A granulação através do uso de dispersões sólidas é um recurso que pode ser utilizado para aumentar a solubilidade de fármacos pouco solúveis, como no processo de Hot Melt Granulation (HMG). Este processo pode ser realizado utilizando-se o aparelho de leito fluidizado, com a atomização de uma dispersão fundida de carreadores solúveis com fármacos pouco solúveis sobre um substrato efetuando sua granulação. Essa é uma alternativa em relação aos métodos de granulação tradicionais, sendo vantajoso por não utilizar solvente. O objetivo deste trabalho foi realizar a granulação de piroxicam por HMG em leito fluidizado com polietilenoglicol (PEG) na forma de dispersão fundida, usando lactose spray dried como substrato com o intuito de aumentar a solubilidade do fármaco que é pouco solúvel em água, classificado como classe 2 (baixa solubilidade e alta permeabilidade) no Sistema de Classificação Biofarmacêutica. Foi realizada também a avaliação de misturas físicas e dispersões sólidas dos excipientes e do fármaco para obter informações de pré-formulação. O processo de granulação em leito fluidizado foi realizado através de um planejamento fatorial do tipo Box-Behnken, no qual as variáveis de operação carga de substrato, vazão do ar do bico de atomização e altura do bico de atomização foram variadas para a caracterização do processo e o estudo do efeito das variáveis do processo sobre as propriedades dos grânulos também foi realizado. Os grânulos obtidos foram caracterizados pela avaliação das propriedades farmacotécnicas, doseamento, distribuição granulométrica e também pela determinação das propriedades físico-químicas através de análises de calorimetria exploratória diferencial (DSC), espectroscopia no infravermelho e difração de raios-X. O perfil de dissolução de cápsulas contendo os grânulos também foi determinado. De acordo com as análises realizadas, não ocorreram interações nas misturas físicas e dispersões sólidas, nem nos granulados obtidos. Em relação aos grânulos, o resultado da avaliação farmacotécnica demonstrou que a maioria apresentou valores de fluxo excelente e bom. Através da distribuição granulométrica e das imagens dos grânulos obtidas por microscopia eletrônica de varredura (M.E.V.), pode-se observar que ocorreu a aglomeração das partículas de lactose pela atomização da dispersão de piroxicam e PEG 4000. Na avaliação do perfil de dissolução, os grânulos mostraram-se com uma solubilidade superior ao piroxicam isolado, sendo a granulação por Hot Melt em leito fluidizado um processo vantajoso em relação aos métodos atuais de granulação. / Granulation through solid dispersions may be employed to increase drug solubility as in the Hot Melt Granulation (HMG). Fluidized beds are used in the procedure, which by atomizing a melted dispersion of soluble carriers and low solubility drugs on a substrate produces the desired granulation. This is an advantageous alternative to traditional granulation methods since solvents are not involved. The objective of this study was to granulate the low solubility drug, piroxicam, by HMG in a fluidized bed with polyethylene glycol (PEG) in the form of a melted dispersion and dried lactose spray as the substrate. The drug has low aqueous solubility and is classified as Class 2 (low solubility and high intestinal permeability) in the Biopharmaceutical Classification System (BCS). Physical mixtures and solid dispersions of excipients and drug were previously tested as to obtain pre-formulation data. A factorial planning of the Box-Behnken type was used for the granulation in a fluidized bed, with the operation variables as substrate load, air stream velocity through the atomizing outlet and its height being varied to characterize the process and to verify their effects on the granule properties. Characterization of the granules was by evaluation of pharmacotechnical properties, dosage of active principle, granule size distribution and also by physicochemical analyses. These were by differential scanning calorimetry (DSC), infrared spectroscopy and X-ray diffraction. Interactions in the physical mixtures, solid dispersions and granules were not detected. The dissolution profile of capsules containing the granules was determined. Evaluation results showed that most granules had excellent to good flux properties. Granulometric distribution and scanning electron microscopy (SEM) images indicated agglomeration of lactose particles by the atomization of the piroxicamPEG dispersion. Evaluating the granule dissolution profiles it was shown that they were more soluble than piroxicam only. These results suggest that granulation by Hot Melt in a fluidized bed is process with advantages when compared to methods currently used.

