Production and mechanistic evalution of the stability of polymorphic olanzapine in solid dosage forms

Tese de doutoramento, Farmácia (Tecnologia Farmacêutica), Universidade de Lisboa, Faculdade de Farmácia, 2016Research related to drug polymorphism is an important aspect in drug product development since the properties of a formulated product, such as its stability and bioavailability, are often directly related to the physicochemical properties of the existing polymorph in the formulation. Olanzapine (OLZ) belongs to a new generation of benzodiazepines for the treatment of schizophrenia and other related psychoses and may exist in several crystalline forms, including polymorphic anhydrates, hydrates and solvates. Consequently, the physical treatments and technological processes undergone by the drug may have an impact on its solid-state, which in turn may affect its performance in terms of dissolution rate, absorption and therapeutic activity and response. OLZ Form I is the form used in marketed tablets and the most stable form at room temperature. The work presented in this Thesis aimed to provide an in-depth understanding of the conversion of olanzapine polymorphic forms into hydrated forms when exposed to different processing conditions. To perform this study we used several techniques, such as a combination of thermal analysis (differential scanning calorimetry (DSC), thermogravimetry (TGA) and hot stage microscopy (HSM)) with spectroscopic (infrared spectroscopy – DRIFT; FTIR), diffraction analysis (XRPD) and surface measurements (contact angle and surface free energy). Dissolution performance and impact of polymorphism on the mechanical characteristic of solid dosage forms was also evaluated. At first, a thorough investigation of the solid state stability of olanzapine forms I and II was performed. Aspects such as the interaction with water and the conversion of both forms into different dihydrates were fully explored. This allowed the successful clarification of the higher hygroscopic nature and easier ability of olanzapine Form II to undergo hydrate formation. On the other hand, Form I showed to hydrate into the lowest soluble form of olanzapine - dihydrate D – when subjected to high RH environments. The interaction of Form I with humidity and excipients was fully investigated. Form I was found to hydrate at different rates depending on the excipients in which it is formulated. Polymers such as polyethylene glycol (PEG) and hydroxypropyl cellulose (HPC) could induce hydrate transformation at lower relative humidity (75%), whereas PVP could avoid hydrate conversions at 93% RH. PEG, when physically mixed with olanzapine, showed to accelerate hydrate conversion, especially when the materials were subjected to a tableting process before storage. This study showed an interesting interplay between the polymer’s choice, load and chemistry that could further be used to maintain the stability of olanzapine in solid-dosage products. Transformations of olanzapine during processing, namely during the rapid expansion of supercritical solutions (RESS) and rapid expansion of supercritical solutions into aqueous solutions (RESSAS) processes were also taken into consideration. These technologies enabled the production of nanoparticles and nanosuspensions of olanzapine, respectively. During the RESSAS process the selection of the right excipients was imperative to produce stable nanosuspensions before and after freeze drying the products. Microcrystalline cellulose and polymers (PEG, PVP and HPC) were used in the process of extrusion and spheronisation of olanzapine. The transformations which occur during processing (wet environments are involved) and during dissolution of the pellets were taken into consideration. During the extrusion process olanzapine showed to hydrate into a mixture of different hydrates when extruded in the presence of microcrystalline cellulose. The addition of polymers such as PVP and HPC to the formulation allowed olanzapine to remain anhydrous during processing and dissolution, which showed to significantly influence the dissolution of the drug. PEG, on the other hand, could not avoid the hydrate formation of olanzapine, having this transformation an impact on the physical and mechanical characteristics of the pellets, as well as an impact on the drug performance. The impact of the polymer content and molecular weight into olanzapine stabilization during wetting were also taken into consideration. In conclusion, the research carried out contributed to a better understanding of the complex characterization of solid state olanzapine and formulated products prepared by different technologies. In detail, it showed the impact of polymorphic/pseudopolymorphic changes on OLZ’s technological performance and dissolution, which highlighted the importance of this study during preformulation and formulation studies.O estudo do polimorfismo de fármacos é uma área científica importante no desenvolvimento de formas farmacêuticas sólidas, uma vez que as propriedades de um produto formulado, tais como estabilidade e biodisponibilidade, estão muitas vezes diretamente relacionadas com as propriedades físico-químicas dos polimorfos existentes na formulação. A