Dissertations / Theses on the topic 'Lactose powders'

Cette thèse porte sur le problème fondamental du mottage des poudres suite aux mécanismes de transition de phase. Le projet vise à étudier l'impact des facteurs intrinsèques (structure moléculaire des matériaux, propriétés physiques et/ou physicochimiques, etc.) ou des facteurs environnementaux (conditions de stockage ou paramètres de procédé) sur la stabilité de la structure des poudres. Plus précisément, notre étude a mis en évidence le rôle prépondérant du phénomène de cristallisation et des transitions entre les différents polymorphes du lactose. L'accent a été mis sur le rôle des phénomènes de cristallisation et de la transition de phase dans l'apparition du mottage des poudres de lactose. Deux cas ont particulièrement retenu notre attention: (1) des poudres de lactose monohydrate contenant une fraction de particules amorphes et (2) des échantillons de poudre anhydre composés des anomères α et β du lactose. Dans les deux cas, le mottage a été induite par l'exposition des échantillons à l'air humide, soit dans un dispositif de sorption dynamique de vapeur (SPS), soit par des tests accélérés utilisant deux appareils conçus et réalisés dans notre laboratoire (CLAIR & OLAF). Nos résultats ont montré que, dans les deux cas, la principale cause de prise en masse était la formation de lactose monohydrate, qui est la forme la plus stable parmi tous les polymorphes de lactose. Cependant, les mécanismes élémentaires, les étapes limites et la cinétique du processus de transformation étaient différents dans chaque cas. Les paramètres les plus déterminants étaient l’humidité relative et la température alors que la pression n’a pas eu d’effet significatif. La résistance mécanique des échantillons mottés était étroitement liée au taux et à la cinétique de cristallisation. Enfin, des simulations numériques basées sur la méthode des éléments discrets (DEM) de la résistance mécanique des échantillons mottés ont été réalisées. Le modèle permet de décrire le comportement des échantillons mottés soumis à des contraintes mécaniques de compression ou de traction
This PhD study focuses on the fundamental problem of powder caking due to phase transition mechanisms. The project aims to study the impact of intrinsic factors (molecular structure of materials, physical and/or physicochemical properties, etc.) or environmental factors (storage conditions or process parameters) on the stability of the structure of powders. More precisely, our study has highlighted the preponderant role of the crystallization phenomenon and the transitions taking place between the different polymorphs of lactose. Emphasis was placed on the role of crystallization phenomena and phase transition on the advent of lactose powder caking. Two cases attracted particular attention: (1) lactose monohydrate powders containing a fraction of amorphous particles and (2) anhydrous powder samples composed of ð and anomers of lactose. In both cases, the caking was induced by exposure of the samples to moist air, either in a Dynamic Vapor Sorption device (SPS) or in accelerated caking tests using two home-made equipment (CLAIR & OLAF). Our results showed that in both cases, the main cause of caking was the formation of lactose monohydrate, which is the most stable form among all lactose polymorphs. However, the elementary mechanisms, the limiting steps and the kinetics of the transformation process were different in each case. The more influencing parameters were the relative humidity and the temperature whereas the pressure has no significant effect. The yield stress of caked samples was closely linked with crystallization extent and kinetics. Finally, numerical simulations based on Discrete Element Method (DEM) of mechanical resistance of caked samples were performed using the "beam model". The model allows describing the behavior of the caked samples subjected to compressive or tractive mechanical stresses

Dry powder inhalers (DPIs) are used for delivering drugs to the airways. In addition to the drug, the formulations often contain a coarse carrier, most commonly alpha lactose monohydrate. The presence of fine lactose particles in the formulation is known to improve the formulation performance. The active site, drug-fines agglomeration and increased cohesion theories have been suggested to explain improved DPI performance upon addition of fine excipient particles. This project aimed to investigate the validity of those theories. The viability of the active sites theory in explaining the improved DPI performance was investigated by studying the impact of loaded drug dose on the in vitro performance for formulation series prepared with coarse carriers with different surface characteristics. The formulations prepared with the rougher lactose carrier were seen to outperform the formulations prepared with the smoother carrier at all drug concentrations. These findings were concluded to be non-compatible with the active sites theory. The impact of addition of lactose fines with different size distributions on powder flow and fluidisation properties and in vitro performance was studied. Powder cohesion increased independent of size distribution of the fines, but did not necessarily correspond to improved performance. Therefore, the increased cohesion theory was concluded not to be the sole explanation for the improvement in DPI performance in the presence of lactose fines. Instead, the increase in performance could be preliminarily attributed to the formation of agglomerated systems. The formation and co-deposition of drug-fines agglomerates, and consequential improvement in the DPI performance was proved using morphologically directed Raman spectroscopy. The project also aimed to develop a universal model for predicting DPI performance based on the lactose properties for a wide range of carriers with different properties. No simple linear correlations between any the lactose properties and the final DPI performance were found. Therefore no single parameter can be used as a universal predictor for DPI performance. To establish more complex relationships, artificial neural networks were used for modelling the importance of different lactose properties in determining DPI performance. The proportion of fine lactose particles (<4.5 μm) was identified as the most important parameter. However, this parameter was capable of explaining only approximately half of the variation seen in the formulation performance. The current study showed that to obtain more accurate predictions for the purposes of quality-by-design approach, also other lactose properties need to be characterised.

Excipients are used in pharmaceutical formulations as fillers and drug carriers. Their successful function is inextricably linked to their physicochemical properties and, in turn, these properties are directly related to their structure. This thesis is concerned with the structural and spectroscopic characterisation of a selection of excipients by powder and single crystal X-ray diffraction, Raman and IR spectroscopy and MASNMR and an investigation of their stability as a function of temperature, humidity and particle size. As well as being a well-known excipient used in the pharmaceutical industry, lactose is also a common food additive. The diverse usage of lactose has led to a wealth of contradictory information relating to both structure and properties of this material. The first part of experimental work in this thesis identifies the four real lactose polymorphs; the naturally occurring a-lactose monohydrate; the anhydrous stable form of a-lactose; the hygroscopic unstable form of a-lactose; and the anomeric equivalent, p-lactose using powder X-ray diffraction. The work shows that anhydrous lactose formed by solvent dehydration often termed aM is simply the anhydrous stable form of a-lactose formed via a different route. Simple methods for discerning between the polymorphs using standard laboratory equipment are suggested. IlC MASNMR data were collected on all four forms of lactose for the first time and illustrate key differences between the four structures. Single crystal data were successfully collected on the a-lactose monohydrate and refinement carried at low temperature to determine the hydrogen bonded arrangement for the first time. Rietveld refmement of the hygroscopic unstable form of a-lactose using in-situ temperature resolved X-ray diffraction has shown that the hygroscopic form can be produced as a single phase. Refinement of Plactose using the Rietveld method has shown that powder diffraction data were comparable with single crystal data, with respect to structure refinement but attempts at both crystallisation and refinement of the stable anhydrous a-lactose polymorph were unsuccessful due to the complexity of the structure. Powder X-ray diffraction analysis was shown to be an effective tool in the quantification of mixed phase lactose samples with respect to both mixed phase stable anhydrous a-lactose and a-lactose monohydrate; and mixed p-Iactose and a-lactose monohydrate samples. The accuracy of the technique was determined to be at least 5%. Quantification was carried out using relative intensities of a well resolved unique reflection for each phase within the system. Dehydration techniques applied to lactose were applied to other hydrated pharmaceutical sugars; trehalose dihydrate and raffmose pentabydrate. Solid state techniques; powder X-ray diffraction, Raman and IR spectroscopy; showed that discrimination of other sugar hydrates became more complex with increasing levels of hydration.