Orientador: Florencia Cecília Menegalli / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Engenharia de Alimentos / Made available in DSpace on 2018-08-20T07:44:45Z (GMT). No. of bitstreams: 1 Souza_DiogoOtaviodeCastro_D.pdf: 2512415 bytes, checksum: cc03ff39105bf1fed4d6dae52c95bbce (MD5) Previous issue date: 2012 / Resumo: A granulação é um processo de aumento de tamanho de pós finos, que pode ser utilizado na indústria de alimentos para aumentar a qualidade de alimentos em pó, pelo aumento da sua dispersibilidade e solubilidade em líquidos. O modelo de balanço populacional (MBP) é normalmente utilizado para modelar este processo. Entretanto, nos trabalhos existentes, o MBP não leva em consideração as perdas de partículas no processo por elutriação e incrustação, muito relevantes para granulação de sucos em pó. Além disso, não existe na literatura correlações para estimar estas constantes com base nas condições operacionais do equipamento e nas características das partículas. Diante disso, o objetivo deste trabalho foi o estudo do impacto das condições operacionais no modelo de balanço populacional, durante a granulação de suco de goiaba em pó, em leito fluidizado. Diversos experimentos foram realizados de forma a adquirir os dados que alimentaram os modelos matemáticos desenvolvidos. Estes dados foram obtidos fora das zonas de máximo rendimento a fim de se obter um modelo mais abrangente, que pudesses simular o processo de granulação em todas as condições de processo. Foram desenvolvidas e validadas correlações para estimativa da taxa de elutriação, para estimativa das constantes de aglomeração e de quebra do MBP. Além disso, foi desenvolvido um modelo para estimativa da massa incrustada de partículas. Os modelos se mostraram capazes de estimar o rendimento do processo, os valores de diâmetro médio e da distribuição de tamanho de partículas. Foram feitas simulações alterando a velocidade do ar de fluidização, a vazão de ligante, o diâmetro médio inicial da distribuição, o formato da distribuição e a massa total de partículas. A análise das simulações realizadas sugere que as condições ótimas precisam ser avaliadas para cada distribuição de tamanho e para cada quantidade de partículas no equipamento, não somente para cada tipo de produto. De modo geral, os modelos desenvolvidos se mostraram adequados para aumentar a compreensão do processo de granulação e para obtenção de ótimos de processamento. Cabe ressaltar a necessidade de futuras investigações para verificar a aplicação destes modelos com outros tipos de material particulado e em outras faixas de operação / Abstract: Granulation is a size-enlargement process, in which small particles are agglomerated together. It is used in the food industry to increase the quality of food powder, by increasing its solubility. The population balance model (PBM) is a widely used model for this process. However, it is usually applied without account losses in the process by elutriation and wall deposition, which are very important for granulation of powdered juices. In addition, there is no correlation in the literature able to estimate the constants of the model from the operational conditions and from the particles¿ characteristics. The objective of this work was to study the impact of operational conditions into the population balance model for the granulation of guava juice powder, in a fluidized bed. Several experiments were performed in order to acquire data that fed the mathematical models developed in this work. These data weren¿t obtained from the zones of maximum process yield in order to achieve a more comprehensive model, which could simulate the granulation process in all process¿ conditions. It was developed and validated a correlation for the estimation of the rate of elutriation, a model for the estimation of the particles¿ wall deposition, a correlation for estimation the constants of agglomeration and for estimation of the breakage constant of the PBM. The models predicted, with good accuracy, the process yield, the mean diameter and particle size distribution. Simulations were made by changing the fluidizing air temperature, the liquid binder flow rate, the fluidizing air velocity, the initial mean diameter, the shape of the particles size distribution and the total mass of particles. The analysis of the simulations suggests that the optimal conditions must be evaluated for each kind of particle size distribution and for each mass of particles into the equipment, not only for each type of product. The models developed showed to be suitable to increase the understanding of the granulation process and to obtain process¿ optimal conditions. It is worth emphasizing the need of further research to verify the application of these models for others types of particles and others operational ranges / Doutorado / Engenharia de Alimentos / Doutor em Engenharia de Alimentos

