Les plastifiants des dispositifs médicaux stériles (DMS) en PVC souple tels que les tubulures de perfusion ou de nutritionartificielle peuvent migrer vers les liquides de perfusion et ainsi atteindre le patient. Le DEHP (diéthylhexylphtalate) était leprincipal plastifiant utilisé dans ces DMS jusqu’en 2010. Depuis la mise en exergue de sa reprotoxicité, sa classification ensubstance CMR1b et avec sa future interdiction dans les tubulures des services de réanimation néonatale (Loi n° 2012-1442 du 24 décembre 2012), les industriels du DMS ont substitué le DEHP par des plastifiants alternatifs tels que leTOTM*, le DINP*, le DINCH*, le DEHA*, le DEHT* ou encore l’ATBC*. Il est cependant aujourd’hui impossible d’attester del’innocuité de ces molécules via les DMS étant donné le peu d’études de migration réalisées dans les conditions cliniquesd’utilisation, notamment dans les situations médicales à risque telles que la perfusion, la nutrition, l’ECMO (ExtracorporealMembrane Oxygenation), la CEC (Circulation ExtraCorporelle) en chirurgie cardiaque ou l’hémodialyse. L’objectif de cettethèse est d’étudier cette migration, afin d’évaluer le risque d’exposition à ces plastifiants lors de l’utilisation des DMS enpratique clinique. Notre travail bibliographique préliminaire nous a permis d’identifier les techniques analytiques les plusadaptées à la quantification des plastifiants au sein des DMS (méthodes directes ou indirectes associées à une phased’extraction préalable), celles comme la GC (Gas Chromatography) et la LC (Liquid Chromatography), à privilégier pour leuranalyse dans les solutions en contact, médicaments ou simulants et les techniques de pointe très sensibles (LC/MS-MS)(Liquid chromatography coupled to tandem mass spectrometry) utiles pour détecter et quantifier les plastifiants et leursmétabolites présents à des taux très faibles dans des matrices complexes comme les liquides biologiques.Notre analyse des résultats de premiers tests de migration réalisés dans des conditions standardisées adaptées de laméthodologie alimentaire montrent que les plastifiants ont des capacités migratoires variables, qui sont 20 fois et 3 foismoins élevées pour le TOTM et le DEHT respectivement par rapport au DEHP. Quant au DINCH, il migre en proportionsidentiques au phtalate après 24 heures de contact. Ces résultats ont servi de base à l’élaboration d’un modèle de migrationin vitro en situations de perfusion et de nutrition, représentatif des conditions cliniques de worst case. Dans ce modèle,validé par un groupe d’experts pluridisciplinaire, le postulat adulte clinique s’établit ainsi : « 1 patient de 60kg estsusceptible de recevoir chaque jour 2L de médicaments perfusés au moyen de 10 dm2 de tubulure ». Ce modèle servirapour le montage des premiers tests in vitro. En parallèle, le revêtement hybride organique/inorganique déposé par dipcoatingà la surface du PVC permet une bonne protection vis-à-vis du relargage des plastifiants, de l’ordre de 80% sur 48hde contact mais protège encore insuffisamment le PVC de l’absorption de médicaments comme le diazépam ou le dinitrateisosorbide, dont la perte n’est diminuée que de 53% et de 45% respectivement. Il s’agit d’une innovation intéressante,mais dont l’optimisation est nécessaire pour garantir une gestion des risques relatifs aux DMS en PVC plastifié. / Plasticizers in medical devices (MD) made of flexible PVC, such as infusion sets of nutrition tubings, are able to migrate into infused solutions and so come in contact with the patient. DEHP (diethylhexylphtalate) was the main plasticizer used in these MD up until 2010. It has been shown to be reprotoxic has been classified as CMR1b chemical and is soon to be banned from tubings used in neonatalogy, and therefore MD’s manufacturers have replaced DEHP by alternative plasticizers named TOTM*, DINP*, DINCH*, DEHA*, DEHT* or ATBC*. However, it is impossible to ascertain that these new plasticizers are harmless because of the lack of migration studies conducted in clinical situations in which MD are used, particularly in « at risk situations » such as infusion, nutrition, ECMO (Extracorporeal Membrane Oxygenation), ECC (Extracoporeal Circulation) in cardiac surgery and haemodialysis. The aim of this thesis is to study this migration, in order to evaluate the risk of exposure to these plasticizers, during clinical practice. Our preliminary bibliographic review