L’augmentation de la demande en lait infantile génère une forte croissance de la production mondiale de lactose. En raison d’exigences accrues sur la qualité du produit, le mottage, ou prise en masse spontanée de la poudre, est une non-conformité pouvant s’avérer très coûteuse. En utilisant une approche procédé – produit, ce projet vise à identifier les paramètres critiques et comprendre les mécanismes de mottage du lactose, pour donner les moyens aux industriels de prévenir le mottage. Les résultats obtenus sur des poudres produites à l’échelle pilote montrent le rôle déterminant des impuretés (i.e. composés autres que le lactose) et de la granulométrie. En effet, les impuretés renforcent l’hygroscopicité et le mottage. De plus, en augmentant la teneur en impuretés, la surface spécifique et le nombre de points de contact, une diminution de la taille des particules et une hétérogénéité de tailles accrue intensifient le mottage. L’analyse des poudres commerciales a confirmé ces résultatUn autre résultat marquant de ce travail est le développement d’un test de mottage accéléré, qui permet de classer des poudres de lactose en fonction de leur tendance au mottage en moins d’une journée, après un stockage à 50°C et 60% d’HR. Un test similaire implémenté sur chaque site de production permettrait l’identification rapide des lots à risque avant expédition. Grâce à la meilleure compréhension des mécanismes de mottage fourni par ce travail, les industriels peuvent cibler les étapes critiques du procédé à optimiser pour prévenir le mottage du lactose
Driven by the growth in the infant formula market, lactose production is increasing worldwide, and the requirements for the product quality are becoming stricter. Caking, or the unwanted agglomeration of lactose powder particles, is synonym of poor quality for the customers and should therefore be prevented to avoid large economic loss. Focusing on the process–product relationship, this PhD project aimed at finding the critical parameters and understanding the caking mechanisms in lactose powder in order to establish means to limit caking. In samples from pilot production, impurities (i.e. non-lactose components) were shown to increase moisture sorption and caking. The particle size distribution of the powder also exhibited a large effect on caking. Indeed, smaller particles and a broader distribution were characterized by enhanced moisture sorption and stronger caking, which were explained by a larger impurity content and surface area and more contact points.Analyses on the commercial powder confirmed these results and revealed the instability of the water activity during storage of the powder after drying, which was linked to caking in the bags. This PhD project also addressed an essential need in the dairy industry, i.e. the development of an accelerated caking test. Samples from different production sites were discriminated in terms of caking in less than a day, using appropriate test conditions (50°C and 60% RH). A similar test implemented at all sites would highlight batches with a high caking tendency before shipment to the customers. The better understanding of th

La technologie de production du lait en poudre hydrolysé au lactose a été développée pour répondre aux besoins des consommateurs intolérants au lactose. Bien que le produit soit actuellement commercialisé dans certains pays, le secteur est confronté à des problèmes technologiques lors de la production et du stockage de la poudre, tels que l'agglomération, la prise en masse, le brunissement, une hygroscopicité élevée, un faible rendement de production et une perte de propriétés technofonctionnelles. Dans ce contexte, deux objectifs principaux ont été assignés aux travaux de cette thèse: (i) optimiser le processus de séchage du lait en poudre hydrolysé au lactose; (ii) comprendre l'impact de l'hydrolyse du lactose sur la structure interne du lait en poudre hydrolysé au lactose à l'échelle moléculaire. Afin d’optimiser le processus de séchage du lait en poudre hydrolysé au lactose, les échantillons de poudre ont été soumis à diverses conditions de séchage: débits de lait concentré variant de 0,3 à 1,5 kg and h -1 et température d’entrée de l’air allant de 115 à 160 °C. Ensuite, une caractérisation thermodynamique du processus de séchage a été réalisée en utilisant les équations de bilan massique et énergétique. Pour comprendre l'impact de l'hydrolyse du lactose sur la structure interne de la poudre après séchage et pendant le stockage, nous avons analysé l'organisation et la dynamique des molécules dans le lait en poudre hydrolysé au lactose en examinant l'aspect et la structure des échantillons de poudre et leurs propriétés techno-fonctionnelles. Tout au long des expériences, le lait en poudre traditionnel a été utilisé comme témoin. Dans cette étude, il a été observé que les paramètres idéaux pour la production de lait en poudre hydrolysé au lactose étaient les suivants: température de l'air entrant à 145 ° C et débit de 1,0 kg h-1. Cette découverte renforce l'idée selon laquelle les conditions de séchage du lait en poudre hydrolysé au lactose sont différentes de celles utilisées pour la fabrication du lait en poudre traditionnel. Il a également été observé que les molécules présentes dans le lait en poudre hydrolysé au lactose présentaient une organisation moléculaire plus homogène par rapport au lait en poudre traditionnel et permettaient une plus grande interaction protéine-sucre. Dans des conditions de vieillissement accéléré de la poudre hydrolysée, la glycation des protéines était le processus initial qui a déclenché les principales modifications observées dans le lait en poudre hydrolysé au lactose pendant le stockage
The production technology of lactose hydrolyzed milk powder has been developed to meet the needs of lactose intolerant consumers. Although the product is currently marketed in some countries, the industry faces technological issues during the production and storage of the powder such as agglomeration, caking, browning, high hygroscopicity, low production yield and loss of techno-functional properties. In this context, two main objectives were assigned to the work of this thesis: (i) to optimize the drying process of lactose hydrolyzed milk powder; (ii) to understand the impact of lactose hydrolysis on the internal structure of lactose hydrolyzed milk powder on a molecular scale. In order to optimize the drying process of lactose hydrolyzed milk powder, powder samples were subjected to various drying conditions: concentrated milk flow rates varying from 0.3 to 1.5 kg∙h -1 and inlet air temperature ranging from 115 to 160 °C. Then, a thermodynamic characterization of the drying process was carried out using the equations of mass and energy balance. To understand the impact of lactose hydrolysis on the internal structure of the powder after drying and during storage, the organization and dynamics of the molecules in lactose hydrolyzed milk powder were analyzed by examining appearance and structure of the powder samples and their techno-functional properties. Throughout the experiments, traditional milk powder was used as a control. In this study, it has been observed that the ideal parameters for lactose hydrolyzed milk powder production were: inlet air temperature at 145 ° C and 1.0 kg ∙ h-1 flow rate. This finding reinforces the idea that the drying conditions of lactose hydrolyzed milk powder are different from those used to make traditional milk powder. It was also observed that molecules present in milk powder hydrolyzed with lactose presented a more homogeneous molecular organization compared to traditional milk powder and allowed for greater protein-sugar interaction. Under accelerated aging conditions of the hydrolyzed powder, the protein glycation was the initial process that triggers the main modifications observed in lactose hydrolyzed milk powder during storage

