Submitted by Jean Medeiros (jeanletras@uepb.edu.br) on 2017-10-24T12:45:23Z No. of bitstreams: 1 PDF - Isabelly da Silva Venâncio de Macêdo.pdf: 21766192 bytes, checksum: 18670653de69a62d3b2eb439387816e8 (MD5) / Approved for entry into archive by Secta BC (secta.csu.bc@uepb.edu.br) on 2017-10-26T16:55:33Z (GMT) No. of bitstreams: 1 PDF - Isabelly da Silva Venâncio de Macêdo.pdf: 21766192 bytes, checksum: 18670653de69a62d3b2eb439387816e8 (MD5) / Made available in DSpace on 2017-10-26T16:55:33Z (GMT). No. of bitstreams: 1 PDF - Isabelly da Silva Venâncio de Macêdo.pdf: 21766192 bytes, checksum: 18670653de69a62d3b2eb439387816e8 (MD5) Previous issue date: 2017-03-07 / In recent decades to expand the development of nutraceuticals from the use of plants containing active metabolites for the support not treating various diseases.The rutin is a naturally occurring flavonoid widely known to exhibit a variety of pharmacological activities, such as antioxidant, antiplatelet and antitumor agonist making it a promising candidate for nutraceuticals for chemoprevention purposes. However, its low solubility in aqueous media hinders its permeation in biological systems, thus reducing its therapeutic activity. The development of solid dispersions has been shown to be an effective technique for promoting the increase of aqueous solubility of drugs. The aim of this work was to produce solid dispersion microparticles of rutin, aiming to increase their aqueous solubility. The microparticles were produced by spray-drying using a Box-Behnken factorial design. It was used as carrier polyvinylpyrrolidone (PVP K-30) and for drying colloidal silicon dioxide (Aerosil® 200). The variables of the process studied were the temperature, percentage of rutin and the percentage of Aerosil, totaling 15 experiments. Physical mixtures of the active compound with adjuvants in 1: 1 and 1:9 ratios were also prepared. The results obtained were analyzed by the surface response technique (ANOVA). The evaluated parameters, besides the aqueous solubility, were yield, moisture content, solubility, dissolution in vitro. The microparticles as well as the physical mixtures were characterized by thermal analysis techniques: differential thermal analysis and thermogravimetry, X-ray diffraction and scanning electron microscopy. Statistical analysis showed that the yield was influenced by only one variable, while the moisture content was influenced directly by temperature in combination with the percentage of aerosil. The microparticles showed good yield (31% - 52%) and low moisture content (lessthan 2%). Regarding the solubility, there was no significant change between the microparticles related to the studied parameters. However, there was a significant increase in the solubility of the microparticles when related to the pure drug, with a solubility increase of up to 9 times, besides the excellent increase in the dissolution profile of the drug. Regarding thermal analysis and complementary techniques, the results showed good thermal and physical stability profile of the microparticles. Therefore, the development of microparticulate solid dispersions containing rutin by spray drying was able to increase the solubility of this flavonoid, making it a potential candidate as a nutraceutical for use in complementary diets. / Nas últimas décadas tem se expandido o desenvolvimento de nutracêuticos a partir da utilização de plantas que contém metabólitos ativos para suporte no tratamento de diversas doenças. A rutina é um flavonoide natural extensamente conhecido por apresentar variedade de atividades farmacológicas como, por exemplo, antioxidante, anti-agregante plaquetária e antitumoral tornando-a um promissor candidato a nutracêutico para fins de quimioprevenção. Entretanto, sua baixa solubilidade em meio aquoso dificulta sua permeação nos sistemas biológicos diminuindo assim sua atividade terapêutica. O desenvolvimento de dispersões sólidas tem se mostrado como uma técnica eficaz para a promoção do incremento da solubilidade aquosa de fármacos. Esse trabalho teve como objetivo produzir micropartículas de dispersão sólida de rutina visando o incremento de sua solubilidade aquosa. As micropartículas foram produzidas por spray-drying usando um planejamento fatorial Box-Behnken. Foi usando como carreador polivinilpirrolidona (PVP K-30) e para