Orientador: Florencia Cecilia Menegalli / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia de Alimentos / Made available in DSpace on 2018-08-04T04:16:57Z (GMT). No. of bitstreams: 1 Dacanal_GustavoCesar_M.pdf: 2777471 bytes, checksum: b80c63182ebc03483ba92c58dcd7ddb9 (MD5) Previous issue date: 2005 / Mestrado / Engenharia de Alimentos / Mestre em Engenharia de Alimentos

The main purpose of this study was to optimise the grain size distribution of the raw material mixture for the production of iron sinter. It well known that the constitution of the sinter mix is based on the knowledge of chemical composition and grain size distribution. Although Mittal Vanderbijlpark has fixed specifications on the physical and chemical properties of the sinter for optimal blast furnace performance, the particle size distribution of the sinter mix has not yet been optimized. This was achieved by using the granulation characteristics of the sinter mix and the green bed permeability tests. The influence of the moisture content of the feed, granulation time, and mean granule diameter on permeability was investigated on Thabazimbi and Sishen iron ore, as well as on their mixture with fluxes and without fluxes. The iron ore results indicated that the mixture containing 20% Thabazimbi iron ore and 80% Sishen iron ore with fluxes where the coke, lime and return fines were sized by removing the – 0.5 mm size fraction of the return fines and coke, and the 1 mm size fraction of lime has the highest permeability of all the studied mixtures. The sintering properties of the mixtures of optimised grain size distributions were also investigated and the results were very similar for all the mixtures and better than the base case mixture, which was not optimised with respect to grain size distribution. / Dissertation (MEng)--University of Pretoria, 2008. / Materials Science and Metallurgical Engineering / unrestricted

The fluid bed granulation is a well-established method how to improve such properties of powders as flowability and increase content uniformity of the tablets. In this thesis, there was evaluated a granulation process on a lab scale fluid Glatt bed granulator and optimized for highest possible yield. Product yield in the size range of 80-90 % of granules and process reproducibility were stated as most effective. The product was analysed for its particle size distribution, the API distribution within the different particle size fractions and the flowability of the final granules. For process optimization, the most critical parameters such as spraying rate, particle size of raw materials and fluid bed pressure were identified and evaluated. As the highest-yielding dosage for the powder binder was found the spraying rate of 9 g/min. Changes in bed fluid pressure and nozzle pressure showed no significant improvement. Different grades of caffeine were compared for their impact on the granulation properties. Sieved caffeine enhanced yield of the product and reproducibility compared to bulk or disagglomerated caffeine.

Analyses of recent observations of the sole classical Cepheid in the Kepler field, V1154 Cygni, found random changes of about 30 min in the pulsation period. These period changes challenge standard theories of pulsation and evolution because the period change is non-secular, and explaining this period jitter is necessary for understanding stellar evolution and the role of Cepheids as precise standard candles. We suggest that convection and convective hot spots can explain the observed period jitter. Convective hot spots alter the timing of flux maximum and minimum in the Cepheid light curve, hence change the measured pulsation period. We present a model of random hot spots that generate a localized flux excess that perturbs the Cepheid light curve and consequently the pulsation period, which is consistent with the observed jitter. This result demonstrates how important understanding convection is for modeling Cepheid stellar structure and evolution, how convection determines the red edge of the instability strip, and just how sensitive Cepheid light curves are to atmospheric physics.