allowed us to identify the most appropriate analytical methods to quantify the plasticizers in the MD matrix (direct methods or indirect methods requiring an extraction step), techniques such as GC (Gas Chromatography) and LC (Liquid Chromatography) suitable for the analysis of plasticizers in solutions, drugs or simulants in contact with, and sensitive advanced techniques such as (LC/MS-MS) (Liquid chromatography coupled to tandem mass spectrometry) which are useful to detect and to quantify the plasticizers and their metabolites at trace levels in complex matrices like body fluids.The results of preliminary migration tests carried out in standardized conditions adapted from agrifood methodology show that the plasticizers have different migration abilities, which are 20 times and 3 times lower for TOTM and DEHT compared to DEHP. As regards DINCH, it does release as much as DEHP does after 24 hours of contact. These results formed the basis for the development of an in vitro migration model for infusion and nutrition situations, reflecting a worst case scenario. In this model, which has been validated by a pluridisciplinary task force, the clinical assumption is as follows: « A 60kg-patient is likely to get two litres of infused drugs via 10 dm2 of tubing in flexible PVC ». This model will be used to make the first tests in vitro. At the same time, an inorganic/organic hybrid coating deposited on the PVC surface by dip-coating provides a good protection against the release of the plasticizers, at a level of about 80% during 48 hours of contact, but is insufficient to protect PVC from drug sorption such as diazepam or isosobide dinitrate, which loss is reduced by only 53% and 45% respectively. It is an attractive innovation but has to be necessarily optimized to ensure a risk management concerning MD in flexible PVC.This thesis is part of tasks 1 and 2 of the ARMED research project (Assessment and Risk Management of Medical devices in PolyvinylChloride), directed by Pr Valérie Sautou, and which has received the financial support of the French Medicine Agency (ANSM, Agence Nationale de Sécurité du Médicament et des Produits de Santé) in the framework of call of research proposals in 2012.

Cette étude porte sur la relation entre la composition et les propriétés de matériaux à base de farine de maïs. Les lipides et les résidus cellulosiques jouent le rôle de défauts ; l’amidon contrôle principalement le comportement mécanique des farines plastifiées, notamment en ce qui concerne la variation des propriétés en fonction des conditions d’ambiance. Les interactions entre l’amidon, l’eau, et les plastifiants ont été explicitées par un diagramme de phase qui comporte deux transitions. Les différents phénomènes discutés dans la littérature (anti plastification – plastification – sursaturation) ont été mis en relation avec ce diagramme de phase. Les interactions entre l’amidon et les plastifiants, ont été interprétées par un concept de stœchiométrie de sorption, qui a été appliqué à trois plastifiants : le glycérol, l’éthylène glycol et le 1,3-propanediole. Un polycondensat amphiphile original, obtenu à partir d’acide itaconique, a été étudié, pour améliorer la compatibilité de systèmes hétérophasés amidon plastifié / polybutylène succinate. Son utilisation favorise la formation d’une morphologie co-continue. / This present stydy investigates the composition-property of corn flour based materials. Lipids and cellulosic residue act like defects in these materials, starch controls the mechanical properties of corn flour based material and their variations with temperature and humidity. The interactions between starch, water and plasticizers have been highlighted in a phase diagram, in which we distinguished two transitions. The different phenomenons discussed in the literature (antiplasticization – plasticization – phase separation) were correlated with the phase diagram. The characterization of interactions between starch and plasticizers, by water sorption, was interpreted in terms of interaction stoichiometry. This method was applied for three plasticizers: glycerol, ethylene glycol and 1,3-propandiol; Amphiphilic polycondensates, obtained from itaconic acid, were used to improve the compatibilization of poly(butylene succinate) and glycerol-plasticized thermoplastic starch blends. Comptabilized blends presented a co-continuous phase.