secagem dióxido de silício coloidal (Aerosil® 200) . As variáveis do processo estudas foram a temperatura, porcentagem de Rutina e a porcentagem do Aerosil, totalizando 15 experimentos. Foram preparadas também misturas físicas do ativo com os adjuvantes nas proporções 1:1 e 1:9. Os resultados obtidos foram analisados pela técnica de superfície de resposta (ANOVA). Os parâmetros avaliados, além da solubilidade aquosa, foram rendimento, teor de umidade, solubilidade, dissolução in vitro. As micropartículas assim como as misturas físicas foram caracterizadas pelas técnicas de análise térmica: análise térmica diferencial e termogravimetria, difração de raios X e microscopia eletrônica de varredura. A análise estatística demonstrou que o rendimento sofreu influência de apenas uma variável, enquanto que o teor de umidade sofreu influência direta da temperatura em combinação com a porcentagem de aerosil. As micropartículas apresentaram bom rendimento (31% – 52%) e baixo teor de umidade (inferior a 2%). Quanto a solubilidade não houve alteração significativa entre as micropartículas relacionada aos parâmetros estudados. Porém, houve um aumento significativo da solubilidade das micropartículas quando relacionado ao fármaco puro, com incremento de solubilidade de até 9 vezes, além do excelente aumento no perfil de dissolução do fármaco. Com relação a análise térmica e técnicas complementares os resultados mostraram bom perfil de estabilidade térmica e física das micropartículas. Portanto, o desenvolvimento de dispersões sólidas microparticuladas contendo rutina por spray drying foi capaz de aumentar a solubilidade desse flavonóide, tornando-o um potencial candidato como nutracêutico para ser usado em dietas complementares.

Submitted by Irene Nascimento (irene.kessia@ufpe.br) on 2016-08-11T19:25:05Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) SALVANA PRISCYLLA MANSO COSTA_PPGIT_CCB_2016.pdf: 8213740 bytes, checksum: c0b4ea6211a86ddfa6dab45ce846ee02 (MD5) / Made available in DSpace on 2016-08-11T19:25:05Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) SALVANA PRISCYLLA MANSO COSTA_PPGIT_CCB_2016.pdf: 8213740 bytes, checksum: c0b4ea6211a86ddfa6dab45ce846ee02 (MD5) Previous issue date: 2016-02-26 / CAPES / efavirenz (EFZ) é considerado uma das drogas anti-HIV mais utilizadas, porém é classificado como fármaco de classe II (baixa solubilidade, alta permeabilidade), segundo o sistema de classificação biofarmacêutica, apresentando problemas de absorção no trato gastrointestinal e, consequentemente, biodisponibilidade inadequada para sua ação terapêutica. Assim, este trabalho objetivou desenvolver sistemas microparticulados com polímeros inovadores afim de contornar estes entraves através da técnica de dispersões sólidas (DS). Para o desenvolvimento de DS com o EFZ, realizaram-se, inicialmente, estudos teóricos e práticos que permitiram selecionar o PVP-K30, o PVPVA 64 SOLUPLUS e HPMCAS como carreadores da formulação. As DS com esses polímeros foram preparadas pelo método do solvente. A análise de Difração de raios-X (DRX) mostrou que os polímeros são capazes de manter o EFZ em sua forma amorfa até uma concentração de 80% fármaco. Através dos estudos de dissolução in vitro, verificou-se que o sistema DS PVPVA 64 – EFZ 10% seria o mais promissor, uma vez que o mesmo foi capaz de aumentar em até seis vezes a AUC quando comparado ao fármaco isolado, além de manter os níveis de supersaturação por um período de 120 minutos. Os sistemas DS PVP-K30 – EFZ 10% e DS HPMCAS – EFZ 10% obtiveram bons resultado no estudo de dissolução in vitro e, assim, também foram selecionados. O método para quantificação do EFZ otimizado foi co-validado de acordo com o preconizado pela RE nº 899/03 da ANVISA e pelo ICH e demonstrou-se: linear, preciso e exato para os parâmetros avaliados. A caracterização físico-química das DS com PVP K-30 e PVPVA 64 através de técnicas calorimétricas, microscópicas e espectrofotométricas evidenciou a conversão do EFZ para o seu estado amorfo e verificou que o PVPVA 64 interage de maneira mais efetiva quando comparado ao PVP-K30. No entanto com base nos resultados preliminares do estudo de estabilidade acelerada, pode-se observar que tanto o PVP K-30 quanto o PVPVA 64 foram capazes de inibir a cristalização do fármaco, ao final de três meses de estudo. O comportamento e a estabilidade