olanzapina (OLZ) pertence a uma nova geração de benzodiazepínicos para o tratamento da esquizofrenia e outras psicoses relacionadas. Este fármaco pode existir em várias formas cristalinas, incluindo formas anidras, hidratadas e solvatadas. Por conseguinte, os tratamentos físicos e processos tecnológicos sofridos pelo fármaco podem ter um impacto na estabilidade da forma polimórfica escolhida para o produto final. Consequentemente, estes processamentos podem afetar o seu desempenho em termos de taxa de dissolução, absorção e, finalmente, atividade terapêutica. A olanzapina Forma I é a forma usada nos comprimidos existentes no mercado e é a forma polimórfica mais estável à temperatura ambiente. O trabalho apresentado nesta tese teve como objetivo obter uma compreensão aprofundada da conversão de formas polimórficas de olanzapina em formas hidratadas quando expostas a diferentes condições de processamento. Para tal, neste trabalho foram utilizadas diversas técnicas, tais como uma combinação de análise térmica (DSC, TGA, HSM) com espectroscópica (DRIFT; FTIR), análise de difração (XRPD) e energia de superfície (medições de ângulo de contacto e energia livre de superfície). Foi também avaliada a dissolução e o impacto do polimorfismo nas características mecânicas das formas farmacêuticas sólidas. Primeiramente foi realizada uma investigação completa sobre a estabilidade das formas cristalinas anidras I e II. Aspetos como o estudo da estabilidade das formas quando em presença de diferentes humidades relativas e caracterização dos hidratos formados foram explorados. Este estudo permitiu concluir que a Forma cristalina II é mais higroscópica, hidratando mais rapidamente e a menores humidades relativas do que a Forma I. A forma I, por outro lado, mostrou hidratar numa forma hidratada – dihidrato D – que apresenta uma velocidade de dissolução inferior às outras formas hidratadas da olanzapina, alertando para a necessidade de um armazenamento apropriado para este fármaco. Visto que os excipientes podem alterar as cinéticas de hidratação, estes podem fazer com que esta forma hidratada da olanzapina apareça a humidades mais reduzidas e com maior velocidade. Assim sendo, foram investigadas a interação da forma I com humidade e excipientes. Estando descrito que os excipientes poliméricos poderão ter maior impacto no processo de hidratação, 3 polímeros foram escolhidos para o estudo. A Forma I mostrou hidratar a velocidades diferentes, dependendo dos excipientes em que foi formulada. Polímeros, tais como PEG e HPC, mostraram induzir a transformação no hidrato D a uma humidade relativa baixa (75% RH), enquanto a PVP mostrou evitar quaisquer conversões, mesmo a humidades relativas de 93%. O PEG quando misturado fisicamente com olanzapina, mostrou acelerar a conversão em hidrato, especialmente se estas misturas físicas tenham sido pressionadas (submetidas a um processo compactação) antes do armazenamento. Este estudo mostrou que deve ser feito um balanço quando é feita a escolha dos polímeros a serem usados no processo de formulação, nomeadamente tendo em conta a quantidade usada e a sua estrutura química, de forma a manter a estabilidade da olanzapina em formas farmacêuticas sólidas. As transformações da olanzapina durante o processo RESS / RESSAS foram igualmente estudadas. Estas tecnologias permitiram produzir nanopartículas e nanossuspensões de olanzapina, respetivamente. Durante o processo de RESSAS a seleção dos excipientes estabilizadores das suspensões formadas mostrou ser imperativa para produzir nanossuspensões estáveis antes e após o processo de secagem por congelação. A celulose microcristalina, bem como os diferentes polímeros utilizados neste trabalho (PVP, PEG, HPC) foram usados no processo de extrusão e esferonização da olanzapina. Foram estudadas as transformações que ocorreram durante o processamento (ambientes húmidos estão envolvidos) e durante a dissolução dos esferóides. Durante a extrusão a olanzapina mostrou hidratar numa mistura de diferentes hidratos apenas quando em presença da celulose microcristalina. A adição de polímeros à formulação, tais como o PVP e a HPC, permitiram a manutenção da olanzapina na sua forma anidra I tanto durante o processamento como durante a dissolução, o que mostrou influenciar de forma significativa a dissolução da mesma. O PEG, por outro lado, mostrou ser incapaz de estabilizar a olanzapina. Os hidratos formados durante o processo de extrusão mostraram afetar as características físicas e mecânicas dos pellets, bem como a dissolução do fármaco. Os diferentes polímeros usados, os seus pesos moleculares e as suas proporções nas formulações revelaram ter impacto na estabilização da olanzapina durante o processo de extrusão, nomeadamente durante a fase de malaxagem. Em conclusão, a investigação feita no âmbito desta Tese contribuiu para uma melhor compreensão da caracterização das alterações polimórficas e pseudopolimórficas da olanzapina durante o seu processamento e armazenamento. Permitiu ainda perceber em pormenor o impacto das alterações polimórficas e pseudopolimórficas na performance tecnológica e na dissolução da olanzapina, alertando para a importância do seu estudo nas fases de pré-formulação e formulação

