Investigation of sweeping as a sample enrichment method in micellar electrokinetic chromatography in the analysis of pharmaceutical preparations and biological fluids

The present thesis deals with the study of sweeping as one of the most important sample preconcentration techniques in micellar electrokinetic chromatography (MEKC). The work includes the study of the fundamentals of sweeping as well as the application in the pharmaceutical field. The thesis is divided into four main parts. In the first part of the thesis, the processes involved in sweeping under homogeneous and under inhomogeneous electric field conditions are theoretically discussed. These processes include stacking or destacking of micelles when entering the sample zone, sweeping of analytes by the stacked or destacked micelles, and destacking or stacking of the swept analyte zone. A new robust and reliable method for the assessment of the sweeping efficiency is developed based on recording the peak height dependent on the injected sample volume. The values obtained via this method agree well with theoretically predicted ones. The results obtained show that the sweeping efficiency for neutral analytes is independent of the electric conductivity of the sample matrix. It is also shown that under specific conditions unexpectedly high enrichment factors are obtained which are attributed to the focusing of neutral analytes by micellar transient isotachophoresis. In the second part of the thesis, we extend our developed method for the assessment of sweeping efficiency to the general case, in which the distribution coefficient and the electric conductivity is varied in the sample and BGE compartments. It is shown that in the general case – in contrast to the classical description of sweeping – the obtainable enrichment factor is not only dependent on the retention factor of the analyte in the sample zone but also dependent on the retention factor in the BGE. An additional focusing/defocusing step is confirmed and the term “Retention factor gradient effect (RFGE)” is introduced. The validity of the derived equation is confirmed experimentally and theoretically under variation of the organic solvent content (in the sample and/or the BGE), the type of organic solvent (in the sample and/or the BGE), the electric conductivity (in the sample), the pH (in the sample), and the concentration of surfactant (in the BGE). In the third part of the thesis, the processes involved in sweeping in cyclodextrin-modified micellar electrokinetic chromatography (CD-MEKC) are theoretically discussed with a special focus on dynamic pH junction and adsorption of the analyte onto the capillary wall. Ethylparaben (pharmaceutical preservative) as an example of acidic analytes and desloratadine (antihistaminic drug) as an example of basic analytes are investigated using different types of ß-cyclodextrins. The presence of RFGE as an additional focusing/defocusing effect in sweeping-CD-MEKC is confirmed under the conditions of different content of cyclodextrin and different pH between the sample and the BGE. Desloratadine shows an unexpectedly low enrichment factor compared to the less hydrophobic ethylparaben. This unexpected behavior is ascribed to the strong adsorption of the protonated species of this drug onto the inner capillary wall in the sample zone that significantly counteracts the sweeping process. This effect is confirmed by the improvement in the enrichment factor achieved by the addition of a dynamic coating agent to the sample solution. In the fourth part of the thesis, a CD-MEKC method is developed for the simultaneous determination of the antihistaminic drugs loratadine and desloratadine (the major metabolite and an impurity of loratadine). The tendency of these drugs, as hydrophobic basic analytes, to be adsorbed onto the inner capillary wall and the difficulty to separate them due to the extremely high retention factors make the present study challenging. The use of a low pH sample solution overcome problems associated with the low solubility of the studied analytes in aqueous solution while having advantages with regard to online focusing. In addition, the use of a basic BGE and the presence of cyclodextrin reduce the adsorption of these analytes in the separation compartment. The separation is achieved in less than 7 min using a BGE consisting of 10 mmol L-1 sodium borate buffer, pH 9.30 containing 40 mmol L-1 SDS and 20 mmol L-1 hydroxypropyl-β-CD while the sample solution is composed of 10 mmol L-1 phosphoric acid, pH 2.15. All validation parameters are thoroughly investigated. The developed method is successfully applied to the analysis of the studied drugs in tablets and in spiked human urine. Moreover, desloratadine is detected at the stated pharmacopeial limit (0.1%) as an impurity in loratadine bulk powder. The obtained results are compared with those of the official liquid chromatographic method and are found in a good agreement

A greedy heuristic approach for the project scheduling with labour allocation problem

Responding to the growing need of generating a robust project scheduling, in this article we present a greedy algorithm to generate the project baseline schedule. The robustness achieved by integrating two dimensions of the human resources flexibilities. The first is the operators’ polyvalence, i.e. each operator has one or more secondary skill(s) beside his principal one, his mastering level being characterized by a factor we call “efficiency”. The second refers to the working time modulation, i.e. the workers have a flexible time-table that may vary on a daily or weekly basis respecting annualized working strategy. Moreover, the activity processing time is a non-increasing function of the number of workforce allocated to create it, also of their heterogynous working efficiencies. This modelling approach has led to a nonlinear optimization model with mixed variables. We present: the problem under study, the greedy algorithm used to solve it, and then results in comparison with those of the genetic algorithms

