Approximately 80% of pharmaceutical products and the ingredients required for their manufacture are in powder form. The solid dosage form (tablets and capsules) is manufactured by either dry-blending of fine powder ingredients or combining the ingredients in a wet granulation step, followed by drying. Arching, ratholing, caking, segregation and flooding are some of the commonly encountered flow problems in the handling of fine powders. These problems lead to losses worth thousands of dollars at production scale. Poor powder flowability is a consequence of the combined effects of many variables, including improper equipment design, particle size, size distribution, shape, moisture content and surface texture. In the present work, a systematic study has been performed to determine the relationship between the flowability of fine powders and their physical properties of mean size and size distribution, density and shape.<p> Flowability studies were done on six different powders: the NutraSweet® Brand sweetener (aspartame), Respitose ML001, Alpha-D-Lactose monohydrate, the pharmaceutical binder Methocel (R) F50 Premium Hydroxypropyl methylcellulose- HPMC, a placebo pharmaceutical granulate, and common pastry flour. Scanning electron microscopy (SEM) and stereomicroscopy were used for particle shape and size analysis. Particle size distribution was determined using the laser light scattering technique. Powder flowability was measured using shear strength, angle of repose, and tapped-to-bulk density measurements. A novel method of measuring the dynamic angle of repose using electrical capacitance tomography (ECT) was developed. <p> Analysis of the images from microscopy revealed that the particles of aspartame and HPMC powders were elongated, the particles of ML001, pastry flour and lactose monohydrate powders were irregular, and the particles of placebo granulate were nearly spherical. Particle size was found to be the most reliable indicator of powder flowability, with decreasing particle size corresponding to lower flowability; however other parameters such as particle elongation and irregularity, were also found to have an influence on powder flowability. Although HPMC and pastry flour had similar particle sizes, they exhibited differences in flowability. This can be explained by the greater irregularity of the flour particles. Particle irregularity may cause mechanical interlocking between the particles, thus reducing powder flowability. ECT was found to be a promising non-intrusive tool for the measurement of the dynamic angle of repose. Unlike other methods for the measurement of dynamic angle of repose, the results obtained from ECT were not influenced by the effect of end caps. The present technique could be used by pharmaceutical industries in process analytical technology (PAT) for the detection and elimination of potential flow problems early in the manufacturing process.

Orientador: Theo Guenter Kieckbusch / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Engenharia Quimica / Made available in DSpace on 2018-08-07T06:40:25Z (GMT). No. of bitstreams: 1 Martins_PierreCorrea_D.pdf: 10023061 bytes, checksum: 89ac010f9649d69b4042b6a32ddddad2 (MD5) Previous issue date: 2006 / Resumo: A aglomeração de pós é utilizada para melhorar o manuseio das partículas e facilitar sua reconstituição em água. O objetivo principal deste trabalho foi avaliar a influência do tipo e do conteúdo de uma fase lipídica na aglomeração de pós alimentícios. Como alimento-modelo usou-se maltodextrina DE 10 e três diferentes frações de óleo de palma: duas oleínas (pontos de fusão de 14 e 18 °C) e uma estearina (ponto de fusão de 51 °C). Os pós primários contendo lipídeos foram obtidos através da secagem em spray-dryer de emulsões de maltodextrina, óleo e surfactante a 30% p/p. Os ensaios de aglomeração contemplaram pós contendo 5, 10, 15, 20 ou 25% de cada fração de óleo de palma. A umidade, densidade e escoabilidade dos pós diminuíram com o aumento do seu conteúdo de lipídeos. Os pós contendo as oleínas apresentaram maior coesão entre si do que o material com estearina. Os ensaios de aglomeração foram conduzidos em um aglomerador com jato de vapor, em escala piloto. Um planejamento experimental prévio confirmou um aumento significativo do diâmetro dos aglomerados com o aumento da pressão de vapor, do conteúdo de lipídeos dos pós e da temperatura do ar de secagem dos aglomerados. Os ensaios definitivos de aglomeração foram realizados com ar de secagem a 100°C e pressão de vapor de 1,9 bar. As partículas com oleína absorveram menos umidade no contato com o vapor do que o material contendo estearina e o isento de óleo. A influência dos agentes ligantes (umidade e/ou óleo) foi mais importante para o aumento de tamanho dos aglomerados do que a temperatura do ar. Uma pequena adição de óleo (5%) prejudica o mecanismo de aglomeração. Nos pós sem óleo a aglomeração foi controlada pela plastificação da superfície das partículas. Nos pós com alto conteúdo de óleo, sobretudo com as oleínas, a pré-aglomeração devido à alta coesividade das partículas promoveu a formação de grandes e compactos aglomerados. O pó sem óleo produziu aglomerados de melhor aparência e de tamanho similar ou maior do que o produto com 25% de óleo, porém com menor resistência à compressão. Todos os aglomerados apresentaram uma maior facilidade de escoamento em relação aos seus pós originais / Abstract: Agglomeration involves the production of larger and stable particles by aggregation of fine particulated material, in order to enhance flowability, appearance and reconstitution in water. This work evaluated the contribution of an oil phase on the agglomeration mechanisms of food powders. Three different palm oil fractions (two oleins with melting point of 14 and 18 °C and one stearin with melting point of 51 °C) were incorporated to the solid matrix of maltodextrin DE 10. Maltodextrin powders containing lipids were processed by spray-drying emulsions of 30% (w/w) total solids (maltodextrin, lipids and surfactant) content. The emulsions were prepared with 5, 10, 15, 20 or 25% of each palm oil fractions, based on total dry mass. Granulation runs were carried out in a pilot plant steam jet agglomerator. Preliminary experiments performed according to a factorial design indicated an increase of the size of the agglomerates with the increase in steam pressure, lipid content and drying air temperature. The definitive experiments were carried out at a steam pressure of 1.9 bar and air temperature of 100 °C. The influence of the binding agents (moisture and/or oil) was more important than the air temperature. The size increase of maltodextrin powder without oil was controlled by surface plasticization and agglomerates with suitable instant properties were obtained. The influence of moisture content was more important than the oil content for maltodextrins with stearin while the inverse occurred for maltodextrins with olein. Maltodextrins powders containing stearin were less cohesive and showed incomplete surface coating by the lipids facilitating moisture absorption. The pre-agglomeration stage favored the blend of the more cohesive powders and formed larger and more resistent agglomerates. The lower tendency to form pre-agglomerates in powders containing stearin is compensated by higher moisture uptake in the steam section. Small amount of oil degenerated drastically the process. The average size and the mechanical resistance of the agglomerates increased with increasing oil content in the powders. Agglomeration enhanced considerably the flowability of the particles containing oil / Doutorado / Engenharia de Processos / Doutor em Engenharia Química