Process Optimization and Upscaling of Spray-Dried Drug-Amino acid Co-Amorphous Formulations

The feasibility of upscaling the formulation of co-amorphous indomethacin-lysine from lab-scale to pilot-scale spray drying was investigated. A 22 full factorial design of experiments (DoE) was employed at lab scale. The atomization gas flow rate (Fatom, from 0.5 to 1.4 kg/h) and outlet temperature (Tout, from 55 to 75 °C) were chosen as the critical process parameters. The obtained amorphization, glass transition temperature, bulk density, yield, and particle size distribution were chosen as the critical quality attributes. In general, the model showed low Fatom and high Tout to be beneficial for the desired product characteristics (a co-amorphous formulation with a low bulk density, high yield, and small particle size). In addition, only a low Fatom and high Tout led to the desired complete co-amorphization, while a minor residual crystallinity was observed with the other combinations of Fatom and Tout. Finally, upscaling to a pilot scale spray dryer was carried out based on the DoE results; however, the drying gas flow rate and the feed flow rate were adjusted to account for the different drying chamber geometries. An increased likelihood to achieve complete amorphization, because of the extended drying chamber, and hence an increased residence time of the droplets in the drying gas, was found in the pilot scale, confirming the feasibility of upscaling spray drying as a production technique for co-amorphous systems

A potencialidade dos filmes de ficção científica em aprendizagens das temáticas "Estrutura e dinâmica interna da Terra"