térmica do EFZ e da DS PVPVA 64 – EFZ 10% foram investigados por TG, DSC, DSC fotovisual e pirolisador acoplado a CG/MS. Foram observadas diferenças entre as curvas TG do fármaco puro e aquela do produto farmacêutico, devido à presença do polímero. Bem como, pôde-se observar que a DS promoveu uma proteção térmica ao EFZ, mostrando uma boa qualidade da formulação. Para os parâmetros cinéticos obtidos nas condições não-isotérmica e isotérmica, os valores da Ea para a DS foi igual a 101 e 132 kJ/mol, respectivamente, enquanto que os valores de Ea para o EFZ, segundo a literatura, estão entre 88 – 93 kJ/mol. A ordem da cinética de degradação da DS foi de primeira ordem, diferentemente do EFZ puro, que é de ordem zero. Além disso, através da equação de Arrhenius, pôde-se sugerir uma estabilidade de sete meses para a formulação. Os valores dos parâmetros cinéticos determinados pelos métodos isoconvencionais obtiveram valores de Ea na faixa de 88 – 95 kJ.mol-1, isto indica uma boa correlação entre os métodos aplicados. Uma vez que os valores de Ea variaram de acordo com o grau de conversão (a), pode-se verificar que o processo de degradação do EFZ se faz por mecanismos do tipo contração geométrica e nucleação. Dessa forma, a partir do estudo, obteve-se DS estáveis e adequadas para superar as limitações de solubilidade do efavirenz. / Efavirenz (EFV) is considered one of the most widely used anti-HIV drugs, but the drug is classified as class II (low solubility, high permeability) according to the biopharmaceutical classification system, having problems with absorption in the gastrointestinal tract and thereby inadequate bioavailability for its therapeutic action. Thus, this study aimed to overcome these barriers through the technique of solid dispersions (SD). For the development of SD with EFZ theoretical and practical studies were initially held which allowed the selection of PVP-K30, PVPVA 64, SOLUPLUS and HPMCAS as carriers of the formulation. The SD systems with these polymers were prepared by the solvent method. The analysis of X-ray diffraction (XRD) showed that the polymers are able to maintain EFZ in its amorphous form up to a concentration of 80% of drug. Through the in vitro dissolution studies, it was found that the SD system PVPVA 64 - EFV 10% would be the most promising since it was able to increase up to six times the AUC when compared to the drug alone, and to maintain the levels of supersaturation for a period of 120 minutes. The SD systems PVP- K30 - EFZ 10% and HPMCAS – EFZ 10% achieved good result during the in vitro dissolution study and, thus, it was also selected. The method for quantification of co-optimized EFZ was validated according to the criteria of the RE nº 899/03 of ANVISA and the ICH and demonstrated: linear, precise and accurate for all parameters evaluated.The physico-chemical characterization of the SD systems with PVP K-30 and PVPVA 64 through calorimetric, microscopic and spectroscopic techniques revealed the conversion of EFZ to its amorphous state and found that the PVPVA 64 interacts more effectively when compared to PVP- K30. However, based on preliminary results of the accelerated stability study, it can be seen that the PVP K-30 polymer was the most inhibitory effect crystallization of the drug after six months of study. The behavior and thermal stability of EFZ and SD PVPVA 64 - EFV 10% were investigated by TG, DSC, DSC photovisual and pyrolyzer coupled with GC/MS. Differences between the TG curves of the pure drug and the pharmaceutical product were observed due to the presence of the polymer. Also, it was observed that the SD promoted a thermal protection of EFZ, showing the good quality of the formulation. Regarding the kinetic parameters obtained for the non-isothermal and isothermal conditions, the activation energy (Ae) values of the SD were equal to 101 and 132 kJ/mol, respectively, while the Ae values for the EFV, according to literature, are between 88 - 93 kJ/mol. Besides that, a first-reaction order was found for the SD, unlike the one for the pure EFZ, which was a zero-reaction order. Furthermore, by the Arrhenius equation, it could be suggested that the formulation would remain stable for seven months. In conclusion, in this study, we obtained stable and adequate SD systems to overcome the solubility limitations of efavirenz.

