Crystallization as a Tool for Controlling and Designing Properties of Pharmaceutical Solids

The ability to deliver the drug to the patient in a safe, efficacious and cost-effective manner depends largely on the physicochemical properties of the active pharmaceutical ingredient (API) in the solid state. In this context, crystallization is of critical importance in pharmaceutical industry, as it defines physical and powder properties of crystalline APIs. An improved knowledge of the various aspects of crystallization process is therefore needed. The overall goal of this thesis was to gain better understanding of the relationships between crystallization, solid-state form and properties of pharmaceutical solids with a focus on a crystal engineering approach to design technological properties of APIs. Specifically, solid-state properties of the crystalline forms of the model APIs, erythromycin A and baclofen, and the influence of solvent on their crystallization behavior were investigated. In addition, the physical phenomena associated with wet granulation and hot-melting processing of the model APIs were examined at the molecular level. Finally, the effect of crystal habit modification of a model API on its tabletting properties was evaluated. The thesis enabled the understanding of the relationship between the crystalline forms of the model APIs, which is of practical importance for solid-state control during processing and storage. Moreover, a new crystalline form, baclofen monohydrate, was discovered and characterized. Upon polymorph screening, erythromycin A demonstrated high solvate-forming propensity thus emphasizing the need for careful control of the solvent effects during formulation. The solvent compositions that yield the desirable crystalline form of erythromycin A were defined. Furthermore, new examples on solvent-mediated phase transformations taking place during wet granulation of baclofen and hot-melt processing of erythromycin A dihydrate with PEG 6000 are reported. Since solvent-mediated phase transformations involve the crystallization of a stable phase and hence affect the dissolution kinetics and possibly absorption of the API these transformations must be well documented. Finally, a controlled-crystallization method utilizing HPMC as a crystal habit modifier was developed for erythromycin A dihydrate. The crystals with modified habit were shown to posses improved compaction properties as compared with those of unmodified crystals. This result supports the idea of morphological crystal engineering as a tool for designing technological properties of APIs and is of utmost practical interest.

Ultrasound-assisted surface engineering of pharmaceutical powders

Effective processing of powdered particles can facilitate powder handling and result in better drug product performance, which is of great importance in the pharmaceutical industry where the majority of active pharmaceutical ingredients (APIs) are delivered as solid dosage forms. The purpose of this work was to develop a new ultrasound-assisted method for particle surface modification and thin-coating of pharmaceutical powders. The ultrasound was used to produce an aqueous mist with or without a coating agent. By using the proposed technique, it was possible to decrease the interparticular interactions and improve rheological properties of poorly-flowing water-soluble powders by aqueous smoothing of the rough surfaces of irregular particles. In turn, hydrophilic polymer thin-coating of a hydrophobic substance diminished the triboelectrostatic charge transfer and improved the flowability of highly cohesive powder. To determine the coating efficiency of the technique, the bioactive molecule β-galactosidase was layered onto the surface of powdered lactose particles. Enzyme-treated materials were analysed by assaying the quantity of the reaction product generated during enzymatic cleavage of the milk sugar. A near-linear increase in the thickness of the drug layer was obtained during progressive treatment. Using the enzyme coating procedure, it was confirmed that the ultrasound-assisted technique is suitable for processing labile protein materials. In addition, this pre-treatment of milk sugar could be used to improve utilization of lactose-containing formulations for populations suffering from severe lactose intolerance. Furthermore, the applicability of the thin-coating technique for improving homogeneity of low-dose solid dosage forms was shown. The carrier particles coated with API gave rise to uniform distribution of the drug within the powder. The mixture remained homogeneous during further tabletting, whereas the reference physical powder mixture was subject to segregation. In conclusion, ultrasound-assisted surface engineering of pharmaceutical powders can be effective technology for improving formulation and performance of solid dosage forms such as dry powder inhalers (DPI) and direct compression products.

From Polymorph Screening to Dissolution Testing - Solid Phase Analysis during Pharmaceutical Development and Manufacturing

Solid materials can exist in different physical structures without a change in chemical composition. This phenomenon, known as polymorphism, has several implications on pharmaceutical development and manufacturing. Various solid forms of a drug can possess different physical and chemical properties, which may affect processing characteristics and stability, as well as the performance of a drug in the human body. Therefore, knowledge and control of the solid forms is fundamental to maintain safety and high quality of pharmaceuticals. During manufacture, harsh conditions can give rise to unexpected solid phase transformations and therefore change the behavior of the drug. Traditionally, pharmaceutical production has relied on time-consuming off-line analysis of production batches and finished products. This has led to poor understanding of processes and drug products. Therefore, new powerful methods that enable real time monitoring of pharmaceuticals during manufacturing processes are greatly needed. The aim of this thesis was to apply spectroscopic techniques to solid phase analysis within different stages of drug development and manufacturing, and thus, provide a molecular level insight into the behavior of active pharmaceutical ingredients (APIs) during processing. Applications to polymorph screening and different unit operations were developed and studied. A new approach to dissolution testing, which involves simultaneous measurement of drug concentration in the dissolution medium and in-situ solid phase analysis of the dissolving sample, was introduced and studied. Solid phase analysis was successfully performed during different stages, enabling a molecular level insight into the occurring phenomena. Near-infrared (NIR) spectroscopy was utilized in screening of polymorphs and processing-induced transformations (PITs). Polymorph screening was also studied with NIR and Raman spectroscopy in tandem. Quantitative solid phase analysis during fluidized bed drying was performed with in-line NIR and Raman spectroscopy and partial least squares (PLS) regression, and different dehydration mechanisms were studied using in-situ spectroscopy and partial least squares discriminant analysis (PLS-DA). In-situ solid phase analysis with Raman spectroscopy during dissolution testing enabled analysis of dissolution as a whole, and provided a scientific explanation for changes in the dissolution rate. It was concluded that the methods applied and studied provide better process understanding and knowledge of the drug products, and therefore, a way to achieve better quality.

Towards real-time understanding of processes in pharmaceutical powder technology

There is a need for better understanding of the processes and new ideas to develop traditional pharmaceutical powder manufacturing procedures. Process analytical technology (PAT) has been developed to improve understanding of the processes and establish methods to monitor and control processes. The interest is in maintaining and even improving the whole manufacturing process and the final products at real-time. Process understanding can be a foundation for innovation and continuous improvement in pharmaceutical development and manufacturing. New methods are craved for to increase the quality and safety of the final products faster and more efficiently than ever before. The real-time process monitoring demands tools, which enable fast and noninvasive measurements with sufficient accuracy. Traditional quality control methods have been laborious and time consuming and they are performed off line i.e. the analysis has been removed from process area. Vibrational spectroscopic methods are responding this challenge and their utilisation have increased a lot during the past few years. In addition, other methods such as colour analysis can be utilised in noninvasive real-time process monitoring. In this study three pharmaceutical processes were investigated: drying, mixing and tabletting. In addition tablet properties were evaluated. Real-time monitoring was performed with NIR and Raman spectroscopies, colour analysis, particle size analysis and compression data during tabletting was evaluated using mathematical modelling. These methods were suitable for real-time monitoring of pharmaceutical unit operations and increase the knowledge of the critical parameters in the processes and the phenomena occurring during operations. They can improve our process understanding and therefore, finally, enhance the quality of final products.

Investigating physical properties of solid dosage forms during pharmaceutical processing : Process analytical applications of vibrational spectroscopy