Relatório da prática de ensino supervisionada, Ensino de Biologia e Geologia, Universidade de Lisboa, Instituto de Educação, 2012O presente Plano de Cariz Investigativo, realizado no âmbito da formação de professores de ciências, é de natureza interpretativa. Numa abordagem construtivista, pretendeu-se apurar a potencialidade dos filmes de ficção científica e dos blogues como metodologias de aprendizagens, especificamente nas temáticas “Estrutura Interna da Terra" e “Dinâmica Interna da Terra” e investigar a reação dos alunos relativamente a metodologias propostas. Partindo do quotidiano dos alunos, escolheu-se os filmes de ficção científica por abordarem conceitos e processos científicos, tendo como objetivos a promoção da mudança conceptual e o desenvolvimento do espírito crítico dos alunos. As tecnologias de informação e comunicação (TIC), nomeadamente o blogue, surgiram como plataforma de apoio, sendo relevantes no desenvolvimento de competências exigidas na sociedade atual. Embora tenha havido algumas limitações, o filme e o blogue mostraram-se como elementos motivadores e com potencialidade didática, sendo por isso bons aliados na promoção das aprendizagens dos alunos. A componente letiva incidiu numa turma do 7.° ano de escolaridade na disciplina de Ciências Naturais. A intervenção teve a duração de sete semanas, abrangendo catorze aulas de quarenta e cinco minutos, organizadas em blocos de noventa minutos. Foram utilizados como instrumentos de recolha de dados questionários, diário de aula, publicações e comentários dos alunos no blogue e a análise das respostas em instrumentos de avaliação.The present investigative plan is part of a science teaching training and represents an interpretative study. In a constructivist approach, the potential of science fiction movies and blogs as learning methodologies was investigated, specifically in the thematic of the Earth's Internal Structure and the Earth’s Internal Dynamics, as well as the reaction of students to the proposed methodologies. By using student’s everyday lives as a source o f didactic material, science fiction movies were chosen, once they address to scientific concepts and processes, with the purpose of promoting conceptual change and the development of critical thinking in students. The information and communication technologies (ICT), namely the blog, served as a support platform, where some important skills required in today's society could be developed. Despite some limitations in implementation, these methodologies were considered as motivating and as having pedagogical potential, being a good ally in promoting student learning. The learning component focused on a class of seventh grade students in the discipline of Natural Sciences and the intervention lasted seven weeks. Questionnaires, teacher’s class journal, students web publications and comments and assessment instruments were used on collecting data

CONTRIBUIÇÃO DO ESTUDO DAS CARACTERÍSTICAS CULTURAIS DO CLUSTER DA MALACOCULTURA DA GRANDE FLORIANÓPOLIS PARA A GESTÃO DAS ATIVIDADES DE TURISMO NA REGIÃO

No Brasil, no Estado de Santa Catarina, na Grande Florianópolis, encontra-se o cluster da malacocultura, formado por micro e pequena empresas e por produtores autônomos. Embora tenha condições ambientais e econômicas favoráveis, este cluster apresenta problemas de gestão que estão relacionados com o comportamento dos seus integrantes refletido na sua maneira de ser, de agir e de pensar, condicionada pela sua cultura, que afetam a sua competitividade. Será que estas mesmas características culturais locais seriam um entrave para a formação de um cluster de turismo na região, atividade que apesar de também compartilhar condições ambientais e econômicas favoráveis, ainda não conseguiu se organizar de maneira colaborativa? Este trabalho busca fazer uma analogia entre o que ocorre na atividade da malacocultura e no setor de turismo, com base em resultados de um estudo de caso que entrevistou quarenta e três indivíduos, dos diferentes segmentos de atores do cluster da malacocultura, inclusive ligados ao turismo, que constatou que a cultura local, predominantemente de origem açoriana, apresenta fortes traços de individualismo, tolerância à incerteza, indulgência, orientação de curto prazo e acomodação, que afetam a competitividade, a governança e a gestão dos empreendimentos

Increasing Physical Activity in Older Adults: Walking by Prescription in Primary Care

Aim: The present study (PTDC/SAU-SAP/110799/2009) funded by the Portuguese Government (Fundação para a Ciência e Tecnologia – FCT) aimed to test the effectiveness of a behaviour based intervention combined with a cognitive based one, designed to increase physical activity levels in older adults at Primary Health Care Centres. Method: A total of 108 participants aged over 65 years participated in the study. Participants were referred by their General Practitioner (GP) and randomized by gender and marital status at the moment they started the program (single vs. couple), and allocated into one of three conditions: goal intention, action planning, action planning and coping planning. All participants received a pedometer and a logbook and were asked to register their daily number of steps for a period of 24 weeks. Study follows a longitudinal design with five assessments over a 6-month after baseline. Results: The test between subjects’ effects revealed an interaction between condition and participating in the study as single vs. couple. Older adults participating as singles walked more steps on average in the condition goal intention plus action planning and coping planning, whereas participants that entered in the study with their spouse, goal intention without any other planning intervention was the most effective intervention. Conclusion: The 24-week physical activity program based on the recent developments of behavioural-cognitive framework, has proven useful increasing older adults daily walking behaviour

