Cediranib Maleate-From Crystal Structure Toward Materials Control.

Cediranib maleate is an active pharmaceutical ingredient (API) in phase III of development within AstraZeneca's oncology portfolio. Analysis of the crystal structure of this API confirmed that the selected salt form was robust. The salt formation step had to be redesigned to avoid an unwanted metastable polymorph. A solvate with a twist appeared during later development and was avoided using insights gained from its crystal structure. Differences between predicted and experimental aspect ratios correlate with weaker crystal interactions. Acceptable variability in particle size was defined and accommodated. The "Matwall" is introduced as a tool for building control of API performance from the crystal structure upward.

A big data approach to pharmaceutical flow properties.

Flowability is a key consideration during the formulation and process development of oral solid dosage forms as it can have a critical impact on product quality. With a limited number of examples available in the literature, there is a need to better understand and share the typical flow properties of pharmaceutical materials. Here, historical data (3909 experiments) from a shear cell apparatus were extracted and analysed. These data were composed of different material types, including APIs, excipients, blends and granules from nearly a decade of development projects. APIs were found to have poor flow properties (ffc <2), while other materials (excipients, blends and granules) generally had good flow properties. This analysis provided an enhanced understanding of the typical flow properties of pharmaceutical materials. By combining these data with information on the process and achieved drug load, it was possible to characterise our current operating space as a process flow map which could be used to focus future development.

A compressibility based model for predicting the tensile strength of directly compressed pharmaceutical powder mixtures.

A new model to predict the compressibility and compactability of mixtures of pharmaceutical powders has been developed. The key aspect of the model is consideration of the volumetric occupancy of each powder under an applied compaction pressure and the respective contribution it then makes to the mixture properties. The compressibility and compactability of three pharmaceutical powders: microcrystalline cellulose, mannitol and anhydrous dicalcium phosphate have been characterised. Binary and ternary mixtures of these excipients have been tested and used to demonstrate the predictive capability of the model. Furthermore, the model is shown to be uniquely able to capture a broad range of mixture behaviours, including neutral, negative and positive deviations, illustrating its utility for formulation design.

A Longitudinal Study of Financial Difficulties and Mental Health in a National Sample of British Undergraduate Students.

Previous research has shown a relationship between financial difficulties and poor mental health in students, but most research is cross-sectional. To examine longitudinal relationships over time between financial variables and mental health in students. A national sample of 454 first year British undergraduate students completed measures of mental health and financial variables at up to four time points across a year. Cross-sectional relationships were found between poorer mental health and female gender, having a disability and non-white ethnicity. Greater financial difficulties predicted greater depression and stress cross-sectionally, and also predicted poorer anxiety, global mental health and alcohol dependence over time. Depression worsened over time for those who had considered abandoning studies or not coming to university for financial reasons, and there were effects for how students viewed their student loan. Anxiety and alcohol dependence also predicted worsening financial situation suggesting a bi-directional relationship. Financial difficulties appear to lead to poor mental health in students with the possibility of a vicious cycle occurring.

An experimental investigation of temperature rise during compaction of pharmaceutical powders.

During pharmaceutical powder compaction, temperature rise in the compressed powder can affect physiochemical properties of the powder, such as thermal degradation and change in crystallinity. Thus, it is of practical importance to understand the effect of process conditions and material properties on the thermal response of pharmaceutical formulations during compaction. The aim of this study was to examine the temperature rise of pharmaceutical powders during tableting, in particular, to explore how the temperature rise depends on material properties, compression speed and tablet shape. Three grades of microcrystalline cellulose (MCC) were considered: MCC Avicel pH 101, MCC Avicel pH 102 and MCC DG. These powders were compressed using a compaction simulator at various compaction speeds (10-500mm/s). Flat faced, shallow convex and normal convex tablets were produced and temperature distributions on the surface of theses tablets upon ejection were examined using an infrared thermoviewer. It was found that an increase in the compaction speed led to an increase in the average surface temperature. A higher surface temperature was induced when the powder was compressed into a tablet with larger surface curvature. This was primarily due to the increasing degree of powder deformation (i.e. the volume reduction) and the effect of interparticule/wall friction.