In order to improve and continuously develop the quality of pharmaceutical products, the process analytical technology (PAT) framework has been adopted by the US Food and Drug Administration. One of the aims of PAT is to identify critical process parameters and their effect on the quality of the final product. Real time analysis of the process data enables better control of the processes to obtain a high quality product. The main purpose of this work was to monitor crucial pharmaceutical unit operations (from blending to coating) and to examine the effect of processing on solid-state transformations and physical properties. The tools used were near-infrared (NIR) and Raman spectroscopy combined with multivariate data analysis, as well as X-ray powder diffraction (XRPD) and terahertz pulsed imaging (TPI). To detect process-induced transformations in active pharmaceutical ingredients (APIs), samples were taken after blending, granulation, extrusion, spheronisation, and drying. These samples were monitored by XRPD, Raman, and NIR spectroscopy showing hydrate formation in the case of theophylline and nitrofurantoin. For erythromycin dihydrate formation of the isomorphic dehydrate was critical. Thus, the main focus was on the drying process. NIR spectroscopy was applied in-line during a fluid-bed drying process. Multivariate data analysis (principal component analysis) enabled detection of the dehydrate formation at temperatures above 45°C. Furthermore, a small-scale rotating plate device was tested to provide an insight into film coating. The process was monitored using NIR spectroscopy. A calibration model, using partial least squares regression, was set up and applied to data obtained by in-line NIR measurements of a coating drum process. The predicted coating thickness agreed with the measured coating thickness. For investigating the quality of film coatings TPI was used to create a 3-D image of a coated tablet. With this technique it was possible to determine coating layer thickness, distribution, reproducibility, and uniformity. In addition, it was possible to localise defects of either the coating or the tablet. It can be concluded from this work that the applied techniques increased the understanding of physico-chemical properties of drugs and drug products during and after processing. They additionally provided useful information to improve and verify the quality of pharmaceutical dosage forms

Context-sensitive evaluation: Determining the context surrounding the implementation of a government policy

This article explains the essence of the context-sensitive parameters and dimensions in play at the time of an intervention, through the application of Rog’s (2012) model of contextual parameters. Rog’s model offers evaluators a structured approach to examine an intervention. The initial study provided a systematic way to clarify the scope, variables, timing, and appropriate evaluation methodology to evaluate the implementation of a government policy. Given that the government implementation of an educational intervention under study did not follow the experimental research approach, nor the double cycle of action research approach, the application of Rog’s model provided an in-depth understanding of the context-sensitive environment; it is from this clear purpose that the broader evaluation was conducted. Overall, when governments or institutions implement policy to invoke educational change (and this intervention is not guided by an appropriate evaluation approach), then program evaluation is achievable post-implementation. In this situation, Rog’s (2012) model of contextual parameters is a useful way to achieve clarity of purpose to guide the program evaluation.

Promoting articulated action from diverse stakeholders in response to public policy scenarios: A case analysis of the use of ‘scenario improvisation’ method

In this paper we present a novel application of scenario methods to engage a diverse constituency of senior stakeholders, with limited time availability, in debate to inform planning and policy development. Our case study project explores post-carbon futures for the Latrobe Valley region of the Australian state of Victoria. Our approach involved initial deductive development of two ‘extreme scenarios’ by a multi-disciplinary research team, based upon an extensive research programme. Over four workshops with the stakeholder constituency, these initial scenarios were discussed, challenged, refined and expanded through an inductive process, whereby participants took ‘ownership’ of a final set of three scenarios. These were both comfortable and challenging to them. The outcomes of this process subsequently informed public policy development for the region. Whilst this process did not follow a single extant structured, multi-stage scenario approach, neither was it devoid of form. Here, we seek to theorise and codify elements of our process – which we term ‘scenario improvisation’ – such that others may adopt it.

The impacts of policy change on collaborative governance networks

For many complex natural resources problems, planning and management efforts involve groups of organizations working collaboratively through networks (Agranoff, 2007; Booher & Innes, 2010). These networks sometimes involve formal roles and relationships, but often include informal elements (Edelenbos & Klijn, 2007). All of these roles and relationships undergo change in response to changes in personnel, priorities and policy. There has been considerable focus in the planning and public policy literature on describing and characterizing these networks (Mandell & Keast, 2008; Provan & Kenis, 2007). However, there has been far less research assessing how networks change and adjust in response to policy and political change. In the Australian state of Queensland, Natural Resource Management (NRM) organizations were created as lead organizations to address land and water management issues on a regional basis with Commonwealth funding and state support. In 2012, a change in state government signaled a dramatic change in policy that resulted in a significant reduction of state support and commitment. In response to this change, NRM organizations have had to adapt their networks and relationships. In this study, we examine the issues of network relationships, capacity and changing relationships over time using written surveys and focus groups with NRM CEOs, managers and planners (note: data collection events scheduled for March and April 2015). The research team will meet with each of these three groups separately, conduct an in-person survey followed by a facilitated focus group discussion. The NRM participant focus groups will also be subdivided by region, which correlates with capacity (inland/low capacity; coastal/high capacity). The findings focus on how changes in state government commitment have affected NRM networks and their relationships with state agencies. We also examine how these changes vary according to the level within the organization and the capacity of the organization. We hypothesize that: (1) NRM organizations have struggled to maintain capacity in the wake of state agency withdrawal of support; (2) NRM organizations with the lowest capacity have been most adversely affected, while some high capacity NRM organizations may have become more resilient as they have sought out other partners; (3) Network relationships at the highest levels of the organization have been affected the most by state policy change; (4) NRM relationships at the lowest levels of the organizations have changed the least, as formal relationships are replaced by informal networks and relationships.