Le procédé d’agglomération permet d’améliorer les propriétés de réhydratation des poudres de lait par formation de structures poreuses favorisant la pénétration de l’eau par capillarité. Une meilleure compréhension de la contribution des caractéristiques des matières premières et des paramètres du procédé aux mécanismes d'agglomération est nécessaire pour maîtriser les propriétés de réhydratation résultantes. Cette thèse CIFRE a été conduite afin de combler ce manque. Une étude statistique des données de production industrielle de l’entreprise partenaire du projet a d’abord permis de contextualiser la problématique et de proposer des hypothèses sur des mécanismes potentiels. Une étude paramétrique du procédé a été conduite sur un équipement pilote original d’agglomération par injection de vapeur.Les matières premières et poudres agglomérées ont été caractérisées au plan de leur composition, de l'état physico-chimique des constituants, des caractéristiques physiques des particules et des propriétés de réhydratation des agglomérats. Les résultats montrent une influence déterminante des phénomènes de transition vitreuse et de cristallisation du lactose sur le processus d’agglomération et les propriétés de réhydratation des agglomérats. L'optimum des propriétés de réhydratation est fonction de la réactivité de la matière (teneur en eau, température de transition vitreuse, quantité de lactose amorphe), du taux de mouillage lors de l'agglomération et des conditions de séchage. Les constituants amorphes et la transition vitreuse semblent contribuer plus au déterminisme des p
The agglomeration process makes it possible to improve the rehydration properties of milk powders by forming porous structures that favour the water penetration by capillarity. A better understanding of the contribution of raw materials characteristics and process parameters to the agglomeration mechanisms is needed to control the rehydration properties of the agglomerates. This PhD project has been led to fill this gap. A statistical analysis of the data of industrial production obtained from the partner company of the project allowed first to contextualize the issue and formulate hypothesis on the potential underlying mechanisms of agglomeration. Experimental studies of the process were then performed on an original steam-jet agglomeration equipment at a pilot scaleThe raw materials and agglomerated powders were characterized regarding their composition, the physicochemical state of their components, the physical characteristics of the particles and the agglomerates rehydration properties. The results showed a crucial influence of the glass transition and the lactose crystallization phenomena on both the agglomeration process efficiency and the resulting agglomerates rehydration properties. The optimum of rehydration properties depends on the reactivity of the materials (water content, glass transition temperature, quantity of amorphous lactose), the particles wetting during agglomeration and the drying conditions. The amorphous contents and the glass transition seem to contribute more significantly to the determinism of the rehydration properties than the physical

In-situ time-resolved synchrotron X-ray and neutron powder diffraction techniques have been applied to the study of solid state structural transitions within the organic polymorphic molecular systems of lactose, trehalose and theophylline. Diffraction techniques offer an unequalled method of polymorph identification and quantification, and have repeatedly demonstrated throughout this work that they can be utilised to follow and kinetically evaluate structural transitions in real time. The study of lactose crystallisation provides further proof of the transient ( lo::1/3) mixed crystal polymorph as the initial crystallisation product, which is then followed by the typical beta lactose and alpha lactose monohydrate phases. The formation of the (lo:: l,B) mixed crystal form has been mapped and kinetically analysed; the complex multi-step crystallisation behaviour is likely to result from the high degree of polymorphism which is displayed within the lactose system. The dehydration studies of the three systems show that dehydration kinetics can vary as a function of processing conditions and environments. Evidence of a previously undocumeuted theophylline polymorph has been observed which is accessible via the seeded dehydration of theophylline monohydrate with anhydrous theophylline form II. The best production of beta lactose from the 1-biannual dehydration of alpha lactose monohydrate to date is documented and is attained from dehydration within a hydrophobic cocoa butter environment; this transition is mediated via a crystalline phase whose identity is uncertain, yet displays a unique Bragg peak at rv 12.87° 20. Neutron diffraction techniques reveal that the water content and crystalline weight fraction of trehalose dihydrate are decoupled quantities, and the dihydrate lattice can sustain substantial water loss. These observations provide supporting evidence of a transiently stable, partially hydrated state of trehalose. In addition, the applicability of the Dl9 single-crystal diffraction beamline at the Institut Laue-Langevin in the study of hydrated powder samples is reported, demonstrating the versatility of the instrument with the capability of performing dynamic studies with a time-resolution of 15 s.

