The goal of this project was to develop a non-toxic amphiphilic diblock copolymer nanoparticulate drug delivery system that will solubilize paclitaxel (PTX) and retain the drug in plasma. Methoxy poly(ethylene glycol)-block-poly(ε-caprolactone) (MePEG-b-PCL) diblock copolymers loaded with PTX were characterized and their physicochemical properties were correlated with their performance as nanoparticulate drug delivery systems. A series of MePEG-b-PCL was synthesized with PCL blocks ranging from 2-104 repeat units and MePEG blocks of 17, 44 or 114 repeat units. All copolymers were water soluble and formed micelles except MePEG₁₁₄-b-PCL₁₀₄, which was water insoluble and formed nanospheres. Investigation of the effects of block length on the physicochemical properties of the nanoparticles was used to select appropriate copolymers for development as PTX nanoparticles. The critical micelle concentration, pyrene partition coefficient and diameter of nanoparticles were found to be dependent on the PCL block length. Copolymers based on a MePEG molecular weight of 750 g/mol were found to have temperature dependent phase behavior. Relationships between the concentration of micellized drug and the compatibility between the drug and core-forming block, as determined by the Flory-Huggins interaction parameter, and PCL block length were developed. Increases in the compatibility between PCL and the drug, as well as longer PCL block lengths resulted in increased drug solubilization. The physicochemical properties and drug delivery performance characteristics of MePEG₁₁₄-b-PCL₁₉ micelles and MePEG₁₁₄-b-PCL₁₀₄ nanospheres were compared. Nanospheres were larger, had a more viscous core, solubilized more PTX and released it slower, compared to micelles. No difference was seen in the hemocompatibility of the nanoparticles as assessed by plasma coagulation time and erythrocyte hemolysis. Micellar PTX had an in vitro plasma distribution similar to free drug. The majority of micellar PTX associated with the lipoprotein deficient plasma fraction (LPDP). In contrast, nanospheres were capable of retaining more of the encapsulated drug with significantly less PTX partitioning into the LPDP fraction. In conclusion, although both micelles and nanospheres were capable of solubilizing PTX and were hemocompatible, PTX nanospheres may offer the advantage of prolonged blood circulation, based on the in vitro plasma distribution data, which showed that nanospheres retained PTX more effectively.

The goal of this project was to develop a non-toxic amphiphilic diblock copolymer nanoparticulate drug delivery system that will solubilize paclitaxel (PTX) and retain the drug in plasma. Methoxy poly(ethylene glycol)-block-poly(ε-caprolactone) (MePEG-b-PCL) diblock copolymers loaded with PTX were characterized and their physicochemical properties were correlated with their performance as nanoparticulate drug delivery systems. A series of MePEG-b-PCL was synthesized with PCL blocks ranging from 2-104 repeat units and MePEG blocks of 17, 44 or 114 repeat units. All copolymers were water soluble and formed micelles except MePEG₁₁₄-b-PCL₁₀₄, which was water insoluble and formed nanospheres. Investigation of the effects of block length on the physicochemical properties of the nanoparticles was used to select appropriate copolymers for development as PTX nanoparticles. The critical micelle concentration, pyrene partition coefficient and diameter of nanoparticles were found to be dependent on the PCL block length. Copolymers based on a MePEG molecular weight of 750 g/mol were found to have temperature dependent phase behavior. Relationships between the concentration of micellized drug and the compatibility between the drug and core-forming block, as determined by the Flory-Huggins interaction parameter, and PCL block length were developed. Increases in the compatibility between PCL and the drug, as well as longer PCL block lengths resulted in increased drug solubilization. The physicochemical properties and drug delivery performance characteristics of MePEG₁₁₄-b-PCL₁₉ micelles and MePEG₁₁₄-b-PCL₁₀₄ nanospheres were compared. Nanospheres were larger, had a more viscous core, solubilized more PTX and released it slower, compared to micelles. No difference was seen in the hemocompatibility of the nanoparticles as assessed by plasma coagulation time and erythrocyte hemolysis. Micellar PTX had an in vitro plasma distribution similar to free drug. The majority of micellar PTX associated with the lipoprotein deficient plasma fraction (LPDP). In contrast, nanospheres were capable of retaining more of the encapsulated drug with significantly less PTX partitioning into the LPDP fraction. In conclusion, although both micelles and nanospheres were capable of solubilizing PTX and were hemocompatible, PTX nanospheres may offer the advantage of prolonged blood circulation, based on the in vitro plasma distribution data, which showed that nanospheres retained PTX more effectively.