O melhoramento das propriedades de dissolução de produtos farmacêuticos é extremamente importante, visto que houve um aumento de fármacos de baixa solubilidade disponibilizados no mercado farmacêutico nos últimos tempos. Várias técnicas têm sido utilizadas para melhorar as propriedades de dissolução destes fármacos como a cominuição, o uso de surfactantes e o preparo de dispersões sólidas. A preparação de dispersões sólidas é um método útil para dispersar moléculas de fármaco em uma matriz sólida hidrofílica. A técnica de spray congealing é usada para produção de micropartículas não necessitando de solventes orgânicos ou aquosos. O presente trabalho teve o objetivo de produzir micropartículas de dispersão sólida contendo carbamazepina (CBZ) preparadas por spray congealing e estudar a influência dos parâmetros do processo. A CBZ foi usada como fármaco modelo por apresentar baixa solubilidade e ser o medicamento de primeira escolha no tratamento da epilepsia psicomotora. Inicialmente foram preparadas dispersões sólidas usando como carreador o polioxilglicerídeo (Gelucire® 50/13), e os polietilenoglicóis (PEG 4000 e PEG 6000) nas proporções 1:9, 1:5 e 1:1 (fármaco:carreador), pelo método da fusão e posteriormente submetidas a estudos de solubilidade, onde a dispersão sólida com Gelucire® 50/13 (1:9) mostrou melhor solubilidade em relação a CBZ pura, sendo selecionada para o processo de produção de microparticulados por spray congealing. As micropartículas foram obtidas utilizando um planejamento experimental do tipo Box-Behnken, estudando os seguintes parâmetros: vazão de dispersão, vazão do ar de resfriamento e pressão de atomização num total de 15 experimentos. Os microparticulados foram caracterizados pelos estudos de tamanho de partícula, densidade aparente, densidade compactada, fator de Hausner, índice de Carr, ângulo de repouso, eficiência de encapsulação, atividade de água, solubilidade, teor de umidade e rendimento do processo, sendo todas estas propriedades avaliadas pela técnica de superfície de resposta (ANOVA). A análise estatística demonstrou que o rendimento sofreu influência das três variáveis enquanto que o teor de umidade foi dependente apenas da vazão de dispersão. As demais propriedades não sofreram influência significante dos parâmetros estudados. A dispersão sólida, a mistura física e as micropartículas de CBZ em Gelucire® 50/13 tiveram suas características físico-químicas avaliadas por difração de raios-x, espectroscopia em infravermelho, microscopia de plataforma a quente e análises térmicas (DSC e TG). Os resultados das análises mostraram que não ocorreram interações físico-químicas entre o fármaco e o carreador. No entanto, o processo de preparo da dispersão conduziu uma mudança no estado cristalino da CBZ convertendo parcialmente a forma polimórfica III para uma forma I. Os microparticulados apresentaram fluxo de bom a moderado com bons rendimentos (50-80 %), baixo teor de umidade (< 2%), atividade de água menor que 0,550 e boa eficiência de encapsulação (99,5 a 112 %). O tamanho médio das micropartículas variou de 53,09 a 78,75 µm.e sua morfologia analisada por microscopia eletrônica de varredura mostrou forma esférica, superfície lisa com algumas irregularidades e aparentemente não porosa. A solubilidade da CBZ contida nas micropartículas apresentou um aumento de 2,70 vezes em relação ao fármaco puro. As características do estado sólido das micropartículas foram semelhantes às da dispersão sólida. As micropartículas estudadas conduziram a um aumento na taxa de dissolução in vitro da CBZ comparada a sua respectiva dispersão sólida e a CBZ pura. Portanto, o spray congealing, é um método promissor para ser empregado e desenvolvido na fabricação de micropartículas de fármacos pouco solúveis. / Improvement of dissolution properties of pharmaceutical products is extremely important, especially because the percentage of poor water soluble drugs has increased in the pharmaceutical market lately. Several techniques have been used to improve the dissolution properties of drugs such as grinding, the use of surfactants and preparation of solid dispersions. The preparation of solid dispersions is a useful method for disperse the drug molecules in a hydrophilic solid matrix. The spray congealing technique is used for production of microparticles and do not require organic or aqueous solvents. This work aimed to produce microparticles of solid dispersion prepared by spray congealing and to study the influence of process parameters. Carbamazepine (CBZ) was used as model drug due to its poor solubility and because it is the first choice drug for the treatment of psychomotor epilepsy. Initially solid dispersions were prepared using as carriers polyoxylglyceride (Gelucire® 50/13), and polyethylene glycols (PEG 4000 and PEG 6000) in the proportions 1:9, 1:5 and 1:1 (drug: carrier), applying the hot melt method .Solid dispersion with Gelucire ® 50/13 (1:9) showed better solubility compared to pure CBZ, being selected for the further production of microparticles by spray congealing. The microparticles were obtained using a Box Behnken experimental design, studying the following parameters: flow rate of liquid dispersion, flow rate of cooling air and atomizing pressure for a total of 15 experiments. The microparticles were characterized by studies of particle size, bulk density, compacted density, Hausner factor, Carr index, angle of repose, encapsulation efficiency, water activity, solubility, moisture content and yield of the process. These effects were analyzed by response surface technique (ANOVA). Statistical analysis showed that the yield was influenced by all three variables while the moisture was only dependent on the flow dispersion. The other properties were not significantly influenced by the parameters. The solid dispersion, physical mixture and microparticles of CBZ in Gelucire® 50/13 had their physical and chemical characteristics evaluated by x-ray diffraction, infrared spectroscopy, hot stage microscopy and thermal analysis (DSC and TG). The analysis of the results showed that there were no physical-chemical interactions between the drug and carrier. However, the preparation process of dispersion has led to a change in the crystalline state of CBZ, partially converting the polymorphic form III to the polymorphic form I. The microparticles showed good to moderate flow and good yields (50-80%), low moisture content (<2%), water activity lowerless than 0.550 and good encapsulation efficiency (99.5 to 112%) The average size microparticles ranged from 53.09 to 78.75 m. The morphology was analyzed by scanning electron microscopy and showed spherical shape, smooth surface with minor irregularities and apparently non-porous. The solubility of CBZ in the microparticles showed an increase of 2.70 times the solubility CBZ alone. The characteristics of microparticulated solid dispersions were similar to that of the solid dispersion. The microparticles studied led to an increase in dissolution rate of CBZ in vitro compared to its corresponding solid dispersion and pure CBZ. Therefore, the spray congealing is a promising method to be developed and employed in the manufacture of microparticles of poorly soluble drugs.

<p>As amorphous solid dispersions (ASDs) are more widely employed as a formulation strategy for poorly water-soluble drugs, there is a pressing need to increase the drug loading in these formulations. The drug loading is typically kept low to obtain the desired drug release rate, but often results in large or even multiple dosage units, which is undesirable from a patient compliance perspective. We have identified the cause of this conundrum to be the drug loading dependent dissolution mechanism of ASDs. At low drug loadings, the dissolution rate of ASDs is polymer-controlled, while at high drug loadings, the dissolution rate is drug-controlled and considerably slower. This phenomenon is most pronounced for ASDs with hydrophilic polymers, such as poly (vinylpyrrolidone-co-vinyl acetate) (PVPVA) and the change in dissolution mechanism from being polymer-controlled to drug-controlled has been attributed to water-induced amorphous-amorphous phase separation (AAPS) in higher drug loading ASD matrices of hydrophilic polymers. The drug loading limit for this switch has been found to be dependent on drug properties as well as drug-polymer interactions. Interestingly, drug-polymer hydrogen bonding interaction has been found to be detrimental and decrease the drug loading limit for polymer-controlled release while drug log P did not have any impact on this limit. Variable dissolution temperature studies indicated a detrimental impact on the polymer-controlled drug loading limit when the drug-rich phase (of phase separated ASD matrix) exists in a glassy state. ASDs with relatively hydrophobic polymers, such as hypromellose acetate succinate (HPMCAS), have been found to be polymer-controlled up to higher drug loadings. The mechanistic understanding obtained in this body of work can thus be adopted to develop strategies enabling ASD formulations with optimized performance and improved drug loading.</p>

Pullulan is a non-ionic water-soluble polysaccharide which is produced from starch by the yeast-like fungus Aureobasidium pullulans. Pullulan is known for its non-toxicity and biocompatibility. Most pullulan modifications are intended to reduce its water solubility or to introduce charged or reactive groups for functionality. Polysaccharides that have been hydrophobically modified and contain carboxyl groups are commonly used in drug delivery systems because of their ability to provide pH-controlled drug release. We demonstrated in this dissertation the regioselective synthesis of a range of 6-carboxypullulan ethers that are promising anionic derivatives for drug delivery applications. These compounds have also shown impressive surfactant properties. Another class of pullulan derivatives was synthesized by regioselective introduction of amine and amide groups to the pullulan backbone. These chemical groups are known to play a fundamental role in the biological activity of important polysaccharides, such as chitin and chitosan, therefore, the pullulan derivatives synthesized herein, which are structural isomers of those polymers, possess great potential for biomedical applications. Clarithromycin (CLA) is an aminomacrolide antibiotic whose physical properties are fascinating and challenging. It has very poor solubility at neutral intestinal pH, but much higher solubility under acidic conditions. Therefore, CLA dissolves better in the stomach than in the small intestine; but CLA is also quite labile towards acid-catalyzed degradation. We report herein a study on amorphous solid dispersion (ASD) of CLA with promising carboxyl-containing cellulose derivatives, both as macro and nanoparticles. This approach was intended to improve CLA solubility in neutral media, to protect it from acid degradation, and thereby increase its uptake from the small intestine and ultimately its bioavailability. We have also prepared ASDs of selected anti-HIV drugs, ritonavir (RTV), efavirenz (EFV) and etravirine (ETR) with the cellulosic derivative carboxymethyl cellulose acetate butyrate (CMCAB). This polymer was efficient in stabilizing RTV and EFV in their amorphous form in the solid phase and all ASDs provided significant enhancement of drug solution concentration. / Ph. D.

The feasibility of hot melt extrusion (HME) was explored for development of amorphous solid dispersion systems. Controlled release formulations were developed using a cellulose based derivative, AffinisolTMHPMC 100cP and 4M grades. BCS class II drugs ibuprofen and posaconazole were selected due to their difference in glass transition temperature and lipophilicity. This study focused on investigation of the impact the material attributes and process parameters on the critical quality attributes in preparation of amorphous solid dispersions using hot melt extrusion. The critical quality attributes were sub divided into three main attributes of material, process and product. Rheology of ibuprofen-Affinisol 100cP from melt phase to extrudate phase was tracked. A partial factorial design was carried out to investigate the critical parameters affecting HME. For optimisation of 40%IBU-Affinisol 100cP blends, a feed rate of 0.6kg/hr, screw speed of 500rpm and screw configuration with two mixing elements were found to be optimum for single phase extrudates. ATR-FTIR spectroscopy was found to be an indirect technique of choice in predicting the maximum ibuprofen drug load within extrudates. Prediction was based on the prepared extrudates without charging them to stability conditions. An alternative strategy of incorporation of di-carboxylic acids to increase the dissolution of posaconazole-Affinisol 4M blends was investigated. Succinic acid and L- malic acid incorporation was found to increase the dissolution of posaconazole. Although, the extrudates crystallised out quicker than the naïve posaconazole-Affinisol 4M, but free posaconazole formed eutectic and co-crystal with succinic and L-malic acid within extrudates. This lead to an increase in dissolution of the extrudates compared to day 0.