The Politics of Adoption: International Perspectives on Law, Policy and Practice, Third edition

Adoption is a complex social phenomenon, intimately knitted into its family law framework and shaped by the pressures affecting the family in its local social context. It is a mirror reflecting the changes in our family life and the efforts of family law to address those changes. This has caused it to be variously defined in different societies in the same society, at different times and across a range of contemporary societies.

Copyright law and mash-ups: A policy paper

This report provides an analysis of the cultural, policy and legal implications of ‘mash-ups’. This study provides a short history of mash-ups, explaining how the current ‘remix culture’ builds upon a range of creative antecedents and cultural traditions, which valorised appropriation, quotation, and transformation. It provides modern examples of mash-ups, such as sound recordings, musical works, film and artistic works, focusing on works seen on You Tube and other online applications. In particular, it considers - * Literary mash-ups of canonical texts, including Pride and Prejudice and Zombies, The Wind Done Gone, After the Rain, and 60 Years Later; * Artistic mash-ups, highlighting the Obama Hope poster, the ‘Column’ case, and the competition for extending famous album covers; * Geographical mash-ups, most notably, the Google Australia bushfires map; * Musical mash-ups, such as The Grey Album and the work of Girl Talk; * Cinematic mash-ups, including remixes of There Will Be Blood and The Downfall; and This survey provides an analysis of why mash-up culture is valuable. It highlights the range of aesthetic, political, comic, and commercial impulses behind the creation and the dissemination of mash-ups. This report highlights the tensions between copyright law and mash-ups in particular cultural sectors. Second, this report emphasizes the importance of civil society institutions in promoting and defending mash-ups in both copyright litigation and policy debates. It provides a study of key organisations – including: * The Fair Use Project; * The Organization for Transformative Works; * Public Knowledge; * The Electronic Frontier Foundation; and * The Chilling Effects Clearinghouse This report suggests that much can be learnt from this network of organisations in the United States. There is a dearth of comparable legal clinics, advocacy groups, and creative institutions in Australia. As a result, the public interest values of copyright law have only received weak, incidental support from defendant companies – such as Network Ten and IceTV – with other copyright agendas. Third, this report canvasses a succinct model for legislative reform in respect of copyright law and mash-ups. It highlights: * The extent to which mash-ups are ‘tolerated uses’; * The conflicting judicial precedents on substantiality in Australia and the United States; * The debate over copyright exceptions relating to mash-ups and remixes; * The use of the take-down and notice system under the safe harbours regime by copyright owners in respect of mash-ups; * The impact of technological protection measures on mash-ups and remixes; * The possibility of statutory licensing in respect of mash-ups; * The use of Creative Commons licences; * The impact of moral rights protection upon mash-ups; * The interaction between economic and moral rights under copyright law; and * Questions of copyright law, freedom of expression, and political mash-ups.

Policy and Practice Brief: Representative Payment

This brief provides an overview of the Representative Payee program administered by Social Security. Discussed are the many provisions of the programs as well as practice tips and implications for BPA&O and PABSS personnel.

U.S. Asylum Policy and the New World Order

"In the new world order, differences in political ideology have given way to differences in economic conditions between nation states as the prompting force for the outflow of would-be refugees and asylum seekers. In part, these pressures are associated with the political disintegration of the poorer republics of the former Soviet Union and its former satellite nations into ethnic enclaves. But the most endemic of the new contributory pressures are emanating from North-South economic differences between the "have" and "have-not" nations."