No description available.

Thesis (M.S.)--Virginia Polytechnic Institute and State University, 1994. / Vita. Abstract. Includes bibliographical references. Also available via the Internet.

Graduation date: 1999

No description available.

No description available.

Research in cellulose esters in recent years has concentrated on creating a variety of novel esters with a wide range of thermal and mechanical properties. These cellulose derivatives can be used for membranes, coatings, polymer blends, and other products. Novel cellulose solvent systems (DMAc/LiCl) introduced within the last twenty years have allowed the use of several esterification techniques that could not be used effectively in the past. The combination of the new cellulose solvent systems and esterification chemistry has enabled a large variety of novel cellulose esters to be produced. Four groups of novel cellulose esters were produced in this study, cellulose trifluoroethoxy acetate (CT), cellulose acetate trifluoroethoxy acetate (CATA), cellulose esters of long chain linear aliphatic acids, and cellulose acetate laurate (CAL). The derivatives were synthesized in a homogeneous reaction medium of DMAc/LiCl. Several esterification chemistries were used including one based on reactions with TsCl (para-tolulene sulphonyl chloride). A wide range of degree of substitutions (DS) were produced without degradation to the starting polymer using a range of stoichiometric ratios. The fully substituted mixed cellulose esters were synthesized by consecutive reactions (work-up between reactions) and by "single pot" reactions. "Single" cellulose esters, with free hydroxyls, were produced by single pot reactions. Structure property relationships were examined by several thermal and mechanical analyses. Mechanical response was studied with dynamic mechanical thermal analysis (DMTA) and thermal mechanical analysis (TMA). Thermal response was recorded by differential scanning calorimetry (DSC) and visual analysis. The CT derivatives revealed a linear relationship between T_g and DS between a DS range of 0.6 and 3.0, but no T_m was apparent. All the products with DS > 0.6 flowed without discoloration, therefore the materials were assumed to be mainly amorphous. The CATA derivatives revealed sharp T_gs and T_ms. Surprisingly, the T_gs did not change between the CT and CATA derivatives, and the CATA's T_ms decreased linearly with increasing DS of fluoro-ester. Substituent and main chain T_gs were observed for both CT and CATA derivatives, but the substituent T_g remaining constant throughout the DS range of the flouro-esters. Surprising solubilities were also observed for both CT and CATA derivatives. The long linear aliphatic cellulose esters (with C₁₂ to C₂₀ alkyl substituents) revealed a wide range of thermal and mechanical responses. Side chain and main chain T_gs and T_ms were observed for C₁₂ and C₁₄ derivatives. Only one broad T_m with no T_g was observed for C₁₈ and C₂₀ derivatives by DSC analysis. After annealing, multiple crystalline responses were seen for all the highly substituted C₁₂ to C₂₀ cellulose esters. CAL derivatives revealed sharp T_ms with no T_g. The crystallization rate proved to be much faster for the CAL derivatives than any other derivative in this study. / M.S.

Thesis (Ph. D.)--Institute of Paper Chemistry, 1943. / Bibliography: leaves 124-125.