Some plasticizers are endocrine-disrupting chemicals that cause reproductive toxicity in both males and females. Several chemicals already approved by the Food and Drug Administration have been proposed as substitutes for some of these plasticizers, one example is acetyl tributyl citrate (ATBC). However, no studies have tested whether ATBC causes direct toxicity to the ovary. Ovarian antral follicles are essential for female fertility because they are the major producers of ovarian steroids and are the only follicle type that can ovulate in response to gonadotropin stimulation. Previous studies have used in-vitro ovarian follicle culture as a screening tool to demonstrate that EDCs can cause direct ovarian toxicity. Therefore, we designed this study to test whether exposure to in vitro treatment with ATBC causes ovarian toxicity in CD-1 mice. We mechanically isolated antral follicles from the ovaries of adult CD-1 mice (35-39 days old) and individually exposed them (n=5 cultures with n≥8 follicles per treatment) to supplemented media alone (NT), dimethyl sulfoxide (DMSO, vehicle for ATBC), and ATBC (0.001-100 µg/mL) for 24-72 h. Follicle growth and survival were monitored by measuring follicle diameter and cytotoxicity (compromised membrane integrity; CellTox Green) every 24 h, and assessing number of metabolically active cells (ATP concentration; Promega CellTiterGlo) at the end time point. The DNA synthesis inhibitor hydroxyurea (HU, 100 mM) was used as a positive control for the viability assays. Exposure to ATBC did not affect the ability of antral follicles to increase their diameter over time at all concentrations tested. When stratified by growth pattern, there was not a significant difference in the proportion of follicles growing normally, growing slowly, or not growing following ATBC exposure at all concentrations tested. ATBC treatment did not cause compromised membrane integrity and did not inhibit ATP production at any of the concentrations tested. The positive control, HU, inhibited follicle growth (24-72 h), decreased follicle cell membrane integrity (72 h), and inhibited ATP production (24-72 h). The purpose of this experiment is to evaluate the effects of oral exposure to ATBC in female CD-1 mice. For the in vivo experiments, the female mice (n=22; PND 81) were randomly divided into treatment groups and dosed according to daily body weight with one of the following treatments: corn oil (vehicle, n=7), 5 mg/kg/day ATBC (n=8), or 10 mg/kg/day (n=7) ATBC for 15 consecutive days. Vaginal smears were performed and analyzed daily to measure any change in estrous cyclicity. After the 15th day of dosing the female mice were introduced into an individually housed proven breeder male’s cage. Daily body weight measurements continued and plug checks were performed every morning. Pregnancy and time to conception data did not statistically differ from the vehicle (oil) for all ATBC treatments (days to conception: vehicle 2.43 ± 0.65, 5 mg/kg/day ATBC 2 ± 0.33, 10 mg/kg/day ATBC 2.5 ± 0.22; gestation length: vehicle 19.71 ± 0.18, 5 mg/kg/day ATBC 20 ± 0.19, 10 mg/kg/day ATBC 20 ± 0.00). On the day of parturition the dams and pups were sacrificed; organ weight and gross morphology data was collected for: uterus, kidneys, adrenals, spleen, liver, and ovaries. The data analyzed includes: estrous cyclicity, pre-dosing body weight % gain, dosing body weight % gain, pregnant body weight % gain, organ weight, gestation length, litter size (live vs. dead), litter weight, implantation sites, time to conception, and pup sex ratio. Interestingly, there was an increase in spleen weight at the 5 mg/kg/day treatment when compared to vehicle control-treated spleen weights (spleen weight, Oil: n=7; 5 mg/kg ATBC: n= 8). Treatment with 5 mg/kg/day ATBC caused a significant decrease in average estrous cycle length in days compared to the pre-dosing average estrous cycle length. Animals exposed orally to 10 mg/kg/day ATBC showed a significant decrease in total follicle number (10 mg/kg/day ATBC, 313 ± 20.37) when compared to vehicle (oil) treated mice (vehicle, 433.71 ± 34.85). Also treatment with 10 mg/kg/day ATBC resulted in significant reduction in secondary (101.67 ± 5.7) and late antral (4.17 ± 1.45) follicle numbers when compared to the vehicle-treated mice (secondary follicles: 141.14 ± 14.79, late antral follicles: 7.00 ± 1.54). ATBC treatment with 10 mg/kg/day showed a significantly decreased mean body weight percent gain during pregnancy on days 3, 5, and 14 when compared to animals treated with vehicle (oil), while animals treated with 5 mg/kg/day ATBC showed a significant decrease in weight gained on only day 13 when compared to the vehicle (oil). These novel findings show that ATBC could disrupt ovarian function in mice when exposed to low-dose ATBC.

