The use of amorphous solid dispersions (ASDs) is an effective and increasingly widely adopted approach for solubility and bioavailability enhancement of hydrophobic drugs. Cellulose derivatives have strong potential as ASD polymers. We demonstrate herein design, synthesis and structure-property relationship characterization of a new series of organo-soluble cellulose omega-carboxyalkanoates for ASDs, by two different synthetic approaches. These carboxyl-containing cellulose mixed-esters possessed relatively high Tg values with sufficient differences versus ambient temperature, useful to prevent drug mobility and crystallization during storage or transport. Screening experiments were utilized to study the impact of ASD polymers including our new family of cellulose Ω-carboxyesters on both nucleation induction time and crystal growth rate of three poorly soluble model drugs from supersaturated solutions. Attributed to relatively rigid structures and bulky substituent groups, cellulose derivatives were more significant crystallization inhibitors compared to the synthetic polymers. The effective cellulose omega-carboxyesters were identified as possessing a similar hydrophobicity to the drug molecule and high number of ionization groups. Among them, cellulose acetate suberate prepared by us was an extraordinary solution crystal growth inhibitor for ritonavir and its formulated solid dispersions provided a substantial 15-fold enhancement of apparent solution concentration vs. the equilibrium solubility of the crystalline drug. To offset the issue of slow drug release from some cellulose omega-carboxyester based formulations, a new class of amphiphilic cellulosic polymers with hydrophilic oligo(ethylene oxide)-containing side chains was developed via versatile synthetic pathways, and the evaluation of these materials alone or by pairwise polymer blends will be performed as ASD matrices for the enhancement of drug solubility and stability. / Ph. D.

Chemical modification of naturally occurring cellulose into ester and ether derivatives has been of growing interest due to inexhaustible cellulose resources, and to excellent properties and extremely broad applications of these derivatives. However, traditional esterification and etherification involve relatively harsh conditions (strongly acidic or strongly alkaline), greatly limiting the content and range of functional groups that may be installed onto the cellulose backbone. Amorphous solid dispersion (ASD) is an effective method to promote oral delivery of poorly-soluble drugs by dispersing crystalline drugs in a polymer matrix, creating drug supersaturation upon release. Cellulose 𝜔-carboxyesters have been proven to be effective ASD matrices for many different drugs; however, synthesis of such polymers involves protecting-deprotecting chemistry and one synthetic route only leads to one structure. Developing a new generation of cellulosic polymers for oral drug delivery such as ASD matrices requires new synthetic techniques and powerful tools. Olefin cross-metathesis (CM) is a mild, efficient and modular chemistry with extensive applications in organic, polymer, and polysaccharide chemistry. Successful CM can be achieved by appending olefin “handles” from cellulose esters and reacting with electron-deficient olefins like acrylic acid. Cellulose ethers have much better hydrolytic stability compared to esters and are also commercially very important. The overarching theme of this dissertation is to investigate modification of cellulose ether derivatives, and to design and synthesize effective ASD polymers by olefin CM. We first validated the strategy of performing CM by appending metathesis “handles” through etherification and then subjected these terminal olefins to various partners (acrylic acid and different acrylates). After demonstration of the concept, we applied different starting materials (e.g. ethyl cellulose, methyl cellulose, microcrystalline cellulose, and hydroxypropyl cellulose) with distinctive hydrophobicity/hydrophilicity balance. Furthermore, α,β-unsaturated CM products tended to undergo radical crosslinking through abstraction of 𝛾-protons and recombination of polymer radicals. In order to resolve this issue, we first applied post-CM hydrogenation and then explored a thiol-Michael addition to the α,β-unsaturation, which also incorporates an extra functional group through the thioether. We have successfully prepared a collection of cellulose 𝜔-carboxyether derivatives through the above-mentioned method and preliminary drug induction experiments also revealed that these derivatives hold high promise for ASD application. We also explored the possibility of conducting CM in a reverse order: i.e. appending electron-deficient acrylate groups to the polymer, then subjecting it to electron-rich small molecule terminal olefins. The failure of this metathesis approach was speculated to be due mainly to low acrylate reactivity on an already crowded polymer backbone and the high reactivity of rapidly diffusing, small molecule terminal olefins. Last but not least, we further utilized olefin CM to conjugate bile salt derivatives (e.g. lithocholic acid and deoxycholic acid) to a cellulose backbone by converting bile salts into acrylate substrates. Successful CM of bile salt acrylates to cellulose olefin “handles” further demonstrated the great versatility, excellent tolerance, and very broad applicability of this strategy. Overall, we have founded the strategy for performing successful olefin CM in many cellulose ether derivatives with acrylic acid and a variety of different acrylates. Post-CM hydrogenation efficiently removes the α,β-unsaturation and provides stable and effective cellulose 𝜔-carboxyether derivatives for ASD application. Tandem CM/thiol-Michael addition not only eliminates the crosslinking tendency but also enables an even broader library of polymer structures and architectures for structure-property investigations. We anticipate these methods can be readily adapted by polysaccharide chemists and applied with numerous complex structures, which would greatly broaden the range of cellulose and other polysaccharide derivatives for applications including ASDs, P-glycoprotein inhibition, antimicrobial, coating, and other biomedical applications. / Ph. D.