Business plan for Shelf Life

CEM

Role of Polymeric Excipients in the Stabilization of Olanzapine when Exposed to Aqueous Environments

Hydrate formation is a phase transition which can occur during manufacturing processes involving water. This work considers the prevention of hydration of anhydrous olanzapine and hydrate conversions in the presence of water and polymers (polyethyleneglycol; hydroxypropylcellulose; polyvinylpyrrolidone) in forming pellets by wet extrusion and spheronisation. Anhydrous olanzapine was added to water with or without those polymers prior to extrusion with microcrystalline cellulose. Assessment of olanzapine conversion was made by XRP-Diffraction; FTIR spectroscopy; calorimetry (DSC) and microscopy (SEM for crystal size and shape). The addition of water converted the anhydrous form into dihydrate B and higher hydrate; whereas polyethyleneglycol promoted a selective hydrate conversion into the higher hydrate olanzapine form. Both polyvinylpyrrolidone and hydroxypropylcellulose prevented the hydrate transformations of the anhydrous drug; the latter even in the presence of hydrate seeds. This may be explained by the higher H-bond ability; higher network association and higher hydrophobicity of hydroxypropylcellulose by comparison with polyethyleneglycol and polyvinylpyrrolidone; which could contribute to its higher affinity to the crystal surfaces of the hydrate nuclei/initial crystals and promoting steric hindrance to the incorporation of other drug molecules into the crystal lattice; thus, preventing the crystal growth. The addition of microcrystalline cellulose needed for the pellets production (final product) did not eliminate the protector effect of both hydroxypropylcellulose and polyvinylpyrrolidone during pellets’ processing and dissolution evaluation

Multilingual and multicultural practices in higher education: the IntlUni project

The main objectives of the European Erasmus project “International University: The challenges of the multilingual and multicultural learning space” (526646-LLP-1-2012-1-DK-ERASMUS-ENW) are the following: 1) to identify the quality criteria (reference points) that should characterise teaching and learning in the Multilingual and Multicultural Learning Space (M&MLS) and 2) to develop recommendations for how HEIs may implement and ensure the sustainability of quality teaching and learning in the M&MLS. This paper will focus on two of the project tasks: 1) identification of the various different types of settings for the international Higher Education Institution (HEI) with a view to establishing a typology of such settings and 2) identification of the linguistic, cultural and pedagogical / didactic challenges in the various types of HEIs in the typology. These tasks were acomplished through analysis of documents, focus group interviews and reports of real situations related to internationalization. 38 HEIs from 28 countries took part. The results from Minho University will be contrasted with those of other European HEIs and implications for intercultural competencies discussed.info:eu-repo/semantics/publishedVersio

A business intelligence solution for public transportation sector

Smart companies in the 21st century use business intelligence solutions to gain a clearer picture of their internal operations, customers, supply chain and financial performance. In short, they are using business intelligence solutions to become intelligent about the way they do business.. Our paper reflects the result of a project that we conducted in Portugal related to the development of a business intelligence solution for the intelligent transportation system (ITS). This project was developed on a close partnership between the University of Minho and Efacec, that is one of the most important and large Portuguese companies. More specifically, our aim was to: (1) perform a strict identification and selection of the information requirements; (2) develop technical specifications; (3) develop a business intelligence solution that will be used to support the companies top management decisions. Our approach consists on integrating in the computer-aided support system all the relevant information by mixing up different visualization forms (tables, graphs and maps), customized according to each performance indicator, thus enhancing reading efficiency and correct interpretation of every depicted situation being analyzed.The authors acknowledge the financial support provided by the European Commission and the Portuguese Government through the research grant QREN, in compliance with SmartCenter