Application and use of isothermal calorimetry in pharmaceutical development

There are many steps involved in developing a drug candidate into a formulated medicine and many involve analysis of chemical interaction or physical change. Calorimetry is particularly suited to such analyses as it offers the capacity to observe and quantify both chemical and physical changes in virtually any sample. Differential scanning calorimetry (DSC) is ubiquitous in pharmaceutical development, but the related technique of isothermal calorimetry (IC) is complementary and can be used to investigate a range of processes not amenable to analysis by DSC. Typically, IC is used for longer-term stability indicating or excipient compatibility assays because both the temperature and relative humidity (RH) in the sample ampoule can be controlled. However, instrument design and configuration, such as titration, gas perfusion or ampoule-breaking (solution) calorimetry, allow quantification of more specific values, such as binding enthalpies, heats of solution and quantification of amorphous content. As ever, instrument selection, experiment design and sample preparation are critical to ensuring the relevance of any data recorded. This article reviews the use of isothermal, titration, gas-perfusion and solution calorimetry in the context of pharmaceutical development, with a focus on instrument and experimental design factors, highlighted with examples from the recent literature. © 2011 Elsevier B.V.

Data methods in optometry Part 9: experimental design and analysis of variance

The key to the correct application of ANOVA is careful experimental design and matching the correct analysis to that design. The following points should therefore, be considered before designing any experiment: 1. In a single factor design, ensure that the factor is identified as a 'fixed' or 'random effect' factor. 2. In more complex designs, with more than one factor, there may be a mixture of fixed and random effect factors present, so ensure that each factor is clearly identified. 3. Where replicates can be grouped or blocked, the advantages of a randomised blocks design should be considered. There should be evidence, however, that blocking can sufficiently reduce the error variation to counter the loss of DF compared with a randomised design. 4. Where different treatments are applied sequentially to a patient, the advantages of a three-way design in which the different orders of the treatments are included as an 'effect' should be considered. 5. Combining different factors to make a more efficient experiment and to measure possible factor interactions should always be considered. 6. The effect of 'internal replication' should be taken into account in a factorial design in deciding the number of replications to be used. Where possible, each error term of the ANOVA should have at least 15 DF. 7. Consider carefully whether a particular factorial design can be considered to be a split-plot or a repeated measures design. If such a design is appropriate, consider how to continue the analysis bearing in mind the problem of using post hoc tests in this situation.

Problem solving in architectural design

This thesis is presented in two parts. The first part is an attempt to set out a framework of factors influencing the problem solving stage of the architectural design process. The discussion covers the nature of architectural problems and some of the main ways in which they differ from other types of design problems. The structure of constraints that both the problem and the architect impose upon solutions are seen as of great importance in defining the type of design problem solving situation. The problem solver, or architect, is then studied. The literature of the psychology of thinking is surveyed for relevant work . All of the traditional schools of psychology are found wanting in terms of providing a comprehensive theory of thinking. Various types of thinking are examined, particularly structural and productive thought, for their relevance to design problem solving. Finally some reported common traits of architects are briefly reviewed. The second section is a report of u~o main experiments which model some aspects of architectural design problem solving. The first experiment examines the way in which architects come to understand the structure of their problems. The performances of first and final year architectural students are compared with those of postgraduate science students and sixth form pupils. On the whole these groups show significantly different results and also different cognitive strategies. The second experiment poses design problems which involve both subjective and objective criteria, and examines the way in which final year architectural students are able to relate the different types of constraint produced. In the final section the significance of all the results is suggested. Some educational and methodological implications are discussed and some further experiments and investigations are proposed.

Structural behaviour and design of load-bearing falsework

Tne object of this research was to investigate the behaviour of birdcage scaffolding as used in falsework structures, assess the suitability of existing design methods and make recommendations for a set of design rules. Since excessive deflection is as undesirable in a structure as total collapse, the project was divided into two sections. These were to determine the ultimate vertical and horizontal load-carrying capacity and also the deflection characteristics of any falsework. So theoretical analyses were developed to ascertain the ability of both the individual standards to resist vertical load, and of the bracing to resist horizontal load.Furthermore a model was evolved which would predict the horizontal deflection of a scaffold under load using strain energy methods. These models were checked by three series of experiments. The first was on individual standards under vertical load only. The second series was carried out on full scale falsework structures loading vertically and horizontally to failure. Finally experiments were conducted on scaffold couplers to provide additional verification of the method of predicting deflections. This thesis gives the history of the project and an introduction into the field of scaffolding. It details both the experiments conducted and the theories developed and the correlation between theory and experiment. Finally it makes recommendations for a design method to be employed by scaffolding designers.

The implementation of a design of experiments strategy to increase recombinant protein yields in yeast (review)

Biological processes are subject to the influence of numerous factors and their interactions, which may be non-linear in nature. In a recombinant protein production experiment, understanding the relative importance of these factors, and their influence on the yield and quality of the recombinant protein being produced, is an essential part of its optimisation. In many cases, implementing a design of experiments (DoE) approach has delivered this understanding. This chapter aims to provide the reader with useful pointers in applying a DoE strategy to improve the yields of recombinant yeast cultures.