Amorphous active pharmaceutical ingredients remain in the research focus as an avenue to achieve a better solubility of drugs. Several processing techniques are applied to produce amorphous materials. Main two approaches applied to production of amorphous phases are comminution of crystalline materials in order to break down molecular long-range order of their crystal lattices and amorphous phase precipitation from solutions. This thesis is focused on processing challenges in preparation of amorphous API phases from solutions by spray drying and evaporative antisolvent sonoprecipitation. Budesonide (BUD) and simvastatin (SMV) were used as model poorly soluble APIs. Amorphous phases of relatively low-glass transition (Tg) APIs are physically unstable and crystallise upon storage and/or processing conditions. To tackle this issue, for the first time in this work a selection of polyvinylpyrrolidone vinyl acetate (PVP-VA) co-polymers has been applied to investigate impact of sonoprecipitation processing parameters and a composition of PVP-VA on physicochemical and micromeritic properties of BUD/PVP-VA nanoparticulate composites. Studies confirmed that in solid-state BUD is miscible with PVP-VA polymers. Application of factorial design revealed that processing parameters: polymer type, surfactant concentrations, time and amplitude of sonication impact the entrapment efficiency, drug loading, polydispersity and particle size properties of produced nanoparticles. The largest fraction of polymer to drug in produced nanoparticles has been achieved with PVP VA E-535. As it is known that polymer content in formulation of APIs may slow down its dissolution, novel approach to processing and dissolution enhancement of amorphous composites of SMV produced by spray drying has been applied. Introduction of easily crystallising inorganic salt- sodium chloride into spray drying feed rendered SMV-polyvinyl pyrrolidone (PVP) amorphous microparticles loaded with nanocrystalline NaCl. Addition of NaCl successfully facilitated generation of discrete microparticles post spray drying with low-Tg polymers, which otherwise were not processable as binary mixtures. In addition, NaCl content aided tabletability and dissolution of amorphous API composites with more viscous and high-Tg PVP polymers. Studies confirmed that application of factorial design facilitates robust design of production process of amorphous nanocomposites by sonoprecipitation as well as that introduction of soluble nanocrystalline phase into amorphous binary solid dispersion by spray drying aids its processing and dissolution.