Student involvement in the UK sex industry: motivations and experiences.

The Student Sex Work Project was set up in 2012 in the United Kingdom (UK) to locate students who are involved in the sex industry, to discover their motivations and needs, and in doing so provide an evidence base to consider the development of policy and practice within Higher Education. As part of this initiative, a large survey was undertaken comprising students from throughout the UK. Reporting on the findings from this survey, the article sheds some light on what occupations students take up in the sex industry, what motivates their participation and how they experience the work. The study also offers a much-needed empirical input to the ongoing academic debates on the nature of sex work. The results suggest that there can be little doubt of a student presence within the sex industry in the UK. The motivations and experiences of student sex workers cover elements of agency and choice as well as of force and exploitation and it is suggested that student sex work is best understood from a polymorphous framework which leaves room for a wide variety of experiences and challenges.

The control of sea lice in Atlantic salmon by selective breeding.

Sea lice threaten the welfare of farmed Atlantic salmon and the sustainability of fish farming across the world. Chemical treatments are the major method of control but drug resistance means that alternatives are urgently needed. Selective breeding can be a cheap and effective alternative. Here, we combine experimental trials and diagnostics to provide a practical protocol for quantifying resistance to sea lice. We then combined quantitative genetics with epidemiological modelling to make the first prediction of the response to selection, quantified in terms of reduced need for chemical treatments. We infected over 1400 young fish with Lepeophtheirus salmonis, the most important species in the Northern Hemisphere. Mechanisms of resistance were expressed early in infection. Consequently, the number of lice per fish and the ranking of families were very similar at 7 and 17 days post infection, providing a stable window for assessing susceptibility to infection. The heritability of lice numbers within this time window was moderately high at 0.3, confirming that selective breeding is viable. We combined an epidemiological model of sea lice infection and control on a salmon farm with genetic variation in susceptibility among individuals. We simulated 10 generations of selective breeding and examined the frequency of treatments needed to control infection. Our model predicted that substantially fewer chemical treatments are needed to control lice outbreaks in selected populations and chemical treatment could be unnecessary after 10 generations of selection. Selective breeding for sea lice resistance should reduce the impact of sea lice on fish health and thus substantially improve the sustainability of Atlantic salmon production.

Reflection and transmission of guided ultrasonic plate waves by vertical stiffeners.

Ultrasonic guided waves are very useful for structural health monitoring. They have the potential to interrogate and detect damage in a structure over a large area with few transducers. Guided plate modes (Lamb waves) are used and proposed for damage detection at a distance in semi-monococque structures such as airplane fuselages and spacecraft structures. The interaction of guided plate waves with stiffening members such as ribs, stringers, or the integral stiffeners used in spacecraft structures limits the distance over which structural health monitoring non-destructive evaluation systems can detect damage. This paper develops a simple explanatory model for the scattering of low-order ultrasonic Lamb waves crossing a stiffening device. The model illuminates the underlying mechanics of waves crossing a stiffener. The model shows that stop-bands for transmission of S(0) (longitudinal pressure) waves across a stiffener line up with flexural resonances of the stiffener. It also demonstrates why transmission of A(0) (flexural) waves is more complicated and harder to predict. The model is shown to agree well with both boundary element method calculations and experimental measurements.

A comparative study of roll compaction of free-flowing and cohesive pharmaceutical powders.

Roll compaction is widely adopted as a dry granulation method in the pharmaceutical industry. The roll compaction behaviour of feed powders is primarily governed by two parameters: the maximum pressure and the nip angle. Although the maximum pressure can be measured directly using pressure sensors fitted in the rolls, it is not a trivial task to determine the nip angle, which is a measure of the size of the compaction zone and hence the degree of compression. Thus a robust approach based upon the calculation of the pressure gradient, which can be obtained directly from experiments using an instrumented roll compactor, was developed. It has been shown that the resulting nip angles are comparable to those obtained using the methods reported in literature. Nevertheless, the proposed approach has distinctive advantages including (1) it is based on the intrinsic features of slip and no-slip interactions between the powder and roll surface and (2) it is not necessary to carry out wall friction measurements that involve plates that may not be representative of the roll compactor in terms of the surface topography and surface energy. The method was evaluated by investigating the effect of roll speed for two pharmaceutical excipients with distinctive material properties: microcrystalline cellulose (MCC) and di-calcium phosphate dihydrate (DCPD). It was found that the maximum pressure and nip angle for DCPD, which is a cohesive powder, decrease sharply with increasing roll speed whereas they are essentially independent of roll speed for MCC, which is an easy flowing powder. The roll compaction behaviour of MCC-DCPD mixtures with various compositions was also investigated in order to evaluate the effect of flowability. It was found that the nip angle and maximum pressure generally increased with improved flowability of the feed powders.