L'augmentation de la production mondiale de glycérine, en raison de la croissance dans l'utilisation du biodiesel, et la tendance à remplacer les plastifiants dérivés de l'anhydride phtalique dans l'industrie du PVC, ont conduit à la recherche de la plastification du PVC avec des esters de glycérol. Cette étude a utilisé une méthodologie pour la conception du produit, avec une approche du troisième paradigme du génie chimique. Plusieurs esters de glycérol ont été produits avec neuf acides carboxyliques, et l'efficacité et la performance comme plastifiant du PVC ont été évaluées.L'évaluation expérimentale comprend la détermination de la capacité à former des films et six tests de performance utilisés dans l'industrie. La modélisation moléculaire utilise les interactions binaires entre une molécule de plastifiant et une molécule modèle de PVC. Avec les résultats expérimentaux de la performance des films avec le PVC, et en appliquant des méthodes d'évaluation multicritère pour la sélection d'alternatives, trois modèles ont été développés pour la sélection des plastifiants pour des applications générales et une utilisation médicale. Enfin, nous avons étudié expérimentalement la production en laboratoire de deux esters, qui ont montré une performance appropriée selon l'évaluation multicritère. Deux modèles on été construits pour simuler la production, et en utilisant une optimisation multi-objectif des modèles et un outil d'analyse multi-critères, nous avons établi les conditions dans lesquelles une étude de changement d'échelle devrait être réalisée pour une production industrielle. / Phtalates are the most important plasticizers used in the polymer industry. However, their fossil origin and results of recent test have showed a potential negative effect on human health, have encouraged polymer industry to demand free phthalate plasticizers. At the same time, biodiesel industry produces a glut of glycerol, leading the scientific community to seek new applications for this substance. A methodology for the evaluation of new free-phthalate plasticizers for PVC applied to a new type of plasticizers, esters of glycerol, is proposed. This thesis presents an overview of the performance of eight esters derived from glycerol as new plasticizers for poly(vinyl chloride) - PVC and an outline of its compatibility with the polymer based in a method to predict the plasticization effect of glycerol esters, constructed with molecular modeling.Having several alternatives of new PVC-plasticizers, three multicriteria methods were used to construct models to select the best alternatives: multiattribute utility theory - MAUT, Measuring Attractiveness by a Categorical Based Evaluation Technique - Macbeth and Rough sets. With these methods the preferences of a group of experts was modeled.In order to establish the conditions in which this new type of plasticizers must be produced at industrial scale, a model of the process is presented. A parametric identification was done. Also, a multicriteria optimization, in Pareto’s sense, was performed using an evolutionary algorithm. Besides, a decision aid tool based on two different functions to minimize costs and maximize productivity, respectively, was conducted with the technique Macbeth.

É crescente o interesse e a necessidade de substituição de materiais preparados a partir de matéria-prima obtida de fontes fósseis, por materiais oriundos de fontes renováveis, como os compósitos poliméricos reforçados com fibras naturais. Adicionalmente, é acelerada a geração de descarte de embalagens plásticas no país, comparativamente à reciclagem de materiais. Neste contexto, o presente trabalho consistiu na busca pelo aprimoramento de processos de preparação de compósitos baseados em poli (tereftalato de etileno) reciclado (PET reciclado) e fibras de sisal. As fibras de sisal foram caracterizadas segundo o teor de componentes químicos majoritários, difração de raios X, microscopia eletrônica de varredura (MEV), análise térmica (calorimetria exploratória diferencial (DSC) e termogravimetria (TG)) e espectroscopia na região do infravermelho (IV). O PET reciclado foi caracterizado por DSC, TG, IV e determinação do índice de fluidez. Inicialmente, compósitos de PET reciclado/fibras de sisal foram processados via reometria de torque, com posterior termoprensagem, à temperatura de 260ºC, porém foi observada a decomposição térmica das fibras, ou seja, o recobrimento pela matriz não retardou a decomposição das fibras. Consequentemente, visando uma diminuição da temperatura de fusão do PET reciclado (~265ºC), a fim de evitar a decomposição térmica das fibras durante o processamento, os plasticizantes acetil tributil citrato (ATBC), tributil citrato (TBC), glicerol, óleo de mamona (OM) e óleo de soja epoxidado (OSE) foram acrescentados às formulações dos compósitos. Adicionalmente, polibutadieno hidroxilado líquido (PBHL) foi acrescentado à formulação do material, visando avaliar sua ação como agente compatibilizante/de acoplamento na interface fibra-matriz. Destaca-se que estes plasticizantes foram escolhidos por serem oriundos de fontes renováveis, assim como por possuírem grupos nas respectivas estruturas com afinidade tanto por grupos presentes nos componentes da fibra como na matriz. Desta forma a possível ação dos mesmos como compatibilizantes também foi considerada. Os plasticizantes foram caracterizados por DSC, TG e IV. A exploração de parâmetros de processamento, usando plasticizantes, foi feita misturando os componentes usando pás rotativas, seguido de moldagem por compressão. A composição da mistura e parâmetros de processamento, que levaram ao melhor conjunto de resultados, foi considerada para processamento via reometria de torque/termoprensagem. Os compósitos foram caracterizados por MEV, DSC, TG, absorção de água, e com relação às suas propriedades mecânicas por análise térmica dinâmico-mecânica (DMTA), e ensaios de resistência ao impacto e à flexão. Analisando-se os resultados obtidos, observa-se que, com relação aos diferentes processamentos dos compósitos, a moldagem por compressão foi mais adequada para a preparação dos compósitos de PET reciclado/fibras de sisal, principalmente em relação ao superior desempenho mecânico apresentado por estes materiais, em comparação aos compósitos processados por reometria de torque e posterior termoprensagem. O PET reciclado não reforçado, dentre as propriedades mecânicas apresentadas, não apresentou boa resistência ao impacto, assim como os compósitos preparados a partir dele, ou seja, a propriedade do PET reciclado foi predominante nos compósitos. No entanto, o uso de plasticizantes viabilizou não só o processamento dos compósitos à menor temperatura, assim como aumentou a molhabilidade da fibra pelo polímero, por diminuir a viscosidade da mistura. Ainda, no geral, as micrografias das superfícies de fratura dos compósitos demonstraram uma boa adesão na interface fibra-matriz, indicando atuação dos plasticizantes também como compatibilizantes entre fibra e matriz. Destaca-se que, no geral, os resultados de resistência à flexão e DMTA apontaram no sentido de que a presença das fibras e plasticizantes levaram a materiais menos rígidos e mais flexíveis. Dentre os compósitos, pode-se considerar que a mistura PET reciclado/fibras de sisal/glicerol/ TBC apresentou o melhor desempenho mecânico, que levou, no geral, ao melhor resultado de resistência ao impacto, boa resistência à flexão e deformação na ruptura. O compósito de PET reciclado/fibras de sisal, contendo em sua composição somente o plasticizante TBC, também apresentou um bom desempenho frente aos demais compósitos, com o melhor resultado de resistência à flexão, maior módulo de armazenamento e baixo teor de água absorvida. Assim, como pretendido, viabilizou-se o preparo de compósitos de PET reciclado/fibras de sisal, com a adição de diferentes tipos e misturas de plasticizantes, avaliando-se não somente a influência destes, assim como parâmetros de processo, uso de diferentes tipos de processamento e propriedades finais dos materiais gerados. / There is an increasing interest and need for the replacement of materials prepared from raw material obtained from fossil sources by those from renewable sources, such as polymeric composites reinforced with natural fibers. Additionally, the generation of plastic packaging disposal is accelerated in the country compared to materials recycling. In this context, the focus of this investigation was on the search for developing processes for the preparation of composites based on recycled poly (ethylene terephthalate) (recycled PET) and sisal fibers. The sisal fibers were characterized according to the content of major chemical components by X-ray diffraction, scanning electron microscopy (SEM), thermal analysis (differential scanning calorimetry (DSC) and thermogravimetry (TG)) and by infrared spectroscopy (IR). The recycled PET was characterized by DSC, TG, IV and melt index determination. Initially, composites of recycled PET/sisal fibers were processed in a Haake torque rheometer with subsequent thermopressing, at 260ºC, but this method proved to be inefficient, since fiber decomposition was observed, i.e., the decomposition of the fibers was not delayed by the matrix coating. Consequently, by aiming at obtaining a decrease of the melting temperature of the recycled PET (~ 265ºC) in order to avoid thermal decomposition of the fibers during processing, the plasticizers, acetyl tributyl citrate (ATBC), tributyl citrate (TBC), glycerol, castor oil (CO) and epoxidized soybean oil (OSE) were added to the formulations of the composites. In addition, hydroxylated liquid polybutadiene (PBHL) was added to the formulation of the material to evaluate its action as a compatibilizer/coupling agent in the fiber-matrix interface. It is emphasized that these plasticizers were chosen because they come from renewable sources, as well as having groups in the respective structures with affinity for both groups present in components of the fiber and the matrix. Thus the possible action of plasticizers as compatibilizers was also considered. The plasticizers were characterized by DSC, TG and IV. The exploitation of processing parameters using plasticizers was made by