Yes / In the pharmaceutical industry, enhanced process understanding resulting in superior control of product attributes, has the potential to save up to 20% of process engineering and product development costs during drug development. With the aim of achieving enhanced process understating, a novel approach for granulation of fine powders is presented. First, a mould with the desired particle shape and size is created using 3D printing followed by casting using elastomeric material. The formulation is prepared through wet massing and tested as a thin film on flat elastomeric membranes. The thin film itself can be a product but it also gives a good indication of coating performance before coating the patterned elastic membrane with the formulation i.e., 3D printed elastic mould granulation. Results show that following granulation and drying, granules of controlled size and shape (e.g. cubic and 500 μm), strength, friability and flowability can be formed. The method presented may allow for more robust process development in particle engineering. / Research Development Fund Publication Prize Award winner, December 2018.

Damage to our tissues occurs daily and must be repaired by the body in a timely manner in order to prevent infection and restore tissue integrity. Many cell types are involved in the healing process, but it is the cells of the stroma that are largely responsible for rebuilding fibrous tissue, which provides structure and support for all other cell types during healing. This dissertation focuses on stromal tissue repair, the rebuilding of fibrous tissue by fibroblasts following injury. Specifically, I focus on 1) models to study wound healing in vitro, and the specific biological processes of healing that each model captures, 2) the response of engineered stromal microtissues to different methods of injury, namely laceration and laser ablation, and the subsequent clearance and rebuilding of the extracellular matrix by fibroblasts, and 3) how different types of stromal cells and extracellular matrix proteins contribute to tissue repair in vitro.

Aerobic granular sludge has been regarded as a promising alternative to the conventional activated sludge which has been used for a century in that granular sludge offers advantages in high biomass retention, fast sludge-water separation, and small footprint requirement. However, this technology has been rarely applied in continuous flow reactors (CFRs) which are the most common type of bioreactors used in water resource recovery facilities across the world. Hence, the overarching goal of this study is to provide advanced understanding of biogranulation mechanism to enable industrial application of this technology. The lack of long-term stability study in CFRs has restricted its full-scale acceptability. The high settling velocity-based selection pressure has been regarded as the ultimate driving force towards biogranulation in sequential batch reactors (SBRs). In this study, this physical selection pressure was firstly weakened and then eliminated in CFRs to investigate its role in maintaining the long-term structural stability of aerobic granules. Given the fact that implementing settling velocity-based selection pressure only can cultivate biogranules in SBRs but not in completely stirred tank reactors (CSTRs), the essential role of feast/famine conditions was investigated. Seventeen sets of data collected from both literature and this study were analyzed to develop a general understanding of the granulation mechanisms. The outcome indicated that granulation is more sensitive to the feast/famine conditions than to the settling velocity-based selection pressure. The theory was tested in a CFR with 10-CSTR chambers connected in series to provide feast/famine conditions followed by a physical selector separating the slow-settling bioflocs and fast-settling biogranules into feast and famine zones, respectively. Along with successful biogranulation, the startup performance interruption problem inherent in SBRs was also resolved in this innovative design because the sludge loss due to physical washout selection was mitigated by returning bioflocs to the famine zone. Then, a cost-effective engineering strategy was put forward to promote the full-scale application of this advanced technology. With this generalized biogranulation theory, pure culture biogranules with desired functions for high value-added bioproducts were also investigated and achieved for the first time in this study, which paves a new avenue to harnessing granulation technology for intensifying waste valorization bioprocesses. / Doctor of Philosophy / Nowadays, the rapid population growth and unprecedented urbanization are overloading the capacity of many wastewater resource recovery facilities (WRRFs). Therefore, there is a need to develop a cost-effective strategy to upgrade the treatment capacity of existing WRRFs without incurring major capital investment. Because conventional activated sludge comes with loose structure and poor settleability, replacing them with dense aerobic granular sludge offers the opportunity to intensify the capacity of existing WRRF tankage and clarifiers through better retention of high bacterial mass that offers not only a fast pollutant removal rate but also a high water-solids separation rate. The aerobic granulation technology turns traditional activated sludge into granular sludge by inducing microbial cell-to-cell co-aggregation. Although this technology has been developed for more than 20 years, its application in full-scale WRRFs is still limited because majority of WRRFs are constructed with continuous flow reactors in which the aerobic granulation mechanism largely remains unknown. Besides, the long-term stability of aerobic granules in continuous flow reactors also remain unstudied, further constraining the full-scale application of the technology. The sensitivity of aerobic granulation to physical selection and biological selection was analyzed in this study. The results concluded that aerobic granulation is more sensitive to the latter but not to the former. Subsequently, this theory was tested in a novel bioreactor setup that creates feast/famine conditions for biological selection. A physical selector was installed at the end of the bioreactor to separate and return the fast- and slow- settling bioparticles to the feast and famine zones, respectively. This unique reactor design and operational strategy provided an economical approach to retrofitting current WRRFs for achieving treatment capacity upgrading without major infrastructure alternation. It also protected the bioreactor startup performance by enhancing the stability of WRRFs in the future application. Last but not least, this updated understanding of aerobic granulation theory was for the first time extrapolated to and verified with the formation of pure culture biogranules harnessed in this study for value-added bioproduct valorization from waste materials.