No description available.

Polymer functional groups have critical impacts upon physical, chemical and mechanical properties, and thus affect the specific applications of the polymer. Functionalization of cellulose esters and ethers has been under extensive investigation for applications including drug delivery, cosmetics, food ingredients, and automobile coating. In oral delivery of poorly water-soluble drugs, amorphous solid dispersion (ASD) formulations have been used, prepared by forming miscible blends of polymers and drugs to inhibit crystallization and enhance bioavailability of the drug. The Edgar and Taylor groups have revealed that some cellulose omega-carboxyalkanoates were highly effective as ASD polymers, with the pendant carboxylic acid groups providing both specific polymer-drug interactions and pH-triggered release through swelling of the ionized polymer matrix. While a variety of functional groups such as hydroxyl and amide groups are also of interest, cellulose functionalization has relied heavily on classical methods such as esterification and etherification for appending functional groups. These methods, although they have been very useful, are limited in two respects. First, they typically employ harsh reaction conditions. Secondly, each synthetic pathway is only applicable for one or a narrow group of functionalities due to restrictions imposed by the required reaction conditions. To this end, there is a great impetus to identify novel reactions in cellulose modification that are mild, efficient and ideally modular. In the initial effort to design and synthesize cellulose esters for oral drug delivery, we developed several new methods in cellulose functionalization, which can overcome drawbacks of conventional synthetic pathways, provide novel cellulose derivatives that are otherwise inaccessible, and present a platform for structure-property relationship study. Cellulose omega-hydroxyalkanoates were previously difficult to access as the hydroxyl groups, if not protected, react with carboxylic acid/carbonyl during a typical esterification reaction or ring opening of lactones, producing cellulose-g-polyester and homopolyester. We demonstrated the viability of chemoselective olefin hydroboration-oxidation in the synthesis of cellulose omega]-hydroxyesters in the presence of ester groups. Cellulose esters with terminally olefinic side chains were transformed to the target products by two-step, one-pot hydroboration-oxidation reactions, using 9-borabicyclo[3.3.1]nonane (9-BBN) as hydroboration agent, followed by oxidizing the organoborane intermediate to a primary alcohol using mildly alkaline H2O2. The use of 9-BBN as hydroboration agent and sodium acetate as base catalyst in oxidation successfully avoided cleavage of ester linkages by borane reduction and base catalyzed hydrolysis. With the impetus of modular and efficient synthesis, we introduced olefin cross-metathesis (CM) in polysaccharide functionalization. Using Grubbs type catalyst, cellulose esters with terminally olefinic side chains were reacted with various CM partners including acrylic acid, acrylates and acrylamides to afford families of functionalized cellulose esters. Molar excesses of CM partners were used in order to suppress potential crosslinking caused by self-metathesis between terminally olefinic side chains. Amide CM partners can chelate with the ruthenium catalyst and cause low conversions in conventional solvents such as THF. While the inherent reactivity toward CM and tendency of acrylamides to chelate Ru is influenced by the acrylamide N-substituents, employing acetic acid as a solvent significantly improved the conversion of certain acrylamides. We observed that the CM products are prone to crosslinking during storage, and found that the crosslinking is likely caused by free radical abstraction of gamma-hydrogen of the alpha, beta-unsaturation and subsequent recombination. We further demonstrated successful hydrogenation of these alpha, beta-unsaturated acids, esters, and amides, thereby eliminating the potential for radical-induced crosslinking during storage. The alpha, beta-unsaturation on CM products can cause crosslinking due to gamma-H abstraction and recombination if not reduced immediately after reaction. Instead of eliminating the double bond by hydrogenation, we described a method to make use of these reactive conjugated olefins by post-CM thiol-Michael addition. Under amine catalysis, different CM products and thiols were combined and reacted. Using proper thiols and catalyst, complete conversion can be achieved under mild reaction conditions. The combination of the two modular reactions creates versatile access to multi-functionalized cellulose derivatives. Compared with conventional reactions, these reactions enable click or click-like conjugation of functional groups onto cellulose backbone. The modular profile of the reactions enables clean and informative structure-property relationship studies for ASD. These approaches also provide opportunities for the synthesis of chemically and architecturally diverse cellulosic polymers that are otherwise difficult to access, opening doors for many other applications such as antimicrobial, antifouling, in vivo drug delivery, and bioconjugation. We believe that the cellulose functionalization approaches we pioneered can be expanded to the modification of other polysaccharides and polymers, and that these reactions will become useful tools in the toolbox of polymer/polysaccharide chemists. / Ph. D.