Class of 2017 Abstract
Objectives: Milk protein allergy is estimated to affect 1.2% to as much as 17% of people of all ages. Advair® Diskus® (FP/SX) utilizes lactose as an excipient which limits the utility of this product for this population. Furthermore, Advair® Diskus® is formulated as an interactive physical mixture via a micronization process. Alternatively, spray dried engineering achieves narrow particle size distribution, allowing greater deposition in the targeted respiratory bronchioles. The purpose of this dry powder inhaler (DPI) study was to conduct an in vitro comparative analysis of the aerodynamic performance of a co-spray dried lactose-free formulation of FP/SX with a mannitol excipient as a molecular mixture versus the Advair® Diskus® 250/50 (FP/SX) interactive physical mixture product. Methods: Utilizing mannitol as an excipient, a co-spray dried FP/SX powder was prepared using the Buchi Mini-Spray Dryer B-290 under closed system configuration. The resulting feed solution was spray dried at pump rates of 25%, 50%, and 100% with all other parameters remaining constant (aspiration, atomization rate, nitrogen gas rate). The primary outcome measure, aerodynamic performance, was assessed using the Copley Next-Generation Impactor (NGI). NGI data for the DPIs was used to calculate mass median aerodynamic diameter (MMAD), geometric standard deviation (GSD), and fine particle fraction (FPF) of each powder, including the Advair® Diskus®. Residual water content was quantified by Karl Fischer titration. Particle characteristics were visualized by scanning electron microscopy. Results: FPF, MMAD, and GSD were calculated from NGI data; Wolfram Alpha software was used to calculate MMAD and GSD. T-test regression was used for comparative analysis of spray-dried and Advair® Diskus® powders. MMAD for each spray dried sample was analyzed using a t-test regression against the MMAD values from the Advair® Diskus®. Using aerodynamic analysis studies triplicated for each powder, there was no significant difference between the spray dried powder and Advair® Diskus® for MMAD and GSD (p-values >0.05). The 50% and 100% pump rate samples had similar FPF to the Advair® Diskus® (p-values >0.05). However, the 25% pump rate sample had a significantly improved FPF compared to the Advair® Diskus® (p <0.01). Conclusions: A co-spray-dried lactose-free formulation of FP/SX with a mannitol excipient demonstrated similar aerodynamic performance to the Advair® Diskus® which consists of a physical mixture of two drugs with lactose. Of significance, 25% pump rate spray-dry conditions demonstrated an improved FPF compared to the Advair® Diskus®.

Cette étude est menée dans le cadre du projet "PowderReg", financé par le programme européen Interreg VA GR dans le cadre de l'axe prioritaire 4 "Renforcer la compétitivité et l'attractivité de la Grande Région / Groβregion". La compréhension du lien entre l'organisation microscopique et le comportement de l'écoulement des poudres est une avancée majeure dans l'établissement de critères pour optimiser leurs propriétés de transport, de stockage et de traitement. Ainsi, une meilleure compréhension du comportement de l'écoulement des poudres évite aux industries d'énormes pertes économiques. Il est donc essentiel d'évaluer leur aptitude à l'écoulement. Ce travail consiste à étudier expérimentalement l'influence de la formulation des poudres, de la taille des particules, ainsi que l'influence des conditions environnementales telles que l'humidité sur les comportements d'écoulement des poudres. Cinq types de formulations ont été analysés: la bille de verre témoin a été utilisée comme poudre de référence et trois types de formulations de surface consistant en un enrobage hydrophile, hydrophobe et de lactose ainsi qu'une poudre de lactose agglomérée ont été préparés. Tout d'abord, l'influence de deux tailles différentes, 100 et 500 µm, sur le comportement d'écoulement des poudres a été analysée. Ensuite, le comportement de l'écoulement des poudres a été étudié avec différents équipements expérimentaux: FT4, Granutools et rhéomètre Discover HR3. Y compris différentes techniques, telles que la cellule de cisaillement, la compressibilité, l'angle de rotation du repos, etc. L'objectif était de déterminer le comportement des poudres dans différentes conditions de traitement. Les résultats ont montré que le passage d'une technique à l'autre peut modifier la classification de la fluidité des poudres. Comme les poudres subissaient des contraintes mécaniques différentes. Dans la dernière partie de cette thèse, nous avons observé l'influence impressionnante de l'humidité après 80 % sur le comportement d'écoulement de deux tailles différentes de billes de verre de contrôle (40 et 100 µm). Les perles de verre de petit diamètre ont montré une fluidité plus faible qui est due au plus grand nombre de contacts de surface de ces particules. De plus, la comparaison du comportement d'écoulement des billes de verre de contrôle et hydrophobes de taille 100 µm à un taux de cisaillement élevé a révélé la même fluidité pour les deux échantillons. Alors qu'à faible taux de cisaillement, les mesures par rhéologie vibratoire ont révélé une fluidité plus élevée dans les billes de verre de contrôle. La fluidité de la perle de verre témoin a diminué de façon spectaculaire après 80 % de contrôle de l'humidité, mais la perle de verre hydrophobe a conservé son comportement d'écoulement comme auparavant avec une très faible sensibilité à l'humidité. Enfin, l'influence de l'ajout d'une petite quantité d'eau sur le comportement d'écoulement de la bille de verre de contrôle a été étudiée
This study is conducted in the framework of the “PowderReg” project, funded by the European program Interreg VA GR within the priority axis 4 “Strengthen the competitiveness and the attractiveness of the Grande Région Groβregion”. Understanding the link between microscopic organization and powders flow behavior is a major step forward in establishing criteria for optimizing their transport, storage and processing properties. Whereby, better understating of powder flow behavior saves the industries from huge economic loss. Therefore, it is essential to evaluate their flowability. This work consists in experimentally studying the influence of powder formulation, particle size, as well as influence of environmental condition such as humidity on flow behaviors of powders. Five types of formulations have been analyzed: control glass bead has been used as reference powder and three types of surface formulations consisting of hydrophilic, hydrophobic and lactose coating as well as agglomerated lactose powder have been prepared. First, influence of two different sizes 100 and 500 µm on flow behavior of powders has been analyzed. Then, the powders flow behavior has been considered with different experimental equipements: FT4, Granutools and Rheometer Discover HR3. Including different techniques, such as shear cell, compressibility, rotating angle of repose, etc. The objective was to figure out the behavior of powders under different processing conditions. The, results reported that the transition from one technique to another can modify the classification of the powder flowability. Since the powders were experiencing different mechanical stresses. At the last part of this thesis, we observed the impressive influence of humidity after 80 % on flow behavior of two different size of control glass beads (40 and 100 µm). Small diameter glass bead showed lower flowability which is due to the more surface contacts of these particles. Furthermore, the comparison of flow behavior of control and hydrophobic glass beads with 100 µm size at high shear rate reported the same flowability for both samples. While at low shear rate measurements by vibrational rheology revealed higher flowability in control glass bead. The flowability of control glass bead decreased dramatically after 80 % of humid control, however hydrophobic formulated glass bead kept its flow behavior like as before with very low sensitivity to humidity. Finally, influence of addition of small quantity of water on flow behavior of control glass bead has been investigated