abstract: This thesis investigated the effects of differing diameters and varying moisture content on the flowability properties of granular glass beads through use of a Freeman FT4 Powder Rheometer. These parameters were tested in order to construct an empirical model to predict flowability properties of glass beads at differing size ranges and moisture contents. The final empirical model outputted an average error of 8.73% across all tested diameters and moisture ranges. Mohr's circles were constructed from experimentally-obtained shear stress values to quantitatively describe flowability of tested materials in terms of a flow function parameter. A high flow function value (>10) was indicative of a good flow. By testing 120-180 µm, 120-350 µm, 180-250 µm, 250-350 µm, 430-600 µm, and 600-850 µm glass bead diameter ranges, an increase in size was seen to result in higher flow function values. The limitations of testing using the FT4 became apparent as inconsistent flow function values were obtained at 0% moisture with size ranges above 120-180 µm, or at flow function values of >21. Bead sizes larger than 430 µm showed significant standard deviation over all tested trials--when excluding size ranges above that value, the empirical model showed an average error of only 6.45%. Wet material testing occurred at all tested glass bead size ranges using a deionized water content of 0%, 1%, 5%, 15%, and 20% by weight. The results of such testing showed a decrease in the resulting flow function parameter as more water content was added. However, this trend changed as 20% moisture content was achieved; the wet material became supersaturated, and an increase in flow function values was observed. The empirical model constructed, therefore, neglected the 20% moisture content regime. / Dissertation/Thesis / Masters Thesis Chemical Engineering 2019

Charles University, Faculty of Pharmacy in Hradec Králové Department of: Pharmaceutical technology Supervisor: doc. PharmDr. Zdeňka Šklubalová, Ph.D. Consultant: Ing. Hana Hurychová Student: Eliška Dostálová Title of Thesis: Study of bulk and consolidation properties of size fractions of anhydrous lactose The bulk and consolidation behaviour of pharmaceutical excipients belong to their important properties. Properties of five size fractions of anhydrous lactose having the particle size in the range of 1-400 µm were studied in this thesis. The measurement was carried out by using static and dynamic pharmacopoeial methods. The bulk density and the tapped density, the angle of repose were evaluated as well as the true density of particles by using the gas pycnometry. The mass flow rate through the orifice of a model conical hopper by the force of gravity was estimated for the individual size fractions. The discharge rate through the orifice having the diameter in a range of 0.6-1.5 cm was modelled with the Beverloo et al and Jones & Pilpel power regression equations; the precision of the flow rate prediction was about 3 %. The best bulk properties were detected for the particle size fraction 246 µm. The results of the evaluation of the consolidation dynamic during the tapping of powder bed permitted...

