources in the drums. 5 Suppression of Carpophilus spp. populations using synthetic aggregation pheromones and a coattractant appears to be a realistic management option in stone fruit orchards. Pheromone-mediated diversion of beetle populations from ripening fruit may be more practical than perimeter trapping, but more research is needed on the effective range of Carpophilus pheromones and the relative merits of trapping compared to attraction to insecticide-treated areas.

Pheromone-trapping of Carpophilus spp. (Coleoptera: Nitidulidae) in stone fruit orchards near Gosford, New South Wales: Fauna, seasonality and effect of insecticides

Traps baited with synthetic aggregation pheromones of Carpophilus hemipterus (L.), Carpophilus mutilatus Erichson and Carpophilus davidsoni Dobson and fermenting bread dough were used to identify the fauna and monitor the seasonal abundance of Carpophilus spp. in insecticide treated peach and nectarine orchards in the Gosford area of coastal New South Wales. In four orchards 67 178 beetles were trapped during 1994–1995, with C. davidsoni (82%) and Carpophilus gaveni (Dobson) (12.2%) dominating catches. Five species (C. hemipterus, C. mutilatus, Carpophilus marginellus Motschulsky, Carpophilus humeralis (F.) and an unidentified species) each accounted for 0.2–3.2% of trapped beetles. Carpophilus davidsoni was most abundant during late September–early October but numbers declined rapidly during October, usually before insecticides were applied. Spring populations of Carpophilus spp. were very large in 1994–1995 (1843–2588 per trap per week). However, despite a preharvest population decline of approximately 95% and 2–11 applications of insecticide, 14–545 beetles per trap per week (above the arbitrary fruit damage threshold of 10 beetles per trap per week) were recorded during the harvest period and fruit damage occurred at three of the four orchards. Lower preharvest populations in 1995–1996 (< 600 per trap per week) and up to six applications of insecticide resulted in < 10 beetles per trap per week during most of the harvest period and minimal or no fruit damage. The implications of these results for the integrated management of Carpophilus spp. in coastal and inland areas of southeastern Australia are discussed.

Blast response and failure analysis of a segmented buried tunnel

Underground tunnels are vulnerable to terrorist attacks which can cause collapse of the tunnel structures or at least extensive damage, requiring lengthy repairs. This paper treats the blast impact on a reinforced concrete segmental tunnel buried in soil under a number of parametric conditions; soil properties, soil cover, distance of explosive from the tunnel centreline and explosive weight and analyses the possible failure patterns. A fully coupled Fluid Structure Interaction (FSI) technique incorporating the Arbitrary Lagrangian-Eulerian (ALE) method is used in this study. Results indicate that the tunnel in saturated soil is more vulnerable to severe damage than that buried in either partially saturated soil or dry soil. The tunnel is also more vulnerable to surface explosions which occur directly above the centre of the tunnel than those that occur at any equivalent distances in the ground away from the tunnel centre. The research findings provide useful information on modeling, analysis, overall tunnel response and failure patterns of segmented tunnels subjected to blast loads. This information will guide future development and application of research in this field.

Behçet's syndrome involving the gastrointestinal tract: a diagnostic dilemma in childhood

Behçet's syndrome is very rare in children, especially those under 10 years of age. Clinical and radiological features are described in 4 children, including 2 under the age of 5 years, with the syndrome. As in other pediatric cases reported, the incomplete form of Behçet's syndrome was present in each case. All 4 patients had oral and genital mucosal effects, arthritis and gastrointestinal and dermatological manifestations. Ophthalmological symptoms occurred in only 1 patient. Radiologically, the 4 cases demonstrated the spectrum of gastrointestinal involvement, from minimal irregularity and thickening of the terminal ileum to gross irregularity and deformity of the terminal ileum and cecum. Because of the difficulty in differentiating Behçet's syndrome from other forms of inflammatory bowel disease it is suggested that in children with gastrointestinal involvement, 3 major criteria be present before the diagnosis of Behçet's syndrome is made.