The goal of this project was to develop a non-toxic amphiphilic diblock copolymer nanoparticulate drug delivery system that will solubilize paclitaxel (PTX) and retain the drug in plasma. Methoxy poly(ethylene glycol)-block-poly(ε-caprolactone) (MePEG-b-PCL) diblock copolymers loaded with PTX were characterized and their physicochemical properties were correlated with their performance as nanoparticulate drug delivery systems. A series of MePEG-b-PCL was synthesized with PCL blocks ranging from 2-104 repeat units and MePEG blocks of 17, 44 or 114 repeat units. All copolymers were water soluble and formed micelles except MePEG₁₁₄-b-PCL₁₀₄, which was water insoluble and formed nanospheres. Investigation of the effects of block length on the physicochemical properties of the nanoparticles was used to select appropriate copolymers for development as PTX nanoparticles. The critical micelle concentration, pyrene partition coefficient and diameter of nanoparticles were found to be dependent on the PCL block length. Copolymers based on a MePEG molecular weight of 750 g/mol were found to have temperature dependent phase behavior. Relationships between the concentration of micellized drug and the compatibility between the drug and core-forming block, as determined by the Flory-Huggins interaction parameter, and PCL block length were developed. Increases in the compatibility between PCL and the drug, as well as longer PCL block lengths resulted in increased drug solubilization. The physicochemical properties and drug delivery performance characteristics of MePEG₁₁₄-b-PCL₁₉ micelles and MePEG₁₁₄-b-PCL₁₀₄ nanospheres were compared. Nanospheres were larger, had a more viscous core, solubilized more PTX and released it slower, compared to micelles. No difference was seen in the hemocompatibility of the nanoparticles as assessed by plasma coagulation time and erythrocyte hemolysis. Micellar PTX had an in vitro plasma distribution similar to free drug. The majority of micellar PTX associated with the lipoprotein deficient plasma fraction (LPDP). In contrast, nanospheres were capable of retaining more of the encapsulated drug with significantly less PTX partitioning into the LPDP fraction. In conclusion, although both micelles and nanospheres were capable of solubilizing PTX and were hemocompatible, PTX nanospheres may offer the advantage of prolonged blood circulation, based on the in vitro plasma distribution data, which showed that nanospheres retained PTX more effectively. / Pharmaceutical Sciences, Faculty of / Graduate

The aim of this study is to evaluate the specific interactions, solid-state, and solution-state interactions between drug and polymers in amorphous spray dried dispersions and evaluate the subsequent impact on drug dissolution in non-sink media. This is intended to be used as a screening tool for dosage-form development. Formulations with specific theoretical and observed interactions between drug and polymer may exhibit improved dissolution rate, increased absorption rate, increased capacity for drug loading and improved physical stability. Four BCS II class drugs were evaluated: ibuprofen, ketoprofen, nifedipine, and itraconazole. Binary and ternary spray dried dispersions were manufactured with conventional polymers and arabinogalactan. Specific interaction parameters between each drug and polymer were determined using theoretical group contribution calculations and DSC data. Solid-state interactions were evaluated using modulated DSC and FTIR, and solution-state interactions were evaluated using 1H-NMR. The maximum amorphous content for each formulation was calculated from the enthalpy of melting point peaks using DSC. Flory-Huggins Specific Interaction Parameters were calculated and show that a negative specific parameter was associated with increased solid-state interactions and improved capacity to contain drug in the amorphous state. Correlations between Flory-Huggins specific interaction parameter, amorphous drug loading, and equilibrium solubility were established. Ternary