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Using various synthetic strategies, we designed several libraries of novel polysaccharide mixed ester derivatives for oral drug delivery applications. Cellulose and cellulose esters have been extensively studied and utilized for different applications such as separation membranes, sustainable plastics, and enteric coatings in oral drug delivery carriers. We sought to exploit the ring-opening of cyclic anhydrides, succinic and glutaric anhydride, to append ω-carboxyl groups to commercially available cellulose and cellulose ester substrates. We used scalable synthetic strategies and widely available and cheap reagents to show a proof-of-concept for the manufacturability of these different polymer derivatives. We incorporated different degrees of substitution of ω-carboxyl groups to impart a range of water solubility in these polymers. The derivatives displayed excellent <i>T</i>g values for ASD applications, adequate water solubility, and good amphiphilic properties. We designed very effective amorphous solid dispersion (ASD) oral drug delivery polymers that prevented recrystallization of felodipine for hours and had excellent congruent polymer-drug release from the formulation at 20% drug loading. During the ring-opening reactions of the cellulose derivatives with glutaric anhydride we discovered that crosslinking and gelation can occur, especially with cellulose and cellulose ester substrates with a high degree of substitution (DS) of hydroxy groups. We isolated and characterized these gelled products using rheology, and solid-state 1D and 2D NMR spectroscopy, to evaluate whether the gels are physical or chemical in nature and proposed a mechanism for gelation. We determined that the gels are mostly physical but can proceed to chemical crosslinking over time. We designed a library of cellulose ester derivatives, and we investigated their performance as amorphous solid dispersion (ASD) drug delivery vehicles for the lipophilic drug felodipine, through <i>in vitro</i> experiments. Aside from felodipine, many other active pharmaceutical ingredients (APIs) are also highly crystalline and poorly water-soluble. ASDs are used to disrupt the crystalline packing of these drugs through dispersing them in amorphous polymeric carriers, facilitating their water-solubility, and preventing their recrystallization. We showed that our polymers performed remarkably well in the <i>in vitro</i> studies and inhibited crystallization of model compound felodipine for several hours while providing optimal drug release, affording highly promising ASD polymers. If company formulators are unable to develop an effective oral-delivery carrier to prevent a drug from recrystallizing, then the drug cannot be tested in <i>in vivo</i> toxicology studies, and therefore cannot be brought to market because of its poor aqueous solubility and subsequent low bioavailability. To test the robustness of our polymers, we also performed <i>in vitro</i> ASD experiments at the pharmaceutical company AbbVie with their most rapidly crystallizing pipeline compounds, and several commercially available drugs (Compound A, axitinib, and ziprasidone). We demonstrated that our polymers could also prevent drug recrystallization with these rapid crystallizers, outperforming commercial polymers like FDA-approved hydroxypropyl methyl cellulose acetate succinate (HPMCAS (MF)), even at exceptionally high drug loading ratios of 40 times the concentration of polymer. α-1,3-Glucans are an emerging class of polysaccharides and are structurally different than cellulose due to their α (1→3) linkage versus the cellulose β (1→4) glycosidic linkage. We demonstrated that we could modify these derivatives using a variety of esterification strategies and TEMPO-mediated C6 selective oxidation, affording a myriad of different novel polymer products, some of which are structural analogs of the cellulose ester derivatives we previously created. The polymers had higher <i>T</i>g values than the cellulose ester polymers, which may be useful for applications where heat resistance is desired. In the future, we will screen some of these α-1,3-glucan derivatives with poorly water-soluble enzalutamide, posaconazole and celecoxib model drugs, to evaluate their crystallization inhibition properties and the influence of polymer morphology upon structure-property relationships. We expect that these synthetic polymer strategies will offer scalable routes to novel ASD polymers, which we demonstrated to be highly effective drug crystallization inhibitors against a variety of different hydrophobic pharmaceutical compounds. / Doctor of Philosophy / Polysaccharides are polymers comprised of many linked sugar molecules and are an incredibly abundant and renewable resource. They are found everywhere in nature such as the wood from trees, the shells of crabs, the exoskeletons of bugs, and the mushrooms that sprout in damp forests. The research in this dissertation focuses on the use and chemical modification of polysaccharides for designing new, polysaccharide-based oral drug delivery systems called amorphous solid dispersions (ASDs), which significantly aid in the solubility and bioavailability of important medications. We started with the chemical modification of cellulose, the most abundant plant polysaccharide on planet Earth, and previously modified commercial cellulose substrates (known as cellulose esters) to create novel polymers for ASDs. We successfully modified these polymers, characterized them, and evaluated their potential as oral drug delivery vehicles by formulating them with several different classes of potent drugs used to treat a variety of diseases such as hypertension and schizophrenia. We showed that our designed cellulose ester polymers kept these hydrophobic drugs water-soluble for long-enough so that they can be adequately absorbed in the human body through the gastrointestinal tract, significantly outperforming commercial polymers in many cases. During the chemical modification of the cellulose esters, we also observed that they were prone to form gels, and we investigated this gelation phenomena in more detail through rheometry, 1D and 2D solid-state nuclear magnetic resonance spectroscopy (similar in principle to the medical diagnostic method, magnetic resonance imaging or MRI). We discovered that these gels can be physically and/or chemically linked together, and that different gelation mechanisms can dominate depending on the polysaccharide substrate and the esterification reagent used. We extended our research to other polysaccharide derivatives called α-1,3-glucans, which can be sourced from fungi, and/or enzymatically synthesized in the lab. Using various synthetic esterification and oxidation chemical methods to functionalize this polysaccharide, we designed a library of entirely novel polymers with different physical structures relative to the cellulose ester polymers. The polymers displayed thermal properties that show promise in drug delivery vehicle applications and in applications where high heat resistance is required. Overall, we developed next-generation polymers for amorphous solid dispersion oral drug delivery applications. We displayed the versatility of using a select few chemistry strategies to create a variety of different polymers with very different physicochemical properties. We hope that this work will help researchers design sustainable, plant-based polymers for ASD applications and we hope to nurture future structure-function studies to improve ASD performance for the benefit of patients in need.