In an effort to produce new derivatives of cellulose for drug delivery applications, methods were developed to regioselectively modify C-6 halo cellulose esters to produce cationic derivatives via nucleophilic substitution. Reaction of C-6 substituted bromo and iodo cellulose with trialkylated amines and phosphines produced new cationic ammonium and phosphonium cellulose derivatives which can be explored as delivery agents for nucleic acids, proteins and other anionic drug molecules. It was anticipated that these new derivatives would not only be capable of complexing anionic drug molecules but would have greatly improved aqueous solubility compared to their precursors. The phosphonium derivatives described in this work are an obvious example of such improved solubility properties. Given the importance of cellulose derivatives in making amorphous dispersions with critical drugs, it has also been important to analyze commercially available polymers for the potential impact in oral drug delivery formulations. To do so pairwise blends of cellulosics and synthetic polymers commonly used as excipients were tested for miscibility using techniques such as DSC, mDSC, FTIR and film clarity. Miscible combinations highlight the potential to use combinations of polymers currently available commercially to provide drug delivery solutions for specific drug formulations. The use of melt extrusion in processing some of these drug/polymer dispersions provides a means of highlighting the capability for the use of these cellulosics in melt extruded amorphous dispersions. This solvent free, high pressure method significantly reduces cost and time and can be applied on a large scale. The analysis of long chain cellulose esters and ultimately the novel omega carboxy esters for melt processability significantly impacts the possibilities available for use of those excellent drug delivery agents on a much larger scale. / Ph. D.

The feasibility of the injection moulding (IM) was explored for the development of novel drug delivery systems. Controlled release formulations were developed using a substituted cellulose derivative, hydroxypropyl methyl cellulose acetate succinate (HPMCAS) and a graft co-polymer (Soluplus®). BCS class II drugs ibuprofen and the felodipine were selected based on their physicochemical properties. In the present work, a homogenous dispersion of drugs in the polymer matrices was achieved using Hot Melt Extrusion (HME) and extruded pellets obtained were used for the development of the injection moulded systems. Four systems were developed using the IM consisting of ibuprofen-HPMCAS, ibuprofen-Soluplus®, felodipine-PEO-HPMCAS and felodipine-Soluplus®. The ibuprofen acts as a good plasticiser compared to felodipine therefore, felodipine containing IM systems required a plasticiser (PEO) when processed with HPMCAS. The analysis of extruded pellets and injection moulded systems using modulated DSC (MDSC) and Raman spectroscopy confirmed the formation of an amorphous molecular dispersion (i.e solid solution) in the case of all four systems. The phase separation behaviour and the amorphous stability of the systems was studied at various stress conditions. This revealed the “surface crystallisation” behaviour of the ibuprofen-HPMCAS systems. Temperature-composition phase diagram constructed based on the melting point depression and the Flory-Huggins lattice solution theory provided the explanation for the phase separation and crystallisation behaviour of ibuprofen-HPMCAS systems. The advanced characterisation techniques like DMA, 2D XRD and 3D laser microscopy provided the detailed understanding of crystal habits, phase seperation and surface crystallisation. The significant effect of the stress conditions on the rate of shrinkage was observed where, higher shrinkage tendency of a HPMCAS IM system was observed compared to Soluplus® IM systems. The extruded pellets provided the faster drug release compared to the moulded tablets suggests the effect of particle size as well as the densification during IM on the dissolution rate of the dosage form. The nature of the polymer and processing history were the contributing factors for the dissolution of the dosage forms. / The thesis is hardbound in two volumes. Volume II starts at Chapter 5, page 135.