Flexible resources allocation techniques: characteristics and modelling

At the interface between engineering, economics, social sciences and humanities, industrial engineering aims to provide answers to various sectors of business problems. One of these problems is the adjustment between the workload needed by the work to be realised and the availability of the company resources. The objective of this work is to help to find a methodology for the allocation of flexible human resources in industrial activities planning and scheduling. This model takes into account two levers of flexibility, one related to the working time modulation, and the other to the varieties of tasks that can be performed by a given resource (multi–skilled actor). On the one hand, multi–skilled actors will help to guide the various choices of the allocation to appreciate the impact of these choices on the tasks durations. On the other hand, the working time modulation that allows actors to have a work planning varying according to the workload which the company has to face

Decision-based genetic algorithms for solving multi-period project scheduling with dynamically experienced workforce

The importance of the flexibility of resources increased rapidly with the turbulent changes in the industrial context, to meet the customers’ requirements. Among all resources, the most important and considered as the hardest to manage are human resources, in reasons of availability and/or conventions. In this article, we present an approach to solve project scheduling with multi-period human resources allocation taking into account two flexibility levers. The first is the annual hours and working time regulation, and the second is the actors’ multi-skills. The productivity of each operator was considered as dynamic, developing or degrading depending on the prior allocation decisions. The solving approach mainly uses decision-based genetic algorithms, in which, chromosomes don’t represent directly the problem solution; they simply present three decisions: tasks’ priorities for execution, actors’ priorities for carrying out these tasks, and finally the priority of working time strategy that can be considered during the specified working period. Also the principle of critical skill was taken into account. Based on these decisions and during a serial scheduling generating scheme, one can in a sequential manner introduce the project scheduling and the corresponding workforce allocations

Effect of Essential Oils on Storability and Preservation of Some Vegetable Crops

Essential oils, as natural sprout inhibitor and safe fungicides, are a promising tool and good alternative compounds otherwise synthetic due to their high efficacy, biodegradability, eco-safety and volatile nature. They are consisting of a number of various components, i.e., terpenes, phenols, alcohols, esters, aldehydes and ketones in different composition or combinations. These effective compounds supply excess to prevent sprouting in potatoes and Jerusalem artichoke (JA) and less chance to development of resistance in fungi in JA, strawberry and broccoli with low concentrations. On contrary, high concentration of these oils induce the germination of seeds like broccoli and carob. This chapter explains the practical application of using essential oils as natural antisprouting, inducing quality, preserving fungal diseases, eco-friendly compounds, alternating synthetic chemicals, giving high benefits and easy to apply. The foliar application with essential oils increases the productivity, quality and marketable yield and storability and reduces weight losses and decay. Moreover, the essential oils increase broccoli seed germination, antioxidant content and other phytochemical parameters. The chapter provides a novel anti-sprouting agent for inhibiting growth of processing potato tubers and identification of terpenoids that use to inhibit tuber sprouting as well as application of Chloropropham (CIPC) isopropyl-N-(3-chlorophenyl) carbamate as a conventional chemical inhibitor

Prise en compte de la flexibilité des ressources humaines dans la planification et l’ordonnancement des activités industrielles