Social inequality and young pregnancy: the causal attributions of young parents in London, UK.

Although the association between young pregnancy and the socio-economic environment is globally recognised, little is understood about either the processes behind it or how young parents construe this relationship. Twenty-one semi-structured interviews were conducted in four London areas; two 'less deprived' and two 'more deprived' in order to solicit young parent's views. Thematic analysis uncovered three factors indicative of how young parents understand the social gradient in young pregnancy; the parental relationship status (openness and parental control); access to education and career; and acceptance of young pregnancy. It is suggested that differing representations of young parenthood across socio-economic subgroups correspond to differing representations, values and beliefs concerning sexual and reproductive behaviour, education and the social acceptability of young pregnancy. Further work is needed to build up a holistic picture of the influence place has on young people's sexual and reproductive health.

Young parents: the role of housing in understanding social inequality.

BACKGROUND: Since publication of the Social Exclusion Report in 1999, the adverse outcomes associated with young pregnancy have been a focus for Government policy. The ensuing Teenage Pregnancy Strategy sought to reduce social exclusion of young parents and their children. METHOD: In this exploratory study, semi-structured interviews were conducted with young mothers (n=16) and fathers (n = 5) from a variety of socioeconomic environments, to explore their experience of being a young parent and some of the influences on their sexual and reproductive behaviours. They were recruited from two "more deprived" and two "more affluent" areas (Index of Multiple Deprivation classification). Their personal deprivation was measured by their parents' occupation. Thematic analysis was used to analyse the interview transcripts and identified themes were explored. FINDINGS: Although housing was not included as a topic in the interview guide, responses indicated that housing is a cause of stress for young parents throughout and beyond pregnancy. Findings suggest that existing policies on supportive housing units adversely affect the relationship between young parents and between young fathers and their children. CONCLUSIONS: It is suggested that existing policies on supportive housing units should be reviewed to produce more supportive environments for parents and child. It was noted that the semi-structured interview method was successful in enabling the researchers to more fully understand the world as experienced by these young parents, and the researchers suggest that this research method may be particularly useful for use with vulnerable groups to suggest effective interventions.

Therapy planning and monitoring of tissue ablation by high intensity focused ultrasound (HIFU) using imaging and simulation.

High intensity focused ultrasound (HIFU) 'cooks' or ablates the target tissue at the focus of the ultrasound beam by thermal and cavitation effects. The HIFU is emerging as a non-invasive method for tumor ablation. The HIFU application for tissue ablation requires tools for dosimetry therapy planning, and real-time feedback of the intended and actual target tissues. Pretreatment planning is an important step for a successful HIFU therapy outcome. Typically, the therapy planning approach involves the use of pretreatment imaging data, defining the target and surrounding tissues by manual or semiautomatic segmentation, development of a 3-D anatomy model of the region of interest from segmentation or registration with a reference dataset, simulation of the HIFU beam and thermal dosimetry around the target tissue, display and 3-D visualization of imaging and simulation data, and review of the treatment plan options. Recent developments in therapy planning using imaging are targeted for specific applications such as prostate cancer using 3-D ultrasound images and uterine fibroids using MRI. However, significant developments have been accomplished in image guidance and feedback during the delivery of HIFU treatments. This talk reviews recent work towards therapy planning and presents approaches for developing strategies for HIFU therapy. It describes general and target-specific techniques and software tools for HIFU treatment planning using pretherapy imaging, and monitoring and controlling the HIFU delivery and tissue lesion using 1D, 2D and 3D ultrasound imaging. This aids development of optimized, high-precision HIFU applications for a controlled ablation of the target tumor. It also potentially reduces the overall treatment duration and exposure to non-target tissues.

