Predicting Skin Permeability by means of Computational Approaches : Reliability and Caveats in Pharmaceutical Studies

© 2019 American Chemical Society.The skin is the main barrier between the internal body environment and the external one. The characteristics of this barrier and its properties are able to modify and affect drug delivery and chemical toxicity parameters. Therefore, it is not surprising that permeability of many different compounds has been measured through several in vitro and in vivo techniques. Moreover, many different in silico approaches have been used to identify the correlation between the structure of the permeants and their permeability, to reproduce the skin behavior, and to predict the ability of specific chemicals to permeate this barrier. A significant number of issues, like interlaboratory variability, experimental conditions, data set building rationales, and skin site of origin and hydration, still prevent us from obtaining a definitive predictive skin permeability model. This review wants to show the main advances and the principal approaches in computational methods used to predict this property, to enlighten the main issues that have arisen, and to address the challenges to develop in future research.Peer reviewedFinal Accepted Versio

Kinetic model construction using chemoinformatics

Kinetic models of chemical processes not only provide an alternative to costly experiments; they also have the potential to accelerate the pace of innovation in developing new chemical processes or in improving existing ones. Kinetic models are most powerful when they reflect the underlying chemistry by incorporating elementary pathways between individual molecules. The downside of this high level of detail is that the complexity and size of the models also steadily increase, such that the models eventually become too difficult to be manually constructed. Instead, computers are programmed to automate the construction of these models, and make use of graph theory to translate chemical entities such as molecules and reactions into computer-understandable representations. This work studies the use of automated methods to construct kinetic models. More particularly, the need to account for the three-dimensional arrangement of atoms in molecules and reactions of kinetic models is investigated and illustrated by two case studies. First of all, the thermal rearrangement of two monoterpenoids, cis- and trans-2-pinanol, is studied. A kinetic model that accounts for the differences in reactivity and selectivity of both pinanol diastereomers is proposed. Secondly, a kinetic model for the pyrolysis of the fuel “JP-10” is constructed and highlights the use of state-of-the-art techniques for the automated estimation of thermochemistry of polycyclic molecules. A new code is developed for the automated construction of kinetic models and takes advantage of the advances made in the field of chemo-informatics to tackle fundamental issues of previous approaches. Novel algorithms are developed for three important aspects of automated construction of kinetic models: the estimation of symmetry of molecules and reactions, the incorporation of stereochemistry in kinetic models, and the estimation of thermochemical and kinetic data using scalable structure-property methods. Finally, the application of the code is illustrated by the automated construction of a kinetic model for alkylsulfide pyrolysis

Unified modelling of aerospace systems: a bond graph approach

Systems Integration is widely accepted as the basis for improving the efficiency and performance of many engineering products. The aim is to build a unified optimised system not a collection of subsystems that are combined in some ad hoc manner. This moves traditional design boundaries and, in so doing, enables a structured evolution from an integrated system concept to an integrated system product. It is recognised that the inherent complexity cannot be handled effectively without mathematical modelling. The problem is not so much the large number of components but rather the very large number of functional interfaces that result. The costs involved are high and, if the claims of improved efficiency and performance are to be affordable (or even achievable), predictive modelling and analysis will play a major role in reducing risk. A modelling framework is required which can support integrated system development from concept through to certification. This means building a 'system' inside a computer and demonstrating the feasibility of an entire development cycle. The objective is to provide complete coverage of system functionality so as to gain confidence in the design before becoming locked into a full development programme with associated capital investment and contractual arrangements. With these points in mind the purpose of this thesis is threefold. First, to demonstrate the application of bond graphs as a unified modelling framework for aerospace systems. Second, to review the main principles involved with the modelling of engineering systems and to justify the selection of the bond graph notation as a suitable means of representing the power flow (i.e. the dynamics) of physical systems. Third, to present an exposition of the bond graph method and to evolve it into a versatile notation for integrated systems. The originality of the work is based on the recognition that systems integration is a relatively new field of interest without a mature body of academic literature or reported research. Apparently, there is no open literature on the modelling of complete air vehicles plus their embedded vehicle systems which deals with issues of integrated dynamics and control. To this end, bond graph concepts need to be developed and extended in new direction in order to facilitate an intuitive approach to the modelling of integrated systems

Hierarchial hydrogen storage in clathrates of Ammonia Borane. Theoretical study

A brief overview of the dissertation given in this abstract is divided into five points showing its topicality, objective, goals, scientific novelty, and practical significance. The topicality is reflected in a need for the replacement of the fossil fuels driven economy with economy oriented towards renewable sources of energy, in which hydrogen is used as an energy carrier. This need is dictated by three reasons: (i) ecological problems mostly induced by the carbon dioxide emission; (ii) limitedness of the reserves of hydrocarbons; (iii) political issues related to the localization of hydrocarbons in few places around the globe. In any implementation of hydrogen economy, which is a possible cure for the mentioned issues, the production and storage of hydrogen are the most challenging tasks to solve. The dissertation is focused on the problem of hydrogen storage. For today, none of the known materials meets all the requirements imposed on practical on-board hydrogen storage media. The main idea proposed and explored in this dissertation is the "hierarchical storage of hydrogen". We envisage materials that would offer various means of reversible hydrogen binding. Each level of hydrogen storage would have different characteristics that become advantageous in different circumstances. A material with hierarchical hydrogen storage could be superior in comparison with conventional materials, in which hydrogen is bound at one level only. In particular, we explore materials in which a fraction of hydrogen is physically bound and the remaining part is chemically bound. The physical binding provides hydrogen that is kinetically easily accessible, whereas the chemical binding assures a high overall hydrogen density. We suggest that hydrogen clathrates of a high hydrogen content material, like ammonia borane, could serve as models of hierarchical hydrogen storage. An objective of the dissertation is thus to validate the possibility of storage of molecular hydrogen in clathrates of ammonia borane using methods of theoretical chemistry and materials science. The goals of the dissertation can be formulated as follows: (i) to identify possible structures of clathrates of ammonia borane; (ii) to estimate hydrogen capacity of the clathrates; (iii) to estimate pressure-temperature regimes required for the stabilization of these clathrates. The scientific novelty of the dissertation includes: (i) formulation of the "hierarchical hydrogen storage" concept; (ii) formulation of construction principles for clathrates of ammonia borane and identification of their possible structures; (iii) estimation of hydrogen capacity of the clathrates; (iv) development of a model of clathrates phase equilibria, which is based on the energy of intermolecular host-guest interactions and the entropy of guest molecules enclosed in clathrate cages; (v) an estimation of the pressure-temperature stability zone for these clathrates. The practical significance of the dissertation is in justification of further experimental works on clathrates of ammonia borane, for which the required stabilization pressure and temperature conditions are determined. The work proposed and thoroughly explored hierarchical method of hydrogen storage and resulted in identification of stable cages and periodic structures of possible clathrates of ammonia borane. The most stable extended system of these clathrates was found to be more stable than molecular crystal of ammonia borane at low temperatures. Hydrogen capacity of this hypothetical clathrate structure was estimated to be 21 wt%. To predict the pressure-temperature stability zone of the material a model of clathrate phase equilibria has been formulated and tested on known hydrates. The model showed that clathrates of ammonia borane could be stabilized at ambient pressure when temperature is lowered to 77 K

Evaluation of VOC Degradation in Photo-Catalytic Air Reactors: TiO2 Immobilization, Energy Efficiency and Kinetic Modeling

The high VOC emissions from anthropogenic sources are detrimental to both the environment and humans, contributing with ground-level ozone and particle matter formation. Heterogeneous photocatalysis provides significant potential for VOC degradation. However, the approaches to be used for photocatalyst immobilization in scaled and highly efficient photoreactors are still not well established. Furthermore, there is a lack of reported photonic efficiencies and a shortage of required methods to establish these efficiencies. To address these issues, this PhD Dissertation reports the study of photonic efficiencies, TiO2 immobilization on a stainless steel mesh and kinetic models in a scaled-up Photo-CREC-Air Reactor. Acetone and acetaldehyde are considered with a 25-320 initial concentration range. The irradiation field is experimentally evaluated in order to estimate the photon absorption on the TiO2 film through macroscopic balances. Quantum Yields (QYs) and Photochemical Thermodynamic Efficiency Factors (PTEFs) are also established. TiO2 coatings are prepared using two methods: an Air Assisted Spray with an Automatized Spinning Coating (TiO2-AAS-ASC) and a Spread Coating (TiO2-SCM). TiO2-AAS-ASC shows a more efficient use of the photocatalyst than the TiO2-SCM, and also displays homogeneity, limited particle agglomeration and stability under flow. Moreover, the TiO2-AAS-ASC shows a high degree of photonic energy utilization. A series-parallel Langmuir-Hinshelwood based kinetic model describes the photodegradation of acetone and acetaldehyde data well with a 0.97-0.98 range correlation coefficient. It is believed that altogether the approach reported in the present PhD Dissertation contributes to clarify key engineering issues of significant value for the scale-up of photocatalytic reactors for air treatment