Králové doc. PharmDr. Zdeňka Šklubalová, Ph.D. Ing. Hana Hurychová, Ph.D. Monika Hnatková The objective of this diploma thesis was to evaluate the flow and consolidation behaviour of the size fractions of lactose for direct compression - Tabletose® 80 in a range of 80-400 μm obtained by sieving. The nonlinear influence of the particle size on the flow rate was detected; the fractions of Tablettose® 80 with the mean size of 245 and 346 µm showed the best flowability. The influence of the diameter of the hopper opening on the flow rate was modeled using the Beverloo and/or Jones & Pilpel flow equation; the latter described the results better. The assessment of volume changes by gravitational tapping allowed to observe dynamics of consolidation and to express porosity factor for the powder bed, which enabled an estimation of the angle of internal friction.

1 Abstract Charles University, Faculty of Pharmacy in Hradci Králové Department of: Department of Pharmaceutical Technology Supervisor: Doc. PharmDr. Zdeňka Šklubalová, Ph. D. Consultant PharmDr. Karel Palát, CSc., Mgr. Žofie Trpělková Student: Martina Litošová Title of Thesis: Homogenization of powder blends using a Turbula mixer. In this experimental work, the influencing of the homogeneity of the powder mixture of acetylsalicylic acid (ASA) and microcrystalline cellulose (Avicel PH102) due to the rotational speed of the mixing container in a range of 23−101 rpm, and the mixing time was studied using the Turbula shaker mixer. Within time interval 2-62 minutes, the content of ASA in samples was measured by near-infrared spectrometry. The expression of standard deviation was used to evaluate the homogeneity of samples. The best results were detected at a rotational speed of 34 rpm within time interval of 14−30 min.

Charles University, Faculty of Pharmacy in Hradci Králové Department of: Pharmaceutical technology Supervisor: doc. PharmDr. Zdeňka Šklubalová, Ph.D. Consultant: Mgr. Žofie Trpělková Student: Aneta Mrázková Title of Thesis: The study of influence of the measurement method on static angle of repose of free-flowable excipients. Good flow and consolidation properties of powders represent significant characteristics of pharmaceutical excipients They are important for manufacturing of powders into solid dosage forms. Flow behavior of 6 free flowing excipients was evaluated in this diploma thesis. The main target was a study of the influence of the masurement method and the orifice size of a conical hopper on static angle of repose (AOR). The automatic tester and the prototype for measuring AOR having orifice sizes in a range of 6-15 mm were used for the measurement. A significant difference between the results of these two methods (P <0.01) was observed. The decrease in AOR was detected when increased the orifice diameter, the effect was significant (P <0.01) only in automatic tester for two out of six measured powders. Surprisingly, the significant influence of the orifice size on AOR was registered for a sweetener Palatinose with protype equipment.

<div>Cocoa is widely used by confectionary industries as a powder raw material for chocolate production. The chemical properties such as high- or low-fat content determine the functionality of the cocoa powder and constitute as a major factor in controlling the behavior of the final product. Additionally, the physicochemical properties such as the cohesive characteristics of cocoa powders create undesirable issues in industrial manufacturing settings. Thus, the evaluation of physical and chemical attributes is relevant to differentiate the powder surface structure and define the material behavior in presence of other materials or distinct environments.</div><div>This work evaluated three kinds of cocoa powders—varying mainly on the lipid content—to assess the powder performance in terms of the role of surface properties on the physical attributes (flowability and wettability) and stability under distinct frameworks. Various analytical tools were used, and several methodologies were developed and implemented to determine the surface area, changes in lipid melting phases at the surface level and particle interactions. The characterization methods included particle true density, flow properties under aerated conditions, bulk permeability, thermal properties, surface energetics, water sorption, and chemical surface compositional analyses.</div><div>The findings of this work revealed that the cocoa surface composition, amount of lipids, did not explain the low-flow performance or the water uptake. On the other hand, physicochemical properties such as lipid polymorphism was introduced as an avenue to further understand the results. From the surface energetics standpoint, a water diffusion mechanism is proposed as a result of the observed effect of water on the performance and stability of the cocoa powder systems. Owing to the hydrophobic nature of cocoa particles, this material can be used as a unique reference to understand cohesive particle models with implications on the performance (flowability and wettability) of lipid-based surface materials. The results indicated that powder behavior on the performance is a confounding effect of all variables.</div><div>The major contribution of this thesis work demonstrates the importance of surface chemistry characterization on the physical attributes of cocoa powder systems and the potential to control surface composition to improve the performance and stability of food complex systems.</div>