Direct compression has gained significant interest since its advent in the late 1950's due to its potential ease compared to wet granulation. The primary prerequisites for powders used in direct compression are (i) good flow properties (ii) good compressibility and (iii) an acceptable dilution potential to accommodate a relative high percentage of active ingredient. Several filler/binders have been manufactured especially for direct compression and co–processing is one of the recent methods used to produce good compressible excipients with acceptable flow properties. In this study, lactose–based filler/binders were used which included simple and modified lactose materials (Granulac, Lactopress, Flowlac and Tablettose) as well as co–processed excipients (Starlac, Cellactose and Microcelac). A comprehensive literature study on direct compression revealed the importance of the physical properties of filler/binders such as interparticle forces, particle shape, particle size and distribution, powder density, particle surface structure and particle packing geometry which influence the flow of powders. All the materials were subjected to the various tests available to evaluate powder flow, namely (i) angle of repose (AoR), (ii) critical orifice diameter (COD), (iii) flow rate and percentage compressibility (%C) in terms of the powders' bulk and tap densities. The results of these tests confirmed the expected flow properties of the various filler/binders, with only one material exhibiting extremely poor flow properties. The following rank order in terms of all flow tests conducted was established; Starlac >> Microcelac ~ Flowlac >> Cellactose > Tablettose > Lactopress >>> Granulac. The co–processed filler/binders presented with superior flow compared to the other lactose–based materials. During the next phase of the study, the compaction properties of the various fillers were evaluated, employing direct compression. Compacts of pure filler were tabletted on an eccentric tablet press at different compression pressures (manipulated by the upper punch setting of the tablet press). The modified lactose filler/binders (Lactopress, Flowlac and Tablettose) exhibited unexpectedly poor compression profiles, where the co–processed filler/binders (Starlac, Cellactose and Microcelac) produced compacts with acceptable appearance and compact properties. Two lubricants (Mg–St or Pruv), which were tested separately in formulations were added since no compacts could be produced from the pure filler/binders. None of the modified lactose filler/binders, in combination with a lubricant, were able to produce an acceptable compact, since lamination occurred during compression. The co–processed filler/binders produced satisfactory compacts with the addition of a lubricant, but lactose–cellulose fillers (Cellactose and Microcelac) also required the inclusion of a disintegrant (Ac–Di–Sol) to induce satisfactory compact disintegration. Poor compressible active ingredients (paracetamol), which exhibit very poor flow properties, are usually difficult to use during direct compression. Many excipients (tested in this study) are formulated to accommodate these drugs and produce acceptable functional tablets. After identifying the best filler/binders (co–processed fillers), according to their flow and compressible properties, paracetamol was added to the formulations. During a pilot study, the percentage paracetamol these fillers could accommodate in a 400 mg tablet was determined. Both Microcelac and Cellactose could accommodate 24.5% w/w paracetamol, whilst Starlac could only accommodated 19.5% w/w. Paracetamol is well known for its tendency to cause tablet capping and lamination. An acceptable upper punch setting range (20–22) was chosen for tabletting, followed by quality control tests done. All three formulations produced suitable tablets for testing and exhibited good tablet properties. All tablets disintegrated within two minutes, with hardness profiles between 120 N and 148 N and friability percentages less than 1%. Dissolution studies, however, are probably the ultimate test to distinguish between the capability of filler/binders to release the optimum percentage drug after disintegration. Dissolution studies were done on all three formulations using the AUC (area under the curve) and IDR (initial drug release) as parameters to evaluate drug release. All tablets exhibited high initial dissolution rates (between 0.018 - 0.023 mg/min/ml) and 100% drug release was observed. Starlac presented with a lower amount of drug released compared to the other two, but can be explained by the lower percentage (19.5%) paracetamol present in the formulation. It was once again confirmed that the physical and compressible properties of potential directly compressible filler/binders play a major role in direct compression. It was concluded that co–processed filler/binders (Starlac, Microcelac and Cellactose) definitely exhibited better tabletting properties during direct compression. They were able to accommodate a certain percentage of paracetamol, although it was expected that they would accommodate a higher amount (at least 50% of total tablet weight).
Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2011.

Submitted by Diego Luiz Tita (diego.tita@gmail.com) on 2018-05-11T17:51:31Z No. of bitstreams: 1 DR_TITA_DL_FINAL_A.pdf: 8672085 bytes, checksum: af81639f689b5a5fc78999ae952240a8 (MD5)
Approved for entry into archive by Ana Carolina Gonçalves Bet null (abet@iq.unesp.br) on 2018-05-15T12:53:22Z (GMT) No. of bitstreams: 1 tita_dl_dr_araiq_int.pdf: 8328482 bytes, checksum: be0fe77b0059e1880c4d517105e2c2f6 (MD5)
Made available in DSpace on 2018-05-15T12:53:22Z (GMT). No. of bitstreams: 1 tita_dl_dr_araiq_int.pdf: 8328482 bytes, checksum: be0fe77b0059e1880c4d517105e2c2f6 (MD5) Previous issue date: 2018-04-20
O refinamento de estruturas cristalinas pelo método de Rietveld (MR) consiste em ajustar um modelo estrutural a uma medida de difração. Essa é uma ferramenta eficiente para identificação e quantificação de estruturas polimórficas presentes em fármacos e excipientes. Uma forma avançada do método é o refinamento sequencial por Rietveld (RSR) que visa, a partir de um conjunto de difratogramas de uma mesma amostra, estudar o comportamento do material em função de uma variável externa (e.g. temperatura, pressão, tempo ou ambiente químico). No presente trabalho, com o objetivo de estudar as transições polimórficas e as expansões/contrações dos parâmetros de cela unitária (PCU) dos insumos farmacêuticos: espironolactona (SPR), lactose monoidratada (LACMH) e lactose anidra (LACA), empregou-se o RSR em medidas obtidas em diferentes temperaturas. O RSR foi eficiente para que os PCU fossem refinados até temperaturas próximas ao ponto de fusão dos materiais. Após o RSR, a partir da análise matemática dos PCU obtidos, foram propostas funções que regem a tendência desses parâmetros quando submetidos à variação de temperatura. Com essas funções modelaram-se os PCU em uma outra modalidade de refinamento, o refinamento paramétrico por Rietveld (RPR), assim, os PCU seguem a modelagem imposta pelas equações obtidas via RSR. O RPR mostrou-se mais eficiente nas análises, o que evitou perda de fases ou problemas de ajustes, resultando assim em informações mais precisas do sistema. Embora o RSR e RPR serem métodos sofisticados para a caracterização dos materiais, a preparação das rotinas de programação dos refinamentos não é trivial, assim, nesse trabalho desenvolveu-se uma planilha (i.e. planilha SP-DLT) que facilita o emprego dos métodos. A planilha mostrou-se eficiente e rápida para programar todas as rotinas de refinamentos apresentadas nesse trabalho. Com os estudos dos insumos farmacêuticos observou-se que na amostra SPR a forma I, com o aumento da temperatura, se converte para forma II. A alfalactose monoidratada sofre desidratação e se converte para alfalactose, na amostra LACMH, e para betalactose, na amostra LACA. E, ainda com aumento de temperatura, a betalactose não sofre mudança de fase polimórfica. Assim, entende-se que o meio pode causar influência na rota de transição polimórfica.
The crystal structural refinement by the Rietveld method (MR) consists of fitting a structural model to a diffraction measure. This is an efficient tool for identification and quantification of polymorphic structures present in drugs and excipients. An advanced way to use this method is the Sequential Rietveld Refinement (RSR), which aims, from a set of data of the same sample, to study the behavior of the material as a function of an external variable (e.g. temperature, pressure, time or chemical environment). In the present work, with the objective of studying the polymorphic transitions and the expansions / contractions of the unit cell parameters (PCU) of the pharmaceutical ingredients: spironolactone (SPR), lactose monohydrate (LACMH) and anhydrous lactose (LACA), the RSR in measurements obtained at different temperatures. The RSR was efficient so that the PCU were refined to temperatures close to the melting point of the materials. After the RSR, from the mathematical analysis of the obtained PCU, functions were proposed that govern the trend of these parameters when submitted to the temperature variation. With these functions the PCU were modeled in another modality of refinement, the Parametric Rietveld Refinement (RPR), thus, the PCU follow the modeling imposed by the equations obtained via RSR. The RPR was more efficient in the analyzes, which avoided loss of phases or problems of adjustments, resulting in more accurate information of the system. Although RSR and RPR are sophisticated methods for characterization of materials, preparation of refinement programming routines is not trivial, so a spreadsheet (i.e. SP-DLT spreadsheet) has been developed in this paper to facilitate the use of methods. The worksheet proved to be efficient and quick to program all the refinement routines presented in this paper. With the studies of the pharmaceutical inputs it was observed that in the SPR sample, the form I, with the increase in temperature, converts to form II. Alfalactose monohydrate undergoes dehydration and converts to alfalactose in the LACMH sample and to betalactose in the LACA sample. And, even with temperature increase, the betalactose does not undergo polymorphic phase change. Thus, it is understood that the medium may cause influence on the polymorphic transition route.