Le besoin croissant de réactivité dans les différents secteurs industriels face à la volatilité des marchés soulève une forte demande de la flexibilité dans leur organisation. Cette flexibilité peut être utilisée pour améliorer la robustesse du planning de référence d’un programme d’activités donné. Les ressources humaines de l’entreprise étant de plus en plus considérées comme le coeur des structures organisationnelles, elles représentent une source de flexibilité renouvelable et viable. Tout d’abord, ce travail a été mis en oeuvre pour modéliser le problème d’affectation multi-périodes des effectifs sur les activités industrielles en considérant deux dimensions de la flexibilité: L’annualisation du temps de travail, qui concerne les politiques de modulation d’horaires, individuels ou collectifs, et la polyvalence des opérateurs, qui induit une vision dynamique de leurs compétences et la nécessité de prévoir les évolutions des performances individuelles en fonction des affectations successives. La nature dynamique de l’efficacité des effectifs a été modélisée en fonction de l’apprentissage par la pratique et de la perte de compétence pendant les périodes d’interruption du travail. En conséquence, nous sommes résolument placés dans un contexte où la durée prévue des activités n’est plus déterministe, mais résulte du nombre des acteurs choisis pour les exécuter, en plus des niveaux de leur expérience. Ensuite, la recherche a été orientée pour répondre à la question : « quelle genre, ou quelle taille, de problème pose le projet que nous devons planifier? ». Par conséquent, les différentes dimensions du problème posé sont classées et analysés pour être évaluées et mesurées. Pour chaque dimension, la méthode d’évaluation la plus pertinente a été proposée : le travail a ensuite consisté à réduire les paramètres résultants en composantes principales en procédant à une analyse factorielle. En résultat, la complexité (ou la simplicité) de la recherche de solution (c’est-à-dire de l’élaboration d’un planning satisfaisant pour un problème donné) peut être évaluée. Pour ce faire, nous avons développé une plate-forme logicielle destinée à résoudre le problème et construire le planning de référence du projet avec l’affectation des ressources associées, plate-forme basée sur les algorithmes génétiques. Le modèle a été validé, et ses paramètres ont été affinés via des plans d’expériences pour garantir la meilleure performance. De plus, la robustesse de ces performances a été étudiée sur la résolution complète d’un échantillon de quatre cents projets, classés selon le nombre de leurs tâches. En raison de l’aspect dynamique de l’efficacité des opérateurs, le présent travail examine un ensemble de facteurs qui influencent le développement de leur polyvalence. Les résultats concluent logiquement qu’une entreprise en quête de flexibilité doit accepter des coûts supplémentaires pour développer la polyvalence de ses opérateurs. Afin de maîtriser ces surcoûts, le nombre des opérateurs qui suivent un programme de développement des compétences doit être optimisé, ainsi que, pour chacun d’eux, le degré de ressemblance entre les nouvelles compétences développées et les compétences initiales, ou le nombre de ces compétences complémentaires (toujours pour chacun d’eux), ainsi enfin que la façon dont les heures de travail des opérateurs doivent être réparties sur la période d’acquisition des compétences. Enfin, ce travail ouvre la porte pour la prise en compte future des facteurs humains et de la flexibilité des effectifs pendant l’élaboration d’un planning de référence. ABSTRACT : The growing need of responsiveness for manufacturing companies facing the market volatility raises a strong demand for flexibility in their organization. This flexibility can be used to enhance the robustness of a baseline schedule for a given programme of activities. Since the company personnel are increasingly seen as the core of the organizational structures, they provide the decision-makers with a source of renewable and viable flexibility. First, this work was implemented to model the problem of multi-period workforce allocation on industrial activities with two degrees of flexibility: the annualizing of the working time, which offers opportunities of changing the schedules, individually as well as collectively. The second degree of flexibility is the versatility of operators, which induces a dynamic view of their skills and the need to predict changes in individual performances as a result of successive assignments. The dynamic nature of workforce’s experience was modelled in function of learning-by-doing and of oblivion phenomenon during the work interruption periods. We firmly set ourselves in a context where the expected durations of activities are no longer deterministic, but result from the number and levels of experience of the workers assigned to perform them. After that, the research was oriented to answer the question “What kind of problem is raises the project we are facing to schedule?”: therefore the different dimensions of the project are inventoried and analysed to be measured. For each of these dimensions, the related sensitive assessment methods have been proposed. Relying on the produced correlated measures, the research proposes to aggregate them through a factor analysis in order to produce the main principal components of an instance. Consequently, the complexity or the easiness of solving or realising a given scheduling problem can be evaluated. In that view, we developed a platform software to solve the problem and construct the project baseline schedule with the associated resources allocation. This platform relies on a genetic algorithm. The model has been validated, moreover, its parameters has been tuned to give the best performance, relying on an experimental design procedure. The robustness of its performance was also investigated, by a comprehensive solving of four hundred instances of projects, ranked according to the number of their tasks. Due to the dynamic aspect of the workforce’s experience, this research work investigates a set of different parameters affecting the development of their versatility. The results recommend that the firms seeking for flexibility should accept an amount of extra cost to develop the operators’ multi functionality. In order to control these over-costs, the number of operators who attend a skill development program should be optimised, as well as the similarity of the new developed skills relative to the principal ones, or the number of the additional skills an operator may be trained to, or finally the way the operators’ working hours should be distributed along the period of skill acquisition: this is the field of investigations of the present work which will, in the end, open the door for considering human factors and workforce’s flexibility in generating a work baseline program

Resistance to Direct-Acting Antiviral Agents in Treatment of Hepatitis C Virus Infections

Compounds targeting nonstructural (NS) proteins of hepatitis C virus (HCV) demonstrate clinical promise, suggesting that NS3/NS4a, NS5A, or NS5B inhibitors are potential components in direct-acting antiviral (DAA) combination therapies. In vitro studies revealed dramatic inhibition of viral replication or alteration in subcellular localization of NS proteins. DAAs bind either to catalytic sites (NS3 and NS5B) or to domain-1 of NS5A. Although >90% of the patients clear HCV RNA from their sera, a significant portion of cirrhotic patients suffer from resistance or virological relapse. Mutations in specific residues (Q80K) in NS3 (M28, A30, L31, and Y93 in genotypes 1a and 1b or L28, L30, M31, and Y93 in genotype 4) in NS5A and A282T in NS5B are associated with resistance to DAA [resistance-associated variants (RAVs)]. Current knowledge on the NS functions, mode of action of DAAs, and impacts of RAVs on treatment response are discussed. Not only mutations affecting the binding of DAAs to target proteins but also substitutions affecting the replication fitness of mutant quasispecies are major determinants of treatment failures. These resistance-associated substitutions (RASs) are now considered the major viral mutants that influence the virological outcome after DAA treatment