spray-dried dispersions containing drug, conventional polymer, and arabinogalactan displayed similar hydrogen bonding as was observed with binary spray-dried dispersions. Solid and solution-state interactions observed in binary systems may be incorporated into ternary systems with arabinogalactan to both maintain amorphous drug capacity and improve dissolution rate compared to the binary. Supersaturation of amorphous binary and ternary dispersions was attained as compared to the crystalline drug. Mechanical properties of polymers as related to dissolution rate were investigated, and ternary systems containing to rapidly swelling and dissolving arabinogalactan had more pronounced erosion properties as compared to binary drug : HPMC dispersions. The resultant ternary systems are an improvement over binary drug polymer systems. / Pharmaceutical Sciences

Yes / In this study, a comparison of different methods to predict drug−polymer solubility was carried out on binary systems consisting of five model drugs (paracetamol, chloramphenicol, celecoxib, indomethacin, and felodipine) and polyvinylpyrrolidone/vinyl acetate copolymers (PVP/VA) of different monomer weight ratios. The drug−polymer solubility at 25 °C was predicted using the Flory−Huggins model, from data obtained at elevated temperature using thermal analysis methods based on the recrystallization of a supersaturated amorphous solid dispersion and two variations of the melting point depression method. These predictions were compared with the solubility in the low molecular weight liquid analogues of the PVP/VA copolymer (N-vinylpyrrolidone and vinyl acetate). The predicted solubilities at 25 °C varied considerably depending on the method used. However, the three thermal analysis methods ranked the predicted solubilities in the same order, except for the felodipine−PVP system. Furthermore, the magnitude of the predicted solubilities from the recrystallization method and melting point depression method correlated well with the estimates based on the solubility in the liquid analogues, which suggests that this method can be used as an initial screening tool if a liquid analogue is available. The learnings of this important comparative study provided general guidance for the selection of the most suitable method(s) for the screening of drug−polymer solubility. / The Irish Research Council and Eli Lilly S.A. through an Irish Research Council Enterprise Partnership Scholarship for C.M.B., in part by The Royal Society in the form of Industrial Fellowship awarded to G.A., and in part by a research grant from Science Foundation Ireland (SFI) under Grant Number SFI/12/RC/2275 (for A.M.H., L.T., K.P., and A.K.).

Made available in DSpace on 2014-12-17T15:01:56Z (GMT). No. of bitstreams: 1 AlessandroALA_TESE.pdf: 2166690 bytes, checksum: 87b921d322f56a3c11d668a0ad8d9341 (MD5) Previous issue date: 2013-11-11 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / The nonionic surfactants when in aqueous solution, have the property of separating into two phases, one called diluted phase, with low concentration of surfactant, and the other one rich in surfactants called coacervate. The application of this kind of surfactant in extraction processes from aqueous solutions has been increasing over time, which implies the need for knowledge of the thermodynamic properties of these surfactants. In this study were determined the cloud point of polyethoxylated surfactants from nonilphenolpolietoxylated family (9,5 , 10 , 11, 12 and 13), the family from octilphenolpolietoxylated (10 e 11) and polyethoxylated lauryl alcohol (6 , 7, 8 and 9) varying the degree of ethoxylation. The method used to determine the cloud point was the observation of the turbidity of the solution heating to a ramp of 0.1 ? C / minute and for the pressure studies was used a cell high-pressure maximum ( 300 bar). Through the experimental data of the studied surfactants were used to the Flory - Huggins models, UNIQUAC and NRTL to describe the curves of cloud point, and it was studied