Yes / Ciprofloxacin (CIP) is a poorly soluble drug that also displays poor permeability. Attempts to improve the solubility of this drug to date have largely focused on the formation of crystalline salts and metal complexes. The aim of this study was to prepare amorphous solid dispersions (ASDs) by ball milling CIP with various polymers. Following examination of their solid state characteristics and physical stability, the solubility advantage of these ASDs was studied, and their permeability was investigated via parallel artificial membrane permeability assay (PAMPA). Finally, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the ASDs were compared to those of CIP. It was discovered that acidic polymers, such as Eudragit L100, Eudragit L100C==, Carbopol and HPMCAS, were necessary for the amorphization of CIP. In each case, the positively charged secondary amine of CIP was found to interact with carboxylate groups in the polymers, forming amorphous polymeric drug salts. Although the ASDs began to crystallize within days under accelerated stability conditions, they remained fully XCray amorphous following exposure to 90% RH at 25 oC, and demonstrated higher than predicted glass transition temperatures. The solubility of CIP in water and simulated intestinal fluid was also increased by all of the ASDs studied. Unlike a number of other solubility enhancing formulations, the ASDs did not decrease the permeability of the drug. Similarly, no decrease in antibiotic efficacy was observed, and significant improvements in the MIC and MBC of CIP were obtained with ASDs containing HPMCASC") and HPMCASCMG. Therefore, ASDs may be a viable alternative for formulating CIP with improved solubility, bioavailability and antimicrobial activity.

Yes / Real time measurement of melt rheology has been investigated as a Process Analytical Technology (PAT) to monitor hot melt extrusion of an Active Pharmaceutical Ingredient (API) in a polymer matrix. A developmental API was melt mixed with a commercial copolymer using a heated twin screw extruder at different API loadings and set temperatures. The extruder was equipped with an instrumented rheological slit die which incorporated three pressure transducers flush mounted to the die surface. Pressure drop measurements within the die at a range of extrusion throughputs were used to calculate rheological parameters such as shear viscosity and exit pressure, related to shear and elastic melt flow properties respectively. Results showed that the melt exhibited shear thinning behavior whereby viscosity decreased with increasing flow rate. Increase in drug loading and set extrusion temperature resulted in a reduction in melt viscosity. Shear viscosity and exit pressure measurements were found to be sensitive to API loading. These findings suggest that this technique could be used as a simple tool to measure material attributes in-line, to build better overall process understanding for hot melt extrusion.

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.).

A nistatina (NYS) é o fármaco de primeira escolha no tratamento da candidíase oral, que frequentemente acomete mais os indivíduos imunocomprometidos e pacientes com outras desordens (diabetes não tratada, neoplasias, imunodeficiências). No mercado brasileiro, a NYS é encontrada na forma de suspensão oral aquosa, onde o procedimento para sua administração consiste em bochechar o medicamento. Apesar de haver a indicação de que se mantenha o contato direto entre fármaco e a mucosa oral, na qual se encontra a Candida spp., o que aumentaria expressivamente o sucesso terapêutico, a suspensão não apresenta tal propriedade. Assim, a NYS que é fármaco com ação efetiva contra a candidíase oral, é considerada pertencente à Classe IV do Sistema de Classificação Biofarmacêutica, ou seja, apresenta baixa solubilidade e baixa permeabilidade. A baixa solubilidade pode comprometer sua disponibilidade na cavidade oral, e consequentemente, sua ação farmacológica. Diante desse quadro, o objetivo do presente trabalho foi o desenvolvimento de dispersões sólidas de NYS para o tratamento da candidíase oral, e sua posterior incorporação em gel mucoadesivo oral, favorecendo a formulação no local de ação. As dispersões sólidas são sistemas farmacêuticos, onde um fármaco pouco solúvel em água encontra-se dispersado em um carreador, no estado sólido. Os carreadores normalmente são hidrofílicos, o que permite que esses sistemas sejam empregados para aumentar a solubilidade aquosa do fármaco. Assim, foram desenvolvidas as dispersões sólidas de NYS, pelo método de eliminação do solvente, empregando como carreadores, lactose, HPMC, poloxamer 407 e poloxamer 188. Essas foram submetidas à caracterização por análise térmica, usando os ensaios de calorimetria exploratória diferencial (DSC) e termogravimetria/termogravimetria derivada (TG/DTG). Dentre essas dispersões sólidas, aquelas que se mostraram com comportamento térmico sugerindo a formação de um novo \"sistema\", foram analisadas por meio de ensaio de solubilidade. Dessa forma, a formulação