Design and Synthesis of New Modulators of Liver Receptor Homologue – 1

Nuclear receptor (NR) liver receptor homologue-1 (LRH-1) is a potential target for the treatment of breast cancers as a consequence of its regulation of aromatase and the estrogen receptor (ER). Development of modulators of NRs historically focuses on production of high affinity small molecules that compete for binding with natural ligands at the ligand-binding pocket (LBP) of the NR ligandbinding domain (LBD). Ligand-bound NRs induce transcriptional activity by subsequent recruitment of coactivator proteins. The majority of this thesis describes approaches towards the development of the first antagonists of LRH-1. In the first instance, small molecules that bind at the LBP of the receptor were developed through use of ligand-based virtual screening (VS) programs Cresset and SHop. Secondly, small molecules that directly disrupt the binding of cofactor proteins to the NR activation function-2 (AF-2) were developed through use of rational design and further Cresset VS

The design and scale-up of spray dried particle delivery systems

INTRODUCTION: The rising demand for pharmaceutical particles with tailored physicochemical properties has opened new markets for spray drying especially for solubility enhancement, improving inhalation medicines and stabilization of biopharmaceuticals. Despite this, the spray drying literature is scattered and often does not address the principles underpinning robust development of pharmaceuticals. It is therefore necessary to present clearer picture of the field and highlight the factors influencing particle design and scale-up. Areas covered: The review presents a systematic analysis of the trends in development of particle delivery systems using spray drying. This is followed by exploring the mechanisms governing particle formation in the process stages. Particle design factors including those of equipment configurations and feed/process attributes were highlighted. Finally, the review summarises the current industrial approaches for upscaling pharmaceutical spray drying. Expert opinion: Spray drying provides the ability to design particles of the desired functionality. This greatly benefits the pharmaceutical sector especially as product specifications are becoming more encompassing and exacting. One of the biggest barriers to product translation remains one of scale-up/scale-down. A shift from trial and error approaches to model-based particle design helps to enhance control over product properties. To this end, process innovations and advanced manufacturing technologies are particularly welcomed

MI5 and the Cold War in South-East Asia: Examining the Performance of Security Intelligence Far East (SIFE), 1946-1963

From 1946–1963, MI5 operated a South-East Asian regional headquarters in Singapore: Security Intelligence Far East (SIFE). This article responds to growing interest in theatre-level intelligence organisation and the importance of intelligence to Britain’s Cold War and decolonisation by examining the performance of SIFE. On the organisational level, SIFE was strongest when it remained wedded to its charter functions and closely adhered to the priorities of its principal consumer: the Commissioner-General for South-East Asia. Its assessments were influential in shaping decision-makers’ understandings of key regional developments, although this did not always translate into public policy. Lastly, SIFE enjoyed success in developing lasting liaison relationships to cement British influence, but failed to utilise these to improve its intake of raw intelligence

Analysis of Minor Component Segregation in Ternary Powder Mixtures

In many powder handling operations, inhomogeneity in powder mixtures caused by segregation could have significant adverse impact on the quality as well as economics of the production. Segregation of a minor component of a highly active substance could have serious deleterious effects, an example is the segregation of enzyme granules in detergent powders. In this study, the effects of particle properties and bulk cohesion on the segregation tendency of minor component are analysed. The minor component is made sticky while not adversely affecting the flowability of samples. The segregation extent is evaluated using image processing of the photographic records taken from the front face of the heap after the pouring process. The optimum average sieve cut size of components for which segregation could be reduced is reported. It is also shown that the extent of segregation is significantly reduced by applying a thin layer of liquid to the surfaces of minor component, promoting an ordered mixture

Numerical Analysis of the Effect of Particle Shape and Adhesion on the Segregation of Powder Mixtures

Segregation of granules is an undesired phenomenon in which particles in a mixture separate from each other based on the differences in their physical and chemical properties. It is, therefore, crucial to control the homogeneity of the system by applying appropriate techniques. This requires a fundamental understanding of the underlying mechanisms. In this study, the effect of particle shape and cohesion has been analysed. As a model system prone to segregation, a ternary mixture of particles representing the common ingredients of home washing powders, namely, spray dried detergent powders, tetraacetylethylenediamine, and enzyme placebo (as the minor ingredient) during heap formation is modelled numerically by the Discrete Element Method (DEM) with an aim to investigate the effect of cohesion/adhesion of the minor components on segregation quality. Non-spherical particle shapes are created in DEM using the clumped-sphere method based on their X-ray tomograms. Experimentally, inter particle adhesion is generated by coating the minor ingredient (enzyme placebo) with Polyethylene Glycol 400 (PEG 400). The JKR theory is used to model the cohesion/adhesion of coated enzyme placebo particles in the simulation. Tests are carried out experimentally and simulated numerically by mixing the placebo particles (uncoated and coated) with the other ingredients and pouring them in a test box. The simulation and experimental results are compared qualitatively and quantitatively. It is found that coating the minor ingredient in the mixture reduces segregation significantly while the change in flowability of the system is negligible

An experimental investigation of the swirling flow in a tall-form counter current spray dryer