Charles University, Faculty of Pharmacy in Hradci Králové Department of: Supervisor: Pharmaceutical Technology doc. PharmDr. Zdeňka Šklubalová, Ph.D. Consultant: Mgr. Jana Brokešová Student: Daniela Ferechová Title of Thesis: Study of the influence of tablet mixture composition on the flow and consolidation properties Good flow properties of a tabletting mixture play an important role in the manufacturing of tablets. Flow behaviour of the commercial (original) tabletting mixture with poor flowability was evaluated in this thesis. The main aim was to find alternative fillers that may improve its flow. The granulometric characteristics and flowability of eight types of lactose and microcrystalline cellulose and their binary mixtures were studied. In comparison to the original tabletting mixture, the proposed modified one with both original fillers were replaced with new ones showed significantly better flow properties with steady state flow through the hopper orifice having a diameter of 10 mm. The results were confirmed using powder rheometer. The lower shear stress necessary to achieve flow under different normal loads as well as approximately 72 times lower cohesion value were detected for the modified tabletting mixture.

Dans les secteurs industriels tels que l’industrie chimique, pharmaceutique ou agro-alimentaire une faible aptitude à l’écoulement des poudres est souvent à l’origine du mauvais fonctionnement d’un procédé. Une mauvaise coulabilité peut ainsi entrainer le blocage de poudres dans un silo, des problématiques de dosages et de remplissage ou encore une détérioration de la qualité du produit final. Pour assurer un bon fonctionnement du procédé, il est donc nécessaire et essentiel d’évaluer la coulabilité de poudres utilisées. Pour cela, plusieurs techniques expérimentales telles que les dispositifs de mesure d’angle, les cellules de cisaillement, les dispositifs de tassement de poudre peuvent être utilisées. Des indices de coulabilité sont alors définis permettant de classer les poudres selon la qualité de l’écoulement. Des essais expérimentaux ont été menés sur plusieurs types de poudres et les premiers résultats ont montré que le passage d’une technique d’évaluation à une autre peut modifier, voire inverser le classement de la coulabilité des poudres. En effet, selon les techniques étudiées les poudres sont soumises à des sollicitations mécaniques différentes et donc le choix de la technique doit être adapté au cas réel d’étude. Dans ce travail, nous nous sommes intéressé plus particulièrement au cas de l’évaluation de l’écoulement de poudres à partir de dispositifs de compaction. Le travail réalisé a montré que les paramètres dynamiques (amplitude et fréquence de chocs) influencent énormément le classement de la coulabilité des poudres. A partir d’une approche énergétique, il a été montré qu’une évaluation et quantification de la coulabilité à partir du rapport d’Hausner ne peut être donnée par une technique de compaction que si celle-ci permet d’atteindre une valeur d’énergie nécessaire à l’obtention d’une compaction maximale des particules. Enfin, une étude de mise en œuvre des techniques d’évaluation de la coulabilité a été réalisée dans le domaine de la formulation en s’intéressant à l’évaluation quantitative de l’influence d’un agent d’écoulement / In industrial sectors, such as chemical, pharmaceutical or food industries, poor flowability of powders is often the causes of process malfunction. Poor flowability can lead to the blocking of powders in a silo, dosing and filling problems, or even bad quality on final product. To ensure proper process operation, it is therefore necessary and essential to evaluate the flowability of powders used. For this purpose, several experimental techniques such as angle of repose devices, shear cells or powder packing devices can be used. Flowability indices can then be defined in order to classify the powders according to the flow quality. Experimental tests have been carried out on several types of powders and the first results have shown that the transition from one technique to another can modify or even reverse the classification of the powder flowability. Indeed, according to the techniques studied, powders are subjected to different mechanical stresses and therefore the choice of the technique must be adapted to the real case of study. In this work, we were particularly interested to the evaluation of powders flowability from compaction devices. The work carried out has shown that the dynamic parameters (amplitude and frequency of taps) greatly influence the classification of powders flowability. From an energy approach, it has been shown that the evaluation of the flowability from Hausner ratio can be given by a compaction technique only if it achieves a value of energy required to obtain a maximal compaction of the particles. Finally, an implementation study of flowability evaluation techniques was carried out in the field of formulation by focusing on the quantitative evaluation of the influence of a glidant