NYS DS G2 (49) se destacou, pois apresentou maior solubilidade em água (4,484 mg/mL); em pH 5,5 (4,249 mg/mL) e em pH 7,0 (4,293 mg/mL), ou seja, houve um aumento de 1,426 vezes em água; 4,227 vezes em pH 5,5; e 2,743 vezes em pH 7,0. Essa formulação foi, por fim avaliada por difração de raio-X e espectroscopia de infravermelho com transformada de Fourier, técnicas que corroboraram com a análise térmica quanto à indicação de formação da dispersão sólida. Por sua vez, essa dispersão sólida foi incorporada em 4 bases de géis mucoadesivos de carbopol ® 934 PNF, alterando apenas a concentração do polímero (0,5; 1,0; 1,5; 2,0 %p/p). Foi observado que a liberação de NYS DS G2 (49) foi superior, quando comparada à liberação de NYS MP a partir do gel, e através do ensaio de mucoadesão, percebeu-se que os géis desenvolvidos apresentaram propriedades mucoadesivas compatíveis com relatos na literatura, independentemente da quantidade de carbopol ® empregada. As características reológicas foram distintas, e foi observado que as formulações Gel A e Gel B, que possuem menor quantidade de polímero, tiverem um indicativo de comportamento de fluido newtoniano, diferente dos demais, o que pode não ser desejado para esse tipo de forma farmacêutica tópica e semi-sólida. Ao final desse trabalho, pode-se concluir que foi possível desenvolver um sistema farmacêutico na forma de dispersão sólida com maior solubilidade que a NYS pura, e sua incorporação em uma forma farmacêutica mucoadesiva, e que a liberação da NYS na forma DS foi muito superior que o fármaco na forma \"convencional\", o que permite que a NYS esteja mais disponível na cavidade oral, e também junto à mucosa bucal, o que levaria a efeito farmacológico mais efetivo do antifúngico. / Nystatin (NYS) is the drug of first choice in the treatment of oral candidiasis that most often affect immunocompromised individuals, and patients with other disorders. In the Brazilian market, NYS is found in the form of aqueous oral suspension, a medication used in the form of mouthwash. Although there is an indication to maintain direct contact between the drug and the oral mucosa, where Candida spp. is found, as well as where therapeutic success would significantly be increased, the suspension has no such property. Thus, the NYS is an effective drug against oral candidiasis, and belongs to Class IV of the Biopharmaceutical Classification System, it has low solubility and low permeability. The low solubility can compromise its availability in the oral cavity, and consequently, its pharmacological action. Given this situation, the objective of this work was the development of solid dispersions of NYS for the treatment of oral candidiasis, and its subsequent incorporation into oral mucoadhesive gel, in order to facilitate its action. Solid dispersions are pharmaceutical systems, in which a solid drug poorly soluble in water is dispersed in a carrier. These carriers are usually hydrophilic, and this allows the systems to be employed in order to increase the aqueous solubility of the drug. Thus, the solid NYS dispersions were developed by the solvent evaporation method, employing lactose, HPMC, poloxamer 407 and poloxamer 188 as carrier. These samples were subjected to characterization by thermal analysis, using differential scanning calorimetry (DSC) and thermogravimetry / derivative thermogravimetry (TG / DTG). Among these solid dispersions, those samples which showed a specific thermal behavior suggesting the formation of new \"system\" were analyzed by solubility test. Thus, the NYS DS G2 formulation (49) stood out, once it showed greater solubility in water (4.484 mg/mL); at pH 5.5 (4.249 mg/mL) and pH 7.0 (4.293 mg/mL), in other words, an increase of 1,426 times in water; 4,227 times at pH 5.5; and 2,743 times at pH 7.0. This formulation was finally evaluated by X-ray diffraction, infrared spectroscopy with Fourier transform, techniques that corroborate the thermal analysis, indicating the formation of the solid dispersion. On the other hand, this solid dispersion was incorporated into 4 Carbopol ® 934 PNF mucoadhesive gels, with a variation of the polymer concentration. It was observed that NYS is improved of delivery from the gels, employing mucoadhesion test, and was also observed that the gels have mucoadhesive properties consistent with reports in the literature. However, the rheological characteristics are different, and it was observed that the Gel A and Gel B formulations, which has a lower amount of polymer behaved as a Newtonian fluid, which may not be desired for this type of topical gel. As conclusion, it was possible to develop a pharmaceutical system in the form of solid dispersion with greater solubility than the pure NYS, and their incorporation in a mucoadhesive dosage form and the release of NYS as DS was far superior wherein the drug in the \"conventional\" manner, which allows the NYS is longer available in the oral cavity, and also adjacent to the buccal mucosa, leading to more effective pharmacological effect of the antifungal agent.