mixing the components using shovels, followed by compression molding. The composition of the mixture and the processing parameters, which led to the best set of results, were considered for processing via torque rheometry/thermopressing. The composites were characterized by SEM, DSC, TG, water absorption, and regarding their mechanical properties, by dynamic mechanical thermal analysis (DMTA) and impact and flexural strength. Analyzing the results, it is observed that when it comes to different processes of composites, compression molding was the most suitable for the preparation of the composites of recycled PET/sisal fibers, especially in relation to the superior mechanical performance presented by these materials compared to composites processed by torque rheometry and subsequent thermopressing. The non-reinforced recycled PET, among the mechanical properties shown, did not show a good impact strength, nor did the composites prepared from it, i.e., the property of recycled PET in the composites was predominant. However, not only did the use of plasticizers allow the processing of the composites at a lower temperature, but also it increased the wettability of the polymer-fiber by reducing the viscosity of the mixture. Still, in general, the SEM images of fractured surfaces of the composites showed a good adhesion between fiber-matrices, indicating activity of plasticizers and also compatibilizers between fiber and matrix. It is noteworthy that, in general, the results of flexural strength and DMTA pointed out that the presence of plasticizers led to less rigid and more flexible materials. Among the composites, it can be assumed that the mixture recycled PET/sisal fibers/glycerol/TBC presented the best mechanical performance, which in general led to the best result of impact strength, good flexural strength and fracture strain. The composite of recycled PET/sisal fibers in its composition, containing only the TBC plasticizer, also performed well compared to other composites, with the best result of flexural strength, higher storage modulus and low moisture absorption. Thus, as desired, the preparation of composites based on recycled PET/sisal fibers with the addition of different types and mixtures of plasticizers was enabled, evaluating not only their influence but also process parameters, the use of different types of processing and the final properties of the generated materials.

Tesis por compendio / "Development of polylactic acid (PLA)-derived formulations by plasticization and additives from renewable resources" The main objective of this doctoral thesis is the study, development and characterization of biodegradable or biocompatible materials from poly(lactic acid) (PLA) with improved properties for uses in several sectors such as food packaging, medical sector, etc. In order to modify the ductility and the stiffness of PLA, with the subsequent effects on its potential uses in different sectors, different fillers and/or additives were incorporated to PLA formulations by extrusion. Several plasticizers derived from vegetable oils and fatty acids were used; particularly, an epoxidized plasticizer derived from stearic acid (octyl epoxy stearate - OES) and a maleinized linseed oil - MLO were used. Another strategy that has been used in this research has focused on the development of binary blends with other polymers with increased ductility such as polycaprolactone (PCL) and thermoplastic starch (TPS). Finally, incorporation of several biocompatible/resorbable fillers derived from calcium orthophosphate (Ca3(PO4)2) such as ß-tricalcium phosphate (ß-TCP) and hydroxyapatite (HA), was carried out to widen the potential of these PLA-based materials in medical applications. / "Desarrollo de formulaciones derivadas de ácido poliláctico (PLA), mediante plastificación e incorporación de aditivos de origen natural" El objetivo principal de esta tesis doctoral es el estudio, desarrollo y caracterización de materiales biodegradables o biocompatibles de ácido poliláctico (PLA) con propiedades mejoradas para su aplicación en diversos sectores como el envasado de alimentos, sector médico, etc. Para modificar la ductilidad o rigidez del PLA y con ello su aptitud en los distintos campos, se lleva a cabo un estudio de la incorporación de diferentes cargas o aditivos, mediante mezclado por extrusión. Se han utilizado plastificantes derivados de aceites vegetales y ácidos grasos; en particular, un plastificante epoxidado derivado del ácido esteárico (epoxi estearato de octilo - OES) y un derivado maleinizado de aceite de linaza - MLO. Otra de las estrategias que se han abordado se ha centrado en el desarrollo de mezclas binarias con otros biopolímeros con mayor ductilidad como la policaprolactona (PCL) y el almidón termoplástico (TPS). Finalmente, se ha llevado a cabo la incorporación de cargas biocompatibles tipo ortofosfato cálcico (Ca3(PO4)2) como el ß-fosfato tricálcico (ß-TCP) y la hidroxiapatita (HA) para ampliar el potencial de estos materiales basados en PLA en el sector médico. / "Desenvolupament de formulacions derivades d'àcid polilàctic (PLA), mitjançant