Twin screw wet granulation (TSG) has been studied as a continuous manufacturing alternative to batch granulation for nearly twenty years. One of the main differences between batch granulation and TSG lies in the exiting granules being presented as a bimodal particle size distribution (PSD) in the latter case. Current process analytical technologies (PAT) can monitor a monomodal distribution well but there have been no techniques disclosed in the public domain so far that can accurately monitor this unusually shaped PSD. Acoustic emissions (AE) has been identified as a PAT of interest due to its ease of use (lack of calibration), low cost, and non-invasive design relative to other PATs used for monitoring PSDs. Hence the goal of this thesis was to develop AE as a process analytical technology (PAT) capable of estimating the full distribution of produced granules by TSG in real time. The first research study of this thesis focused on the development of the new technology. The AE PAT consisted of an acoustic sensor, an impact plate, and software to convert the time-domain signal of particle collisions into a time-averaged frequency-domain spectrum to be subsequently used to estimate a weight-averaged particle size distribution. A novel and much required addition to the PAT was inclusion of a digital filter based on particle mechanics parameters to overcome auditory masking which hindered accurately converting the cumulative sounds of impact into a PSD. The PAT was tested in this study with granulated lactose monohydrate and with the new digital filter, obtaining a maximum error of 1 wt% across all particle sizes tested. In the second research study, as more formulations commonly used in the industry were tested, the filter proved unable by itself to account for the differences in impact mechanics and therefore needed to be modified to incorporate the more inelastic behaviour now being seen. Two micromechanical models were explored, and the Walton-and-Braun model was found to be the most suitable for the AE PAT – reducing its error from 8 wt% down to 2.75 wt% across four formulations producing coefficients of restitution from 0.79 to 0.24. In the last research study in this thesis, the now-functional inline PAT was used to reveal mechanistic details related to the transition state in granulation as a TSG starts up, to improve the field’s understanding of the granulation mechanism. The technique was able to estimate the PSD over much shorter periods of material collection compared to sieving, allowing the evolution of the PSD as a function of time to be examined for varying degrees of fill (DF) and liquid-to-solids ratios. It was determined that the time to steady state, at both DF tested, occurred at approximately 5 times the mean residence time of the process by both PAT and sieving analyses. Particle sizes between 102-2230 μm were then tracked as a function of time below 120 s and variations of granule growth were seen for each degree of fill which added to the understanding of the granulation mechanism. This PAT shows great promise as a monitoring tool to implement quality by design principles for TSG in pharmaceutical manufacturing. / Thesis / Doctor of Philosophy (PhD)