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.

A nistatina (NYS) é o fármaco de primeira escolha no tratamento da candidíase oral, que frequentemente acomete mais os indivíduos imunocomprometidos e pacientes com outras desordens (diabetes não tratada, neoplasias, imunodeficiências). No mercado brasileiro, a NYS é encontrada na forma de suspensão oral aquosa, onde o procedimento para sua administração consiste em bochechar o medicamento. Apesar de haver a indicação de que se mantenha o contato direto entre fármaco e a mucosa oral, na qual se encontra a Candida spp., o que aumentaria expressivamente o sucesso terapêutico, a suspensão não apresenta tal propriedade. Assim, a NYS que é fármaco com ação efetiva contra a candidíase oral, é considerada pertencente à Classe IV do Sistema de Classificação Biofarmacêutica, ou seja, apresenta baixa solubilidade e baixa permeabilidade. A baixa solubilidade pode comprometer sua disponibilidade na cavidade oral, e consequentemente, sua ação farmacológica. Diante desse quadro, o objetivo do presente trabalho foi o desenvolvimento de dispersões sólidas de NYS para o tratamento da candidíase oral, e sua posterior incorporação em gel mucoadesivo oral, favorecendo a formulação no local de ação. As dispersões sólidas são sistemas farmacêuticos, onde um fármaco pouco solúvel em água encontra-se dispersado em um carreador, no estado sólido. Os carreadores normalmente são hidrofílicos, o que permite que esses sistemas sejam empregados para aumentar a solubilidade aquosa do fármaco. Assim, foram desenvolvidas as dispersões sólidas de NYS, pelo método de eliminação do solvente, empregando como carreadores, lactose, HPMC, poloxamer 407 e poloxamer 188. Essas foram submetidas à caracterização por análise térmica, usando os ensaios de calorimetria exploratória diferencial (DSC) e termogravimetria/termogravimetria derivada (TG/DTG). Dentre essas dispersões sólidas, aquelas que se mostraram com comportamento térmico sugerindo a formação de um novo \"sistema\", foram analisadas por meio de ensaio de solubilidade. Dessa forma, a formulação NYS DS G2 (49) se destacou, pois apresentou maior solubilidade em água (4,484 mg/mL); em pH 5,5 (4,249 mg/mL) e em pH 7,0 (4,293 mg/mL), ou seja, houve um aumento de 1,426 vezes em água; 4,227 vezes em pH 5,5; e 2,743 vezes em pH 7,0. Essa formulação foi, por fim avaliada por difração de raio-X e espectroscopia de infravermelho com transformada de Fourier, técnicas que corroboraram com a análise térmica quanto à indicação de formação da dispersão sólida. Por sua vez, essa dispersão sólida foi incorporada em 4 bases de géis mucoadesivos de carbopol ® 934 PNF, alterando apenas a concentração do polímero (0,5; 1,0; 1,5; 2,0 %p/p). Foi observado que a liberação de NYS DS G2 (49) foi superior, quando comparada à liberação de NYS MP a partir do gel, e através do ensaio de mucoadesão, percebeu-se que os géis desenvolvidos apresentaram propriedades mucoadesivas compatíveis com relatos na literatura, independentemente da quantidade de carbopol ® empregada. As características reológicas foram distintas, e foi observado que as formulações Gel A e Gel B, que possuem menor quantidade de polímero, tiverem um indicativo de comportamento de fluido newtoniano, diferente dos demais, o que pode não ser desejado para esse tipo de forma farmacêutica tópica e semi-sólida. Ao final desse trabalho, pode-se concluir que foi possível desenvolver um sistema farmacêutico na forma de dispersão sólida com maior solubilidade que a NYS pura, e sua incorporação em uma forma farmacêutica mucoadesiva, e que a liberação da NYS na forma DS foi muito superior que o fármaco na forma \"convencional\", o que permite que a NYS esteja mais disponível na cavidade oral, e também junto à mucosa bucal, o que levaria a efeito farmacológico mais efetivo do antifúngico. / Nystatin (NYS) is the drug of first choice in the treatment of oral candidiasis that most often affect immunocompromised individuals, and patients with other disorders. In the Brazilian market, NYS is found in the form of aqueous oral suspension, a medication used in the form of mouthwash. Although there is an indication to maintain direct contact between the drug and the oral mucosa, where Candida spp. is found, as well as where therapeutic success would significantly be increased, the suspension has no such property. Thus, the NYS is an effective drug against oral candidiasis, and belongs to Class IV of the Biopharmaceutical Classification System, it has low solubility and low permeability. The low solubility can compromise its availability in the oral cavity, and consequently, its pharmacological action. Given this situation, the objective of this work was the development of solid dispersions of NYS for the treatment of oral candidiasis, and its subsequent incorporation into oral mucoadhesive gel, in order to facilitate its action. Solid dispersions are pharmaceutical systems, in which a solid drug poorly soluble in water is dispersed in a carrier. These carriers are usually hydrophilic, and this allows the systems to be employed in order to increase the aqueous solubility of the drug. Thus, the solid NYS dispersions were developed by the solvent evaporation method, employing lactose, HPMC, poloxamer 407 and poloxamer 188 as carrier. These samples were subjected to characterization by thermal analysis, using differential scanning calorimetry (DSC) and thermogravimetry / derivative thermogravimetry (TG / DTG). Among these solid dispersions, those samples which showed a specific thermal behavior suggesting the formation of new \"system\" were analyzed by solubility test. Thus, the NYS DS G2 formulation (49) stood out, once it showed greater solubility in water (4.484 mg/mL); at pH 5.5 (4.249 mg/mL) and pH 7.0 (4.293 mg/mL), in other words, an increase of 1,426 times in water; 4,227 times at pH 5.5; and 2,743 times at pH 7.0. This formulation was finally evaluated by X-ray diffraction, infrared spectroscopy with Fourier transform, techniques that corroborate the thermal analysis, indicating the formation of the solid dispersion. On the other hand, this solid dispersion was incorporated into 4 Carbopol ® 934 PNF mucoadhesive gels, with a variation of the polymer concentration. It was observed that NYS is improved of delivery from the gels, employing mucoadhesion test, and was also observed that the gels have mucoadhesive properties consistent with reports in the literature. However, the rheological characteristics are different, and it was observed that the Gel A and Gel B formulations, which has a lower amount of polymer behaved as a Newtonian fluid, which may not be desired for this type of topical gel. As conclusion, it was possible to develop a pharmaceutical system in the form of solid dispersion with greater solubility than the pure NYS, and their incorporation in a mucoadhesive dosage form and the release of NYS as DS was far superior wherein the drug in the \"conventional\" manner, which allows the NYS is longer available in the oral cavity, and also adjacent to the buccal mucosa, leading to more effective pharmacological effect of the antifungal agent.

No Brasil a esquistossomose é causada pela espécie Schistosoma mansoni e leva principalmente à formação de granulomas e fibroses, hipertensão portal e hepatoesplenomegalia. O praziquantel (PZQ) é o fármaco de primeira escolha para o tratamento e possui baixa solubilidade aquosa, sendo necessárias altas doses para ação terapêutica. A taxa de dissolução do PZQ é fator limitante para a sua biodisponibilidade, portanto, melhorar sua solubilidade é fundamental. O objetivo deste trabalho foi aumentar a solubilidade do PZQ pela obtenção de grânulos contendo dispersões sólidas deste fármaco pelo processo hot melt em leito fluidizado. Além disto, buscou-se estudar a fluidodinâmica e as variáveis do processo de granulação. Inicialmente, dispersões sólidas foram preparadas por simples fusão em polietilenoglicol (PEG) 4000 e PEG 6000 nas proporções 2:1; 1:1; 1:2; 1:5 e 1:10 e estas foram caracterizadas por teste de solubilidade, difração de raios-X, espectroscopia em infravermelho e análises térmicas (DSC e TG). Foram obtidas dispersões sólidas com uma solubilidade duas vezes maior do PZQ, uma menor cristalinidade, uma possível interação fármaco-carreador e sem degradação ou alteração nos principais grupos funcionais. Com estes resultados, a dispersão sólida 1:10 PZQ:PEG 6000 foi escolhida para a etapa da granulação. Os granulados foram obtidos utilizando o planejamento fatorial Box Behnken com as seguintes variáveis: % de dispersão sólida, proporção PZQ:PEG das dispersões e carga de lactose spray-dried (SD) (g). A caracterização dos grânulos foi realizada pelos testes: granulometria, densidade aparente, densidade compactada, fator de Hausner, índice de Carr, ângulo de repouso e doseamento do fármaco, sendo todas estas propriedades avaliadas pela técnica de superfície de resposta (ANOVA). A análise estatística demonstrou que as características dos granulados são, na maioria dos casos, dependentes da % de dispersão sólida e da proporção de PZQ:PEG, sendo satisfatórios e toleráveis os resultados do fluxo dos granulados. Os três melhores granulados foram escolhidos para as análises de microscopia eletrônica de varredura, espectroscopia em infravermelho, difração de raios-X, análise térmica e perfil de dissolução. Estas análises mostraram que nos grânulos houve diminuição da cristalinidade, possíveis interações entre PZQ, PEG e lactose, além do grande aumento no perfil de dissolução. Com estes resultados, confirmam-se as vantagens da granulação por hot melt em leito fluidizado e a importância do estudo de suas variáveis. / In Brazil, schistossomiasis is mainly attributed to the species Schistosoma mansoni, which causes granulomas and fibrosis, portal hypertension and hepatosplenomegaly. Praziquantel (PZQ) is the first choice in the treatment; however, it has low water solubility, thus requiring high doses for a proper therapeutical result. The PZQ dissolution rate is the limiting factor for its bioavailability; therefore, it is fundamental to improve of this drug solubility. The objective of this work was to increase the PZQ solubility with the production of granules containing its solid dispersions, prepared by hot melt process in fluidized bed. Moreover, the fluid dynamic and several variables of the process were studied. First, solid dispersions were prepared by mixing with melted polyethylene glycol (PEG) 4000 and PEG 6000 at the ratios of 2:1; 1:1; 1:2; 1:5 and 1:10. These were characterized by solubility test, x-ray powder diffraction, fourier transform infrared spectroscopy and thermal analyses (DSC and TG). Solid dispersions were obtained with PZQ solubility two times higher than the pure drug, lower crystallinity and without degradation or alteration in the main functional groups. With these results, the solid dispersion 1:10 PZQ:PEG 6000 was chosen for the studies of granulation. The granulates were obtained using the Box Behnken factorial design with the following independent variables: % of solid dispersion, ratio PZQ:PEG in the dispersions and amount of spray-dried lactose (g). The granules characterization was made by the tests of granulometry, bulk density, tapped density, Hausner ratio, Carr index, angle of repose and PZQ assay. In addition, all these properties were evaluated by response surface technique (ANOVA). The statistical analysis, in most cases, showed that the granules characteristics depend significantly on the % of solid dispersion and on the ratio PZQ:PEG. The results on the granules flow properties are satisfactory and acceptable for tableting. The three granulates with best properties were submitted to scanning electron microscopy, fourier transform infrared spectroscopy, x-ray powder diffraction, thermal analysis and dissolution test. These analyses showed that there were, in the granules, decrease of crystallinity, possible interaction among PZQ, PEG and lactose, and also, greater increase in the dissolution test. The advantages of fluid bed hot melt granulation and the importance of studying the process variables are confirmed by the results in this work.