plastificació i incorporació d'additius d'origen natural" L'objectiu principal d'aquesta tesi doctoral és l'estudi, desenvolupament i caracterització de materials biodegradables i biocompatibles d'àcid polilàctic (PLA) amb propietats millorades per a la seua aplicació en diversos sectors com ara l'envasat d'aliments, sector mèdic, etc. Per tal de modificar la ductilitat o rigidesa del PLA, i amb això, la seua aptitud en els esmentats camps, s'ha fet un estudi de la incorporació de diferents càrregues o additius, mitjançant mesclat per extrusió. S'han utilitzat plastificants derivats d'olis vegetals i àcids grassos; en particular, un plastificant epoxidat derivat de l'àcid esteàric (epoxi estearat d'octil - OES) i un derivat maleinitzat d'oli llinós - MLO. Una altra estratègia que s'ha seguit s'ha centrat en el desenvolupament de mescles binàries amb altres polímers amb major ductilitat com ara la policaprolactona (PCL) i el midó termoplàstic (TPS). Finalment, s'ha dut a terme la incorporació de càrregues biocompatibles de tipus ortofosfat càlcic (Ca3(PO4)2) com ara el ß-fosfat tricàlcic (ß-TCP) i la hidroxiapatita (HA) per tal d'ampliar el potencial d'aquests materials basats en PLA al sector mèdic. / Ferri Azor, JM. (2017). Desarrollo de formulaciones derivadas de ácido poliláctico (PLA), mediante plastificación e incorporación de aditivos de origen natural [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/86166 / Premios Extraordinarios de tesis doctorales / Compendio

The modification of polymeric materials using plasticizers or elastomers has been investigated in three research programs. The first describes epoxy resins modified with dimethylsiloxane, dimethyl-co-methyltrifluoropropyl siloxane, and dimethyl-co-diphenyl siloxane. The apparent compatibility between the epoxy and the siloxanes was enhanced by increasing methyltrifluoropropyl or diphenyl siloxane content or lowering molecular weight, resulting in profound changes in morphology and the resultant mechanical properties of the modified resins. Fracture toughness was most significantly improved using siloxanes containing at least 40% methyltrifluoropropyl siloxane or 20 and 40% diphenyl siloxane. Comparison of siloxane modifiers with butadiene acrylonitrile modifiers was valuable with regard to both property and morphological effects. The second research project considers the structure-property behavior of polyvinyl chloride (PVC) plasticized with low molecular weight diesters with emphasis on the contrasting effects of different plasticizers on the breadth of PVC's dynamic mechanical spectrum. It was clearly demonstrated that a less soluble plasticizer promoted a greater broadening at intermediate concentrations. Crystallization phenomena and static mechanical properties reflected the greater diluent effect of a more soluble plasticizer. The dynamic mechanical behavior as well as other critical experimental observations were explained using a model which postulates that the network junctions of plasticized PVC consist of "pockets" containing several small crystallites. These pockets are randomly dispersed in a matrix whose homogeneity is governed by the plasticizer's solubility and molar volume. The third research project describes the modification of high 1,4 polybutadiene (PB) with isopropyl azodicarboxylate (IAD) for potential .use as impact modifiers for polar polymers. A method for finding the extent of IAD modification of the PB has been developed using ¹³C nmr and UV spectroscopy. Solution blends of PVC with PB modified with up to 11 mol% IAD were found to be immiscible. Stress-strain testing suggested that IAD modification (11%) enhanced the apparent compatibility between PB and PVC at 25% rubber content. The relatively poor mechanical response of the blends was believed to be related to their somewhat porous morphology. / Ph. D. / incomplete_metadata

Phthalate esters (PEs) and alternative plasticizers used as additives in numerous consumer products are continuously released into the environment leading to subsequent human exposure. The ubiquitous presence and potential adverse health effects (e.g. endocrine disruption and reproductive toxicity) of some PEs are responsible for their bans or restrictions. This has led to increasing use of alternative plasticizers, especially cyclohexane-1,2-dicarboxylic acid diisononyl ester (DINCH). Human exposure data on alternative plasticizers are lacking and clear evidence for human exposure has previously only been found for di(2-ethylhexyl) terephthalate (DEHTP) and DINCH, with increasing trends in body burdens. In this thesis, a study population of 61 adults (age: 20–66; gender: 16 males and 45 females) living in the Oslo area (Norway) was studied for their exposure to plasticizers. Information on sociodemographic and lifestyle characteristics that potentially affect the concentrations of PE and DINCH metabolites in adults was collected by questionnaires. Using the human biomonitoring approach, we evaluated the internal exposure to PEs and DINCH by measuring concentrations of their metabolites in urine (where metabolism and excretion