This work studies the air flow in a large swirl counter-current dryer using sonic anemometry. Air velocity and turbulence fields are reported at isothermal conditions and in the absence of particles. In a tall-form unit the structure of the flow is largely influenced by the design of the exit. A contraction originates a central jet and suppresses the formation of recirculation zones despite the vortex acquires a high swirl intensity Ω (i.e. 1<Ω<2). Access to a full scale tower has permitted to: (a) identify asymmetries owed to the design of inlet and exhaust ducts, (b) present the first detailed turbulence data in production units, characterized by a highly anisotropic field and the axial decay of the turbulence kinetic energy, (c) study the flow stability, identifying the precession of the vortex core and oscillations at a constant Strouhal number and (d) study the impact that a rough wall has in the strength of the swirl. This work presents the first clear evidence of significant friction in spray dryers. The swirl intensity Ω decays exponentially in the dryer at a rate between 0.08 and 0.09, much higher than expected in pipe flow and independent of Re in the range 105-2.2{dot operator}105. Production dryers have a large characteristic wall roughness due the presence of deposits, which explains the stronger friction and the discrepancies found in the past between data at full scale or clean laboratory or pilot scale units. It is essential to address this phenomenon in current numerical models, which are validated on laboratory or pilot scale facilities and ignore the role of deposits, thus causing an overprediction of the tangential velocity above 30-40%

Residence Time Distribution of Glass Ballotini in Isothermal Swirling Flows in a Counter-Current Spray Drying Tower

The particle residence time in counter-current spray drying towers has a significant influence on the moisture content of the powder exiting the tower. Therefore, the reliability of predictions of residence time by numerical methods is highly desirable. A combined experimental and computational fluid dynamics investigation is reported for the prediction of the residence time distributions of glass beads with a narrow size range of 300-425 m in a counter-current tower with isothermal swirling flows of air. The particle-wall collision is taken into account using a rough-wall collision model. Overall, a reasonably good agreement is obtained between the measurements and predictions. Consideration of wall roughness results in greater axial dispersion of particles in the tower compared to a smooth wall assumption. The rough particle-wall collision is important for a reliable prediction of residence time distributions. In addition, analysis of the results infers that the clustering effect of particles on drag and particle-particle interactions are important and should be investigated in a future study

Particle aggregation in large counter-current spray drying towers: Nozzle configuration, vortex momentum and temperature

This work investigates particle growth in a counter-current swirl detergent dryer, operating with a single nozzle, at a range of nozzle heights, air drying temperatures, TA, and superficial air velocities, UA, which were selected to enhance or inhibit particle aggregation in the dryer. The growth kinetics are discussed paying special attention to the impact of the cycle of deposition and re-entrainment of material from the wall deposits. All cases lead to substantial aggregation and mono-modal product size distributions. The operation at low UA and high TA, (i.e. low momentum) does not inhibit growth as one would expect from a lower particle concentration and faster heat and mass transfer, conditions which would lead to less particle collisions resulting in growth. In contrast, generation of aggregated particles > 850 μm is promoted, suggesting that a change in the erosion behavior of particles from the wall due to a reduction in energy of particle impacts. As a result of lower stresses, erosion is suppressed and clusters remain at the wall for longer, what allows them to sinter and be re-entrained at larger sizes. In contrast, increasing the momentum of the continuous phase by operation at low TA and high UA inhibits particle growth, particularly in the production of the largest sizes > 850 μm. In this case the rate and energy of impacts to the wall increases, this leads to higher disruptive stresses on the wall deposits, thus, reducing the size of the clusters re-entrained. In summary, this work describes aggregation mechanisms in swirl detergent dryers operated with single nozzles, suggesting that, contrary to expectations, wearing of deposits rather than air-borne contacts may be a key contributor to the enhancement or inhibition of growth

Spreadability of powders for additive manufacturing: a critical review of metrics and characterisation methods

Powder bed fusion methods of additive manufacturing (AM) require consistent, reproducible, and uniform layers of powder for the reliable production of high-quality parts, where properties of powder are central to achieving this. Among these properties, powder flowability and spreadability play critical roles in determining the quality of these powder layers. While extensive research has been conducted on powder flow and spreading behaviour, and on their characterisation, there is little critical comparison and review of these terms in the context of AM. Such a review is necessary to further develop and enhance our comprehension of spreading dynamics and its relation to powder properties in AM systems. This review paper aims to build a coherent understanding of the correlation between powder characteristics and spreading in powder based additive manufacturing and its impact on manufactured parts. It highlights the current progress in comprehending spreading dynamics, the influence of powder characteristics, environmental conditions, spreading system, and the development of testing tools to assess powder spreadability. Furthermore, the paper critically discusses the challenge of finding appropriate quantitative metrics and recent advances in the use of standardised methods for evaluating powder spreadability

"The fruits of independence": Satyajit Ray, Indian nationhood and the spectre of empire

Challenging the longstanding consensus that Satyajit Ray's work is largely free of ideological concerns and notable only for its humanistic richness, this article shows with reference to representations of British colonialism and Indian nationhood that Ray's films and stories are marked deeply and consistently by a distinctively Bengali variety of liberalism. Drawn from an ongoing biographical project, it commences with an overview of the nationalist milieu in which Ray grew up and emphasizes the preoccupation with colonialism and nationalism that marked his earliest unfilmed scripts. It then shows with case studies of Kanchanjangha (1962), Charulata (1964), First Class Kamra (First-Class Compartment, 1981), Pratidwandi (The Adversary, 1970), Shatranj ke Khilari (The Chess Players, 1977), Agantuk (The Stranger, 1991) and Robertsoner Ruby (Robertson's Ruby, 1992) how Ray's mature work continued to combine a strongly anti-colonial viewpoint with a shifting perspective on Indian nationhood and an unequivocal commitment to cultural cosmopolitanism. Analysing how Ray articulated his ideological positions through the quintessentially liberal device of complexly staged debates that were apparently free, but in fact closed by the scenarist/director on ideologically specific notes, this article concludes that Ray's reputation as an all-forgiving, ‘everybody-has-his-reasons’ humanist is based on simplistic or even tendentious readings of his work