Does reviewing lead to better learning and decision making? Answers from a randomized stock market experiment

Background - The literature is not univocal about the effects of Peer Review (PR) within the context of constructivist learning. Due to the predominant focus on using PR as an assessment tool, rather than a constructivist learning activity, and because most studies implicitly assume that the benefits of PR are limited to the reviewee, little is known about the effects upon students who are required to review their peers. Much of the theoretical debate in the literature is focused on explaining how and why constructivist learning is beneficial. At the same time these discussions are marked by an underlying presupposition of a causal relationship between reviewing and deep learning. Objectives - The purpose of the study is to investigate whether the writing of PR feedback causes students to benefit in terms of: perceived utility about statistics, actual use of statistics, better understanding of statistical concepts and associated methods, changed attitudes towards market risks, and outcomes of decisions that were made. Methods - We conducted a randomized experiment, assigning students randomly to receive PR or non–PR treatments and used two cohorts with a different time span. The paper discusses the experimental design and all the software components that we used to support the learning process: Reproducible Computing technology which allows students to reproduce or re–use statistical results from peers, Collaborative PR, and an AI–enhanced Stock Market Engine. Results - The results establish that the writing of PR feedback messages causes students to experience benefits in terms of Behavior, Non–Rote Learning, and Attitudes, provided the sequence of PR activities are maintained for a period that is sufficiently long.

The implementation of a design of experiments strategy to increase recombinant protein yields in yeast (review)

Biological processes are subject to the influence of numerous factors and their interactions, which may be non-linear in nature. In a recombinant protein production experiment, understanding the relative importance of these factors, and their influence on the yield and quality of the recombinant protein being produced, is an essential part of its optimisation. In many cases, implementing a design of experiments (DoE) approach has delivered this understanding. This chapter aims to provide the reader with useful pointers in applying a DoE strategy to improve the yields of recombinant yeast cultures.

Analysis and design of power management scheme for an on-board solar energy storage system

This paper investigates the power management issues in a mobile solar energy storage system. A multi-converter based energy storage system is proposed, in which solar power is the primary source while the grid or the diesel generator is selected as the secondary source. The existence of the secondary source facilitates the battery state of charge detection by providing a constant battery charging current. Converter modeling, multi-converter control system design, digital implementation and experimental verification are introduced and discussed in details. The prototype experiment indicates that the converter system can provide a constant charging current during solar converter maximum power tracking operation, especially during large solar power output variation, which proves the feasibility of the proposed design. © 2014 IEEE.

Uniform design for the optimization of Al2O3 nanofilms produced by electrophoretic deposition

Surface modification by means of nanostructures is of interest to enhance boiling heat transfer in various applications including the organic Rankine cycle (ORC). With the goal of obtaining rough and dense aluminum oxide (Al2O3) nanofilms, the optimal combination of process parameters for electrophoretic deposition (EPD) based on the uniform design (UD) method is explored in this paper. The detailed procedures for the EPD process and UD method are presented. Four main influencing conditions controlling the EPD process were identified as nanofluid concentration, deposition time, applied voltage and suspension pH. A series of tests were carried out based on the UD experimental design. A regression model and statistical analysis were applied to the results. Sensitivity analyses of the effect of the four main parameters on the roughness and deposited mass of Al2O3 films were also carried out. The results showed that Al2O3 nanofilms were deposited compactly and uniformly on the substrate. Within the range of the experiments, the preferred combination of process parameters was determined to be nanofluid concentration of 2 wt.%, deposition time of 15 min, applied voltage of 23 V and suspension pH of 3, yielding roughness and deposited mass of 520.9 nm and 161.6 × 10− 4 g/cm2, respectively. A verification experiment was carried out at these conditions and gave values of roughness and deposited mass within 8% error of the expected ones as determined from the UD approach. It is concluded that uniform design is useful for the optimization of electrophoretic deposition requiring only 7 tests compared to 49 using the orthogonal design method.

Nanotechnology and microfluidics:formulation design and on-chip manufacture of nanoparticles

Nanoparticles offer an ideal platform for the delivery of small molecule drugs, subunit vaccines and genetic constructs. Besides the necessity of a homogenous size distribution, defined loading efficiencies and reasonable production and development costs, one of the major bottlenecks in translating nanoparticles into clinical application is the need for rapid, robust and reproducible development techniques. Within this thesis, microfluidic methods were investigated for the manufacturing, drug or protein loading and purification of pharmaceutically relevant nanoparticles. Initially, methods to prepare small liposomes were evaluated and compared to a microfluidics-directed nanoprecipitation method. To support the implementation of statistical process control, design of experiment models aided the process robustness and validation for the methods investigated and gave an initial overview of the size ranges obtainable in each method whilst evaluating advantages and disadvantages of each method. The lab-on-a-chip system resulted in a high-throughput vesicle manufacturing, enabling a rapid process and a high degree of process control. To further investigate this method, cationic low transition temperature lipids, cationic bola-amphiphiles with delocalized charge centers, neutral lipids and polymers were used in the microfluidics-directed nanoprecipitation method to formulate vesicles. Whereas the total flow rate (TFR) and the ratio of solvent to aqueous stream (flow rate ratio, FRR) was shown to be influential for controlling the vesicle size in high transition temperature lipids, the factor FRR was found the most influential factor controlling the size of vesicles consisting of low transition temperature lipids and polymer-based nanoparticles. The biological activity of the resulting constructs was confirmed by an invitro transfection of pDNA constructs using cationic nanoprecipitated vesicles. Design of experiments and multivariate data analysis revealed the mathematical relationship and significance of the factors TFR and FRR in the microfluidics process to the liposome size, polydispersity and transfection efficiency. Multivariate tools were used to cluster and predict specific in-vivo immune responses dependent on key liposome adjuvant characteristics upon delivery a tuberculosis antigen in a vaccine candidate. The addition of a low solubility model drug (propofol) in the nanoprecipitation method resulted in a significantly higher solubilisation of the drug within the liposomal bilayer, compared to the control method. The microfluidics method underwent scale-up work by increasing the channel diameter and parallelisation of the mixers in a planar way, resulting in an overall 40-fold increase in throughput. Furthermore, microfluidic tools were developed based on a microfluidics-directed tangential flow filtration, which allowed for a continuous manufacturing, purification and concentration of liposomal drug products.