are well understood) and using these data to back-calculate daily intakes. Metabolite levels in finger nails were also determined. Since reference standards of human metabolites for other important alternative plasticizers apart from DINCH (e.g. DEHTP, di(2-propylheptyl) phthalate (DPHP), di(2-ethylhexyl) adipate (DEHA) and acetyl tributyl citrate (ATBC)) are not commercially available, we further investigated the urine and finger nail samples by Q Exactive Orbitrap LC-MS to identify specific metabolites, which can be used as appropriate biomarkers of human exposure. Many metabolites of alternative plasticizers that were present in in vitro extracts were further identified in vivo in urine and finger nail samples. Hence, we concluded that in vitro assays can reliably mimic the in vivo processes. Also, finger nails may be a useful non-invasive matrix for human biomonitoring of specific organic contaminants, but further validation is needed. Concentrations of PEs and DINCH were also measured in duplicate diet, air, dust and hand wipes. External exposure, estimated based on dietary intake, air inhalation, dust ingestion and dermal uptake, was higher or equal to the back-calculated internal intake. By comparing these, we were able to explain the relative importance of different exposure pathways for the Norwegian study population. Dietary intake was the predominant exposure route for all analyzed substances. Inhalation was important only for lower molecular weight PEs, while dust ingestion was important for higher molecular weight PEs and DINCH. Dermal uptake based on hand wipes was much lower than the total dermal uptake calculated via air, dust and personal care products, but still several research gaps remain for this exposure pathway. Based on calculated intakes, the exposure risk for the Norwegian participants to the PEs and DINCH did not exceed the established tolerable daily intake and reference doses, and the cumulative risk assessment for combined exposure to plasticizers with similar toxic endpoints indicated no health concerns for the selected population. Nevertheless, exposure to alternative plasticizers, such as DPHP and DINCH, is expected to increase in the future and continuous monitoring is required. Findings through uni- and multivariate analysis suggested that age, smoking, use of personal care products and many other everyday habits, such as washing hands or eating food from plastic packages are possible contributors to plasticizer exposure. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.</p>

CHARLES UNIVERSITY IN PRAGUE Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical technology Name of the student: Klára Bílková Title of diploma thesis: Influence of plastification on rheological properties of oligoester of lactic acid and glycolic acid branched with dipentaerythritole Consultant: PharmDr. Eva Šnejdrová, Ph.D. The aim of this diploma thesis was the study of rheological properties of the oligoester of DL-lactic and glycolic acids branched with 1% of dipenthaerythritol (1D) and plasticized with 6 various plasticizers in increasing concentrations. Theoretical part was devoted to fundamentals of rheology and measurements of viscosity using rotational viscometers. It describes basic types and constructions of rotational rheometers and summarizes basic facts about bioadhesion and use of rheological method for assessment of bioadhesion. There were prepared matrices from oligoester 1D and plasticizers in concentrations of 20 %, 30 % and 40 % in the experimental part. These plasticizers were tested: ethyl pyruvate, ethyl salicylate, methyl salicylate, triacetin, tributyrin and triethyl citrate. Rheological properties were examinated at 37 řC using spindle viscometer and at 37 řC and 50 řC using rotational rheometer. Rheograms were used to characterize flow properties of tested...

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Technology Student: Lenka Šišáková Supervisor of Diploma thesis: PharmDr. Eva Šnejdrová, Ph.D. Title of Diploma thesis: Aciclovir release from mucoadhesive matrices The aim of this diploma thesis was the study of the mucoadhesive parameters of plasticized oligoester of lactic acid and glycolic acid and 3% mannitol as a branching monomer. Knowledge of dissolution testing of drug release from dosage form, principal theories and mechanisms of mucoadhesion and mucoadhesion testing of adhesive formulation is described in theoretical part. Matrices formed from terpolymer of D,L-lactic acid, glycolic acid branched with mannitol and 5 % aciclovir were examined in the experimental part. Triethylcitrate (TEC), ethylpyruvate (EP), methylsalicylate (MS) and ethylsalicylate (ES) were used as plasticizers. Dissolution test has been done. Hydrated mucin from porcine stomach was used as a base. Phosphate-citrate buffer pH 7.4 was used as a dissolution medium. Dissolution was defined as a quantity of released aciclovir in to the dissolution medium after 15, 30, 60 and 90 minutes. The quantity of the released aciclovir was defined by a spectrophotometry. In 90 minutes was released 43 % of aciclovir from the matrice...