Locating air leaks in manned spacecraft using structure-borne noise.

All manned spacecraft are vulnerable to leaks generated by micrometeorite or debris impacts. Methods for locating such leaks using leak-generated, structure-borne ultrasonic noise are discussed and demonstrated. Cross-correlations of ultrasonic noise waveforms from a leak into vacuum are used to find the location of the leak. Four methods for sensing and processing leak noise have been developed and tested and each of these can be used to reveal the leak location. The methods, based on phased-array, distributed sensor, and dual sensor approaches, utilize the propagation patterns of guided ultrasonic Lamb waves in the spacecraft skin structure to find the source or direction of the leak noise. It is shown that each method can be used to successfully locate the leak to within a few millimeters on a 0.6-m2 aluminum plate. The relative merits of the four methods are discussed.

Structure, solubility, screening, and synthesis of molecular salts.

The preparation of molecular salts as potential delivery vehicles for pharmaceutically active compounds is more common than current appreciation of the phenomena governing the solubility and isolation of salts suggests. In addition, it would appear that there are no reported measurements on a large enough data set for a serious structure-property relationship analysis to have been performed for this class of material. This means that at present, the ability to predict which salt forms will have desirable physical properties is essentially nonexistent. The work reported here sets out to explore these issues using new data on 17 salts obtained from a screen performed on the basic pharmaceutical ephedrine. The importance of solvent choice in salt formation, of salt selection in the control of bioavailability and of ternary phase equilibria in salt isolation and the relationship between a number of measured and calculated crystal properties are illustrated and discussed. The consequences of these relations for the general design, implementation, interpretation, and scale-up of salts screens are also explored.

An ultrasonic array sensor for spacecraft leak direction finding.

We have developed an ultrasonic array sensor useable for locating air leaks in manned spacecraft and have found that this sensor locates leaks in a 1-m(2) plate to within 2 cm. The sensor consists of a 63-element multiplexed array plus a reference element, all constructed from a single PZT disc and a printed circuit board. Cross-correlations of signals from the array elements with signals from the single reference element provide a measurement of the leak noise passing through the spacecraft skin under the array. A spatial Fourier transform reveals the dominant direction of propagation. Triangulation from multiple sensor locations can be used to find the source of the leak.

17 salts of ephedrine: crystal structures and packing analysis.

The structures of two neutral and 17 salt forms of the base (1R, 2S)-(-)-ephedrine are reported. These structures are discussed in the light of the conformers of the ephedrine moiety, the existence of bilayers and the structure determining role of the counterions. Overall, most of the salt structures are essentially derived from the observed packing of the neutral base and are dominated by the amphiphilic nature of the ephedrine molecular structure. In a few cases the size and hydrophobicity of the counterion disrupts this behaviour.

The effects of child sexual abuse in later family life; mental health, parenting and adjustment of offspring.

OBJECTIVE: To investigate links between child sexual abuse (occurring before 13 years), later mental health, family organization, parenting behaviors, and adjustment in offspring. METHOD: The present study investigates a subsample of the Avon Longitudinal Study of Parents and Children an ongoing study of women and their families in the area of Avon, England. A sample of 8292 families met inclusion criteria for identifiable family type and completed self-report data on prior sexual assault. Further data were collected on life course variables, socioeconomic variables, psychological well-being, relationship quality, parent-child relationship quality, and children's adjustment. RESULTS: After adjustment for other childhood adversity, prior child sexual abuse was associated with a range of outcomes in adulthood, including current membership of a nontraditional family type (single mother and stepfather) poorer psychological well-being, teenage pregnancy, parenting behaviors, and adjustment problems in the victim's later offspring. The relationship of child sexual abuse with aspects of the parent-child relationship in later life and with the offspring's adjustment difficulties were mediated in part by mother's mental health--chiefly anxiety. CONCLUSION: Findings indicate that child sexual abuse has long-term repercussions for adult mental health, parenting relationships, and child adjustment in the succeeding generation.