Dry Powder Inhaler (DPI) technology has a significant impact in the treatment of various respiratory disorders. DPI formulations consist of a micronized drug (<5ìm) blended with an inert coarse carrier, for which lactose is widely used to date. DPIs are one of the inhalation devices which are used to target the delivery of drugs to the lungs. Drug delivery via DPI formulations is influenced by the physico-chemical characteristics of lactose particles such as size, shape, surface roughness and adhesional forces. Commercially available DPI formulations, which utilise lactose as the carrier, are not efficient in delivering drug to the lungs. The reasons for this are the surface morphology, adhesional properties and surface roughness of lactose. Despite several attempts to modify lactose, the maximum efficient drug delivery to the lungs remains limited; hence, exploring suitable alternative carriers for DPIs is of paramount importance. Therefore, the objective of the project was to study the performance of spherical polymer microparticles as drug carriers and the factors controlling their performance. This study aimed to use biodegradable polymer microspheres as alternative carriers to lactose in DPIs for achieving efficient drug delivery into the lungs. This project focused on fabricating biodegradable polymer microparticles with reproducible surface morphology and particle shape. The surface characteristics of polymeric carriers and the adhesional forces between the drug and carrier particles were investigated in order to gain a better understanding of their influence on drug dispersion. For this purpose, two biodegradable polymers- polycaprolactone (PCL) and poly (DL-lactide-co-glycolide) (PLGA) were used as the carriers to deliver the anti-asthmatic drug - Salbutamol Sulphate (SS). The first study conducted for this dissertation was the aerosolization of SS from mixtures of SS and PCL or PLGA microparticles. The microparticles were fabricated using an emulsion technique and were characterized by laser diffraction for particle size analysis, Scanning Electron Microscopy (SEM) for surface morphology and X-ray Photoelectron Spectroscopy (XPS) to obtain surface elemental composition. The dispersion of the drug from the DPI formulations was determined by using a Twin Stage Impinger (TSI). The Fine particle Fraction (FPF) of SS from powder mixtures was analyzed by High Performance Liquid Chromatography (HPLC). It was found that the drug did not detach from the surface of PCL microspheres. To overcome this, the microspheres were coated with anti-adherent agents such as magnesium stearate and leucine to improve the dispersion of the drug from the carrier surfaces. It was found that coating the PCL microspheres helped in significantly improving the FPF of SS from the PCL surface. These results were in contrast to the PLGA microspheres which readily allowed detachment of the SS from their surface. However, coating PLGA microspheres with antiadherent agents did not further improve the detachment of the drug from the surface. Thus, the first part of the study demonstrated that the surface-coated PCL microspheres and PLGA microspheres can be potential alternatives to lactose as carriers in DPI formulations; however, there was no significant improvement in the FPF of the drug. The second part of the research studied the influence of the size of the microspheres on the FPF of the drug. For this purpose, four different sizes (25 ìm, 48 ìm, 100 ìm and 150 ìm) of the PCL and PLGA microspheres were fabricated and characterized. The dispersion of the drug from microspheres of different sizes was determined. It was found that as the size of the carrier increased there was a significant increase in the FPF of SS. This study suggested that the size of the carrier plays an important role in the dispersion of the drug from the carrier surface. Subsequent experiments in the third part of the dissertation studied the surface properties of the polymeric carrier. The adhesion forces existing between the drug particle and the polymer surfaces, and the surface roughness of the carriers were quantified using Atomic Force Microscopy (AFM). A direct correlation between adhesion forces and dispersion of the drug from the carrier surface was observed suggesting that adhesion forces play an important role in determining the detachment potential of the drug from the carrier surface. However, no direct relationship between the surface roughness of the PCL or PLGA carrier and the FPF of the drug was observed. In conclusion, the body of work presented in this dissertation demonstrated the potential of coated PCL microspheres and PLGA microspheres to be used in DPI formulations as an alternative carrier to sugar based carriers. The study also emphasized the role of the size of the carrier particles and the forces of interaction prevailing between the drug and the carrier particle surface on the aerosolization performances of the drug.