the influence of NaCl concentration and pressure of the systems in the cloud point. This last parameter is important for the processes of oil recovery in which surfactant in solution are used in high pressures. While the effect of NaCl allows obtaining cloud points for temperatures closer to the room temperature, it is possible to use in processes without temperature control. The numerical method used to adjust the parameters was the Levenberg - Marquardt. For the model Flory- Huggins parameter settings were determined as enthalpy of the mixing, mixing entropy and the number of aggregations. For the UNIQUAC and NRTL models were adjusted interaction parameters aij using a quadratic dependence with temperature. The parameters obtained had good adjust to the experimental data RSMD < 0.3 %. The results showed that both, ethoxylation degree and pressure increase the cloudy points, whereas the NaCl decrease / Os tensoativos n?o i?nicos, quando em solu??o aquosa, apresentam a propriedade de separa??o em duas fases, sendo uma denominada de fase dilu?da, baixa concentra??o em tensoativo, e a outra rica em tensoativo denominada de coacervato. A aplica??o deste tipo de tensoativo nos processos de extra??o de solutos de meios aquosos vem aumentando o que implica na necessidade do conhecimento das propriedades termodin?micas desses tensoativos. Neste trabalho foram determinados os pontos de n?voa dos tensoativos polietoxilados, da fam?lia do nonilfenolpolietoxilado variando o grau de etoxila??o (9,5;10;11;12 e 13), da fam?lia do octilfenolpolietoxilado variando o grau de etoxila??o (10 e 11) e do ?lcool laur?lico polietoxilado nos graus de etoxila??o (6;7;8 e 9). O m?todo utilizado para determina??o do ponto de n?voa foi a observa??o do turvamento da solu??o ao aquecer o sistema a uma rampa de 0,1oC/minuto, e no estudo da press?o foi utilizada uma c?lula de alta press?o, m?ximo (300 bar). Atrav?s dos dados experimentais obtidos dos respectivos tensoativos, foram utilizados os modelos de Flory-Huggins, UNIQUAC e NRTL para descrever as curvas do ponto de n?voa dos referidos tensoativos. Foram tamb?m estudados a influ?ncia da concentra??o do NaCl e da press?o no ponto de n?voa. Este ?ltimo par?metro ? importante para os processos de recupera??o avan?ada de petr?leo nos quais os tensoativos em solu??o s?o submetidos a press?es elevadas. Enquanto que o efeito do NaCl permite obter pontos de n?voa a temperaturas mais pr?xima da temperatura ambiente viabilizando sua utiliza??o em processos sem controle de temperatura. O m?todo num?rico utilizado para ajustar os par?metros foi o Levenberg-Marquardt. Para o modelo de Flory-Huggins foram determinados par?metros de ajuste como a entalpia da mistura, entropia da mistura e o n?mero de agrega??o. Para os modelos UNIQUAC e NRTL foram ajustados par?metros de intera??o aij utilizando uma depend?ncia quadr?tica com a temperatura. Os par?metros obtidos tiveram bons ajustes aos dados experimentais com RMSD < 0,3%. Os resultados mostraram que tanto a etoxila??o quanto a press?o aumentam o ponto de n?voa do tensoativo, enquanto que o NaCl diminui

La perception des emballages alimentaires est passée d’utile à source majeure de contaminants dans les aliments et menace pour l’environnement. La substitution du verre par des con-tenants en plastiques recyclés ou biosourcés réduit l’impact environnemental des boissons embouteillées. La thèse a développé de nouveaux outils de simulation 3D et d’optimisation pour accélérer le prototypage des emballages éco-efficaces pour les boissons alcoolisées. La durée de conservation des boissons, la sécurité sanitaire des matériaux plastiques recyclés, les contraintes mécaniques, et la quantité de déchets sont considérées comme un seul problème d'optimisation multicritères. Les nouvelles bouteilles sont générées virtuellement et itérativement en trois étapes comprenant : i) une [E]valuation multiéchelle des transferts de masse couplés ; ii) une étape de [D]écision validant les contraintes techniques (forme, capacité, poids) et réglementaires (durée de conservation, migrations); iii) une étape globale de ré[S]olution recherchant des solutions de Pareto acceptables. La capacité de prédire la durée de vie des liqueurs dans des conditions réelles a été testée avec succès sur environ 500 miniatures en PET (polyéthylène téréphtalate) sur plusieurs mois. L’ensemble de l’approche a été conçu pour gérer tout transfert de matière couplé (perméation, sorption, migration). La sorption mutuelle est prise en compte via une formulation polynaire de Flory-Huggins. Une formulation gros grain de la théorie des volumes libres de Vrentas et Duda a été développée pour prédire les propriétés de diffusion dans les polymères vitreux de l’eau et des solutés organiques dans des polymères arbitraires (polyesters, polyamides, polyvinyles, polyoléfines). 409 diffusivités issues de la littérature ou mesurées ont été utilisée pour validation. La contribution de la relaxation du PET vitreux a été analysée par sorption différentielle (binaire et ternaire) de 25 à 50 °C. Une partie du code source sera partagé afin d'encourager l'intégration de davantage de paramètres affectant la durée de conservation des boissons et des produits alimentaires (cinétique d'oxydation, piégeage d'arômes). / The view of plastic food packaging turned from useful to a major source of contaminants in food and an environmental threat. Substituting glass by recycled or biosourced plastic containers reduces environmental impacts for bottled beverages. The thesis developed a 3D computational and optimization framework to accelerate the prototyping of eco-efficient packaging for alcoholic beverages. Shelf-life, food safety, mechanical constraints, and packaging wastes are considered into a single multicriteria optimization problem. New bottles are virtually generated within an iterative three steps process involving: i) a multiresolution [E]valuation of coupled mass transfer; ii) a [D]ecision step validating technical (shape, capacity, weight) and regulatory (shelf-life, migrations) constraints; iii) a global [Solving] step seeking acceptable Pareto solutions. The capacity to predict shelf-life of liquors in real conditions was tested successfully on ca. 500 hundred bottle min iatures in PET (polyethylene terephthalate) over several months. The entire approach has been designed to manage any coupled mass transfer (permeation, sorption, migration). Mutual sorption is considered via polynary Flory-Huggins formulation. A blob formulation of the free-volume theory of Vrentas and Duda was developed to predict the diffusion properties in glassy polymers of water and organic solutes in arbitrary polymers (polyesters, polyamides, polyvinyls, polyolefins). The validation set included 433 experimental diffusivities from literature and measured in this work. The contribution of polymer relaxation in glassy PET was analyzed in binary and ternary differential sorption using a cosorption microbalance from 25 to 50°C. Part of the framework will be released as an open-source project to encourage the integration of more factors affecting the shelf-life of beverages and food products (oxidation kinetics, aroma scalping).

Computational methodologies were employed to study a supramolecular micellar structure and its application, nanoreactor. This task was done through rigorous scale-up procedure using both atomistic and mesoscopic simulations. Primarily, density functional theory (DFT) calculation was used to characterize the smallest unit of complex molecules in the multicomponent mixture system. The following step involved transferring the information achieved by DFT calculation to larger scale simulation, such as molecular dynamics (MD) simulation. Lastly, based on the atomistic simulation results, we performed a series of dissipative particle dynamics (DPD) simulations to study a full body of polymeric multicompartment micelle. In the course of research, we built a systematic procedure to minimize the complexity of computation and efficiently characterize macromolecular structures and its application.

Thesis (PhD)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: An instrument, named solution crystallization analysis by laser light scattering (SCALLS), that measures the solution melting and crystallization of polymers in solution was developed further in this study. The instrument was tested in a theoretical study to evaluate the Flory-Huggins relationship of melting point depression in solution of copolymers. It was found that the solvent interaction parameter for propylene/higher 1-alkene copolymers, with low comonomer content is dependent on the comonomer type. It was also showed that the melting point depression is dependent on both the type and amount of comonomer included in the copolymer. The instrument was further developed to include a total of three lasers with different wavelengths. Initial problems with laser interference was rectified by the introduction of dichroic mirrors to direct the laser light to the relevant detectors and broad pass filters in front of the the detectors to ensure that only the relevant laser light passes through. For homogenous polypropylene samples it was found that even though a slower cooling rate increases the relative peak temperatures as well as the relative temperature differences between the peaks, detail in the peak profiles is the same for the faster cooling rate. The subsequent heating analysis does show that there is a definite dependence on the cooling rate. The ZNPP-4 sample shows that the appearance of a shoulder in the heating analysis becomes more defined as a peak if the preceding cooling analysis is slower. Complex impact-polypropylene samples, differing only in the amount of ethylene were analysed and even small differences between samples were detected. The possible application of the SCALLS instrument was investigated. It was proven that the instrument can be used as a screening method for prep-TREF to determine the fractionation temperatures. / AFRIKAANSE OPSOMMING: 'n Instrument, genoem oplossing kristallisasie-analise deur laser lig verstrooiing (SCALLS), wat die smeltpunt asook die kristallisasie temperatuur in oplossing kan meet is verder ontwikkel in hierdie studie. Die Flory-Huggins verhouding oor die smeltpunt depressie in oplossing van ko-polimere is ondersoek in ‘n teoretiese studie. Daar is bevind dat die oplossing interaksie parameter vir propileen/hoër 1-alkeen kopolimere, met lae ko-monomeer inhoud is afhanklik op die ko-monomeer tipe. Dit is ook getoon dat die smeltpunt depressie afhanklik is van beide die tipe en hoeveelheid ko-monomeer in die ko-polimeer. Die instrument is verder ontwikkel om 'n totaal van drie lasers met verskillende golflengtes in te sluit. Aanvanklike probleme met laser inmenging is reggestel deur die bekendstelling van dichromatiese spieëls wat die laser lig na die regte ooreenstemmende detektor rig en filters voor die detektors verseker dat net die relevante laser lig die detektor bereik. Vir homogene polipropileen monsters is dit bevind dat selfs al is die analises gedoen teen ‘n stadiger afkoelings tempo wat lei tot ‘n verhoging in die piek kristallisasie temperatuur asook die relatiewe temperatuur verskille tussen die lasers, bly die detail in die piek profiele dieselfde as wat gesien word met ‘n vinniger afkoelings tempo. Die daaropvolgende verhitting analise toon dat die analise definitief afhanklik is op die voorafgaande afkoelings analise. Die ZNPP-4 monster toon dat die voorkoms van 'n skouer in die verwarming-analise word meer gedefinieerd en ‘n piek word gevorm soos die voorafgaande afkoelings tempo verlaag. Komplekse impak-polipropileen monsters, wat net verskil in die hoeveelheid etileen inhoud is geanaliseer en verskille is bepaal. Moontlike toepassings van die SCALLS instrument is ondersoek. Dit is bewys dat die instrument gebruik kan word om die fraksionering temperature vooraf te bepaal vir prep-TREF.

The impact strength of Nylon 6 was improved by adding Ethylene- n-Butyl acrylate- maleic anhydride (E-nBA-MAH) terpolymer with various concentrations from 0% (w/w) to 15% (w/w). The bare interaction energy between two polymers was investigated by using melting point depression approach utilizing both the Flory-Huggins (FH) theory and the Sanchez-Lacombe Equation of State (SL EOS). The solution of the mixture was electrospun, and the effects of process parameters on the expected radii of nanofibers were investigated. The effects of process parameters such as polymer concentration in solution, electrical field, diameter of syringe needle, feed rate, and collector geometry on nanofibers were studied. The statistical analysis to relate these parameters on the diameter of nanofibers was carried out by using Johnson SB distribution. The ratio of elastic modulus to viscosity coefficient of nanofibers was worked out by using AFM and combined viscoelastic models. The experiments were carried out on single fiber. The ratio came out to be a function of nanofiber diameter and terpolymer concentration. Isothermal crystallization kinetics and WAXS diffraction patterns of blends revealed and also SEM images supported that after 5% addition of elastomeric terpolymer, the interaction between the components of the blend gets weaker. The elastic modulus of the blend with 5% of terpoymer was greater than that of the neat Nylon 6, but the elastic modulus decreased for the blends containing more than 5% terpolymer.