Computer-Aided Sustainable Process Synthesis-Design and Analysis

Processyntese involverer undersøgelse af kemiske reaktioner, der er nødvendige for at producere det ønskede produkt, udvælgelse af separationsteknikker nødvendige for downstream forarbejdning, samt beslutninger om sekvensering af de involverede separationsprocesser. For en effektiv og fleksibel designtilgang, er der behov for en systematisk måde at identificere de typer af opgaver og operationer, der skal udføres, den tilsvarende design af operation-udstyr, deres konfiguration, masse-energistrømme m.v., hvilket giver et optimalt processkema. På grund af det faktum, at processynteseproblemer er af natur kombinatoriske og med flere mulige løsninger, er der blevet foreslået en forskellige metoder til at overkomme dette. Men løsningen til ethvert syntese-design problem er afhængig af søgningsområdet af alternativer og kriterierne for procesydeevne, som i de fleste tilfælde er påvirket af økonomiske faktorer. Dette arbejde fokuserer på udvikling og anvendelse af et computerstøttet platform for bæredygtig syntese-design og analyse af processkemaer ved at generere mulige alternativer, der dækker hele søgningsområdet og omfatter analyseværktøjer for bæredygtighed, LCA og økonomi. Syntesemetoden er baseret på en gruppebidragsbaseret hybridmetode, hvor kemisk processkemaer syntetiseres på samme måde som atomer eller grupper af atomer syntetiseres til dannelse af molekyler i computerstøttet molekylært design (eng: CAMD) teknikker. Byggestenene i et processkemasyntese problem er betegnet som procesgrupper, som repræsenterer en enkelt eller et sæt af enhedsoperationer, der er udvalgt på metoder baseret på termodynamiske grundlag. Disse byggesten kombineres derefter under anvendelse af regler for tilslutningsmuligheder for at generere alle de mulige processkemaalternativer. Den største fordel ved at repræsentere processkemaer med procesgrupper er, at udførelsen af hele processen kan vurderes fra bidragene fra de enkelte procestrinsgrupper mod processkemaegenskaberne (f.eks forbrugt energi). De udviklede processkemaegenskabsmodeller omfatter energiforbrug, carbon footprint, produktudvinding, produktrenhed osv. På denne måde er hele listen over mulige kemiske processkemaer hurtigt genereret, screenet og udvalgt til yderligere analyse. I det næste trin, er udformningen af de mest lovende processkemakandidater udført gennem en omvendt simulationsmetode, hvor designparametre for enhedsoperationer i processkemaet er beregnet ud fra udvalgte definitioner af procesgrupper. I næste fase analyseres det valgte design, til at identificere begrænsninger eller flaskehalse (hot-spots) ved hjælp af en omfattende analysemetode bestående af økonomiske, livscyklus og bæredygtigheds faktorer, der omsættes til procesdesignmål. I den afsluttende fase identificeres hot-spotsne, som er målrettet til den samlede procesforbedring og til at skabe innovative designs. I dette arbejde er den udviklede platform testet sammen med de tilhørende metoder og værktøjer gennem tre casestudier med relation til både kemiske og biokemiske industri med henblik på at fastslå anvendelsesmulighederne af platformen. I hvert af tilfældene er de mange alternativer og litteraturdesignene hurtigt genereret og evalueret. I alle de testede casestudier var de endelige designs, der genereres af platformen, nye og mere bæredygtige.Process synthesis involves the investigation of chemical reactions needed to produce the desired product, selection of the separation techniques needed for downstream processing, as well as taking decisions on sequencing the involved separation operations. For an effective, efficient and flexible design approach, what is needed is a systematic way to identify the types of tasks-operations that need to be performed, the corresponding design of the operation-equipment, their configuration, mass-energy flows, etc., giving an optimal flowsheet. Due to the fact that process synthesis problems are by nature combinatorial and open ended, a number of different solution approaches have been proposed. However the solution for any synthesis-design problem is dependent on the search space of alternatives and the process performance criteria which in most cases are influenced by economic factors. This work focuses on the development and application of a computer-aided framework for sustainable synthesis-design and analysis of process flowsheets by generating feasible alternatives covering the entire search space and includes analysis tools for sustainability, LCA and economics. The synthesis method is based on group contribution and a hybrid approach, where chemical process flowsheets are synthesized in the same way as atoms or groups of atoms are synthesized to form molecules in computer aided molecular design (CAMD) techniques. The building blocks in flowsheet synthesis problem are called as process-groups, which represent a single or set of unit operations that are selected by employing a thermodynamic insights based method. These building blocks are then combined using connectivity rules to generate all the feasible flowsheet alternatives. The main advantage of representing the flowsheet with process-groups is that, the performance of the entire process can be evaluated from the contributions of the individual process-groups towards the selected flowsheet property (for example, energy consumed). The developed flowsheet property models include energy consumption, carbon footprint, product recovery, product purity etc. In this way, the entire list of feasible chemical process flowsheets are quickly generated, screened and selected for further analysis. In the next stage, the design of the most promising process flowsheet candidates is performed through a reverse simulation approach, where the design parameters of the unit operations in the process flowsheet are calculated from selected process-groups definition. In the next stage the selected design is analyzed, for identifying process limitations or bottlenecks (hot-spots) using a comprehensive analysis method consisting of economic, life cycle and sustainability factors that are translated into design targets. In the final stage the identified hot-spots are targeted for overall process improvement and to generate innovative designs. In this work the developed framework along with the associated methods and tools is tested through three case studies related to both chemical and biochemical industry in order to ascertain the applicability of the framework. In each of the cases numerous alternatives of novel and designs reported by others are quickly generated and evaluated. In all the case studies tested, the final design generated by the framework was novel and more sustainable