Small quantities of amorphous content can have a profound influence on the properties of a material, however their instability means that quantifying amorphous content over time is important for proving the stability of a drug. Quantifying amorphous content in α-lactose monohydrate by solid state 13C CP MAS NMR, has been carried out by use of proton saturation recovery relaxation and differentiating between spectra by partial least squares (PLS), however these techniques have not proved sensitive on their own, this work investigates their sensitivity in combination. Crystalline α-lactose monohydrate and a rapidly quenched melt were combined to create a set of calibration mixes, whose spectra were recorded using proton saturation recovery relaxations ranging from 2 to 60 seconds. This technique showed a limit of detection of 0.17% (LOD = intercept + 3xSy/x), with a relaxation delay of 15 s and was able to recognise amorphous materials generated by spray and freeze drying. The atmospheric effects on the proton saturation recovery relaxation times of different amorphous lactose preparations were investigated. This found that an oxygen atmosphere reduced the relaxation times, of amorphous lactose that was prepared from a rapidly quenched melt. The loss of moisture from spray dried and freeze dried samples to less than 1% removed the significance of this effect. Lactose is an important excipient in pharmaceuticals and a key ingredient of confectionary, very little research has been carried out in to the quantification of the isomers of different preparations of amorphous lactose. This work quantifies the isomer content by Gas Chromatography with Flame Ionisation Detection (GC-FID) using a DB-17 15m 0.53mm 1.00 μm column and derivatisation with N- (trimethylsilyl)imidazole.

Orientador: Carlos de Oliveira Paiva Santos
Coorientadora: Selma Gutierrez Antonio
Banca: Marlus Chorilli
Banca: Vinícius Danilo Nonato Bezzon
Banca: Flavio Machado de Souza Carvalho
Banca: Alexandre Urbano
Resumo: O refinamento de estruturas cristalinas pelo método de Rietveld (MR) consiste em ajustar um modelo estrutural a uma medida de difração. Essa é uma ferramenta eficiente para identificação e quantificação de estruturas polimórficas presentes em fármacos e excipientes. Uma forma avançada do método é o refinamento sequencial por Rietveld (RSR) que visa, a partir de um conjunto de difratogramas de uma mesma amostra, estudar o comportamento do material em função de uma variável externa (e.g. temperatura, pressão, tempo ou ambiente químico). No presente trabalho, com o objetivo de estudar as transições polimórficas e as expansões/contrações dos parâmetros de cela unitária (PCU) dos insumos farmacêuticos: espironolactona (SPR), lactose monoidratada (LACMH) e lactose anidra (LACA), empregou-se o RSR em medidas obtidas em diferentes temperaturas. O RSR foi eficiente para que os PCU fossem refinados até temperaturas próximas ao ponto de fusão dos materiais. Após o RSR, a partir da análise matemática dos PCU obtidos, foram propostas funções que regem a tendência desses parâmetros quando submetidos à variação de temperatura. Com essas funções modelaram-se os PCU em uma outra modalidade de refinamento, o refinamento paramétrico por Rietveld (RPR), assim, os PCU seguem a modelagem imposta pelas equações obtidas via RSR. O RPR mostrou-se mais eficiente nas análises, o que evitou perda de fases ou problemas de ajustes, resultando assim em informações mais precisas do sistema. Embora o RSR e R... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: The crystal structural refinement by the Rietveld method (MR) consists of fitting a structural model to a diffraction measure. This is an efficient tool for identification and quantification of polymorphic structures present in drugs and excipients. An advanced way to use this method is the Sequential Rietveld Refinement (RSR), which aims, from a set of data of the same sample, to study the behavior of the material as a function of an external variable (e.g. temperature, pressure, time or chemical environment). In the present work, with the objective of studying the polymorphic transitions and the expansions / contractions of the unit cell parameters (PCU) of the pharmaceutical ingredients: spironolactone (SPR), lactose monohydrate (LACMH) and anhydrous lactose (LACA), the RSR in measurements obtained at different temperatures. The RSR was efficient so that the PCU were refined to temperatures close to the melting point of the materials. After the RSR, from the mathematical analysis of the obtained PCU, functions were proposed that govern the trend of these parameters when submitted to the temperature variation. With these functions the PCU were modeled in another modality of refinement, the Parametric Rietveld Refinement (RPR), thus, the PCU follow the modeling imposed by the equations obtained via RSR. The RPR was more efficient in the analyzes, which avoided loss of phases or problems of adjustments, resulting in more accurate information of the system. Although RSR and RP... (Complete abstract click electronic access below)
Doutor

This project has investigated the mechanism of caking of lactose and identified some possible solutions to minimise caking of lactose and dairy powders, additional to those suggested in the literature. A background to lactose and caking is given. The problems of caking are identified and discussed. The project adds information to the knowledge on the polymorphic forms of lactose and their inter-relationships due to moisture sorption and processes such as milling. This information and many others in the literature are used to complete the simplified lactose conversion diagram developed by King [1965] and improved by Walstra, et al. [1999], which has been widely used in the literature as a guide for lactose manufacturing, processing, and storage.
Doctor of Philosophy (PhD)

PURPOSE: To explore the use of crystal inter-planar d-spacings and slip-plane interaction energies for predicting and characterising mechanical properties of crystalline solids. METHODS: Potential relationships were evaluated between mechanical properties and inter-planar d-spacing, inter-planar interaction energy, and dispersive surface energy as determined using inverse gas chromatography (IGC) for a set of pharmaceutical materials. Inter-planar interaction energies were determined by molecular modelling. RESULTS: General trends were observed between mechanical properties and the largest inter-planar d-spacing, inter-planar interaction energies, and IGC dispersive surface energy. A number of materials showed significant deviations from general trends. Weak correlations and outliers were rationalised. CONCLUSIONS: Results suggest that the highest d-spacing of a material could serve as a first-order indicator for ranking mechanical behaviour of pharmaceutical powders, but with some reservation. Inter-planar interaction energy normalised for surface area shows only a weak link with mechanical properties and does not appear to capture essential physics of deformation. A novel framework linking mechanical properties of crystals to the distinct quantities, slip-plane energy barrier and inter-planar interaction (detachment) energy is proposed.

碩士
大葉大學
生物產業科技學系
97
Among dairy products fermented milk products-yoghurt are growing in popularity specifically for their health image in Taiwan. However, the characteristic milky flavor is very important problem for its utilization by some people in Taiwan. Therefore, we tended to add functional compounds to the products to prefer the domestic consumers. Soybeans rich in protein and contain some functional compounds such as isoflavones,oligosaccharides, polyunsaturated fatty acids and dietary fiber. Thus, we try to make yoghurt using soy milk fermentation. Currently, we have not found any good soy yoghurt products in the market. The present study investigated appropriate formula for yoghurt making. We use soy milk added milk, whey powder and lactose as raw materials and Lactobacilus acidophilus、Bifidobacterium longum、L.bulgaricus and Streptococcus thermophilus as the starter cultures. The raw materials are pasteurized at 85℃, 30min, cooled to 43℃ and inoculated with the starter culture, then incubated at 43℃ for 4hr. The moisture content, titratable acidity, pH, lactic acid bacterial counts, viscosity and curd tension and sensory scores of the products are determined. The results were shown in the follows:The values of moisture content, titratable acidity, lactic acid bacterial counts, viscosity and curd tension were found the highest in soy milk added milk(M), the second in soy milk added with milk and whey powder(W) and the lowest in soy milk with milk and lactose(L). However, pH values of the products were found the order as L>W>M. The sensory scores of yoghurt made from the soy milk added with milk and lactose were the highest and the product made from the soy milk with milk and whey powder were the second and the product made from soy milk with milk were the lowest. The functional compounds of soy yoghurt – isoflavone contents were not significant before and after fermentation. The content of exopolysaccharides was found the highest in soy yoghurt added with whey powder, then lactose was next, and the control was the lowest. And the bands of some of the protein components of soy beans and milk were found to be disappeared from the SDS-PAGE electrophoreto.

The influence of the size and morphology of carrier particles on drug dispersion performance from passive dry powder inhalers has been extensively studied topic, and a consensus has been reached regarding the adverse effect that larger carrier particle diameters impart to aerosol performance. However, previous studies have generally employed only a few carrier particle size fractions, generally possessing similar surface characteristics. Accordingly, theories developed to explain the influence of the physical characteristics of carrier particles on performance relied heavily on both extrapolation and interpolation. To fill in the gaps from the literature and simultaneously evaluate the influence of carrier particle size and morphology, a comprehensive study was undertaken using 4 lactose grades, each sieved into 13 contiguous sizes, to prepare 52 formulations incorporating a unique lactose grade-size population. The aerosol performance results indicated that large carrier particles possessing extensive surface roughness can improve drug dispersion, in contrast to what has been previously reported. It is proposed that this may be attributed to mechanical detachment forces arising from collisions between the carrier particle and inhaler during actuation. Based on these observations, a novel dry powder inhaler platform was developed, employing carrier particles much larger (> 1 mm) than previously explored in both the scientific and patent literature. Optimization of this technology required the judicious selection of a carrier material, and following an extensive screening process, low-density polystyrene was selected as a model candidate. Given its low mass, diameters in excess of 5-mm could be employed as carriers while still generating high detachment forces. To minimize drug particle aggregation, a novel drug-coating method employing piezo-assisted particle dispersion was developed to compensate for the reduced surface area of the novel carrier particles. In addition, the selection of a suitable inhalation device prototype was instrumental to the overall performance of the technology. In vitro testing of the novel large carrier particles yielded emitted fractions in excess of 85%, and overall drug delivery of up to 69% of the nominal dose.
text

Owing to growing markets for Greek yoghurts and soft cheeses, dairy industry generates huge quantity of acid whey creating a significant environmental problem globally. This by-product cannot be simply disposed of due to its toxicity during decomposition, robbing oxygen from rivers and streams creating health and environmental concerns. Currently, there is no solution to acid whey waste, but it seems the behaviour of lactose in presence of LA and Ca in acid whey restricts its further processability due to the failure of lactose to crystallize which thus remains in its amorphous form during concentration and further processing, including spray drying. Hence, the present study aims at fundamentally understand the concentration and crystallisation behaviour of lactose and its interactions with other constituents of acid whey especially LA and Ca. A model based study was thus implemented with varying concentrations of Ca (0.12, 0.072 or 0.035% w/w) and LA (0.05, 0.2, 0.4 or 1% w/w) in establishing behaviour of lactose during concentration up to 50% (w/w). Different concentrations of LA and Ca were selected to imitate the concentrations originally present in acid whey, nanofiltered retentates and sweet whey. Furthermore, the crystallization nature of freeze dried lactose in presence of LA and/or Ca were investigated. Differential scanning colorimetry (DSC) was used to determine the phase transitions while, fourier transform infrared spectroscopy (FTIR) was used to determine the structural changes and screens the molecular vibrations shown by various compounds.

Tese de mestrado, Engenharia Farmacêutica, Universidade de Lisboa, Faculdade de Farmácia, 2018
Pulmonary drug administration has been the subject of investigation due to its advantages such as the avoidance of the first pass effect, rapid onset of action and small drug doses. Carrier-based dry powder inhalers (DPI) are, as the name indicates, dry powder formulations of inhaled medications. In these, the micronized active pharmaceutical ingredient (API) is blended with coarser excipient particles, the carrier, to provide better bulk properties, flowability and achieve reproducible dosing. However, the production of DPI products is quite complex and to obtain stable formulations, particle properties of the API, excipients and their respective mixtures are important factors to consider. The aim of this work was to understand how the mechanical properties of distinct powder particles intended for inhalation, influence the powder bulk properties and, consequently, their influence in the in vitro aerodynamic performance of DPIs. For this, jet-milled Salbutamol Sulphate (SS) was selected as a model API and four different grades of lactose (Duralac H, Flowlac 90, Respitose SV003 and Lactohale 100) were chosen as potential carriers. Adhesive blends of API (2%) and excipients were produced. Particle size distribution (PSD), hardness, porosity and flowability of the powders and blends were studied. It was found that the API increased the values of tensile strength of pure lactoses due to a decrease in porosity. Also, it was demonstrated that cohesivity and compressibility of the powder bed of the raw materials and blends increased with the presence of a higher percentage of fine particles. However, the latter turned the powders less permeable to air. Finally, the aerodynamic performance of the adhesive blends was tested using a Next Generation Impactor (NGI), at two different flow-rates: 60 and 100 L/min. It turned out that a higher flow-rate resulted in a higher fine particle fraction (FPF) values for all the blends. The best performance was achieved with SS+Duralac H, being unresponsive to different flowrates and having the highest and constant values of FPF.

碩士
中原大學
醫學工程學系
83
Polyesters based on lactic acid have been reported safty and biodegradation in the human beings for two decades. The greatest advantage of the material is its degradatio only conducted by the hydrolysis, where the ester backbones are supposed to be unchained in the aqueous condition. The final degradable product are carbon dioxide and water that can be metabolized and digest- ed in the physiological environment. The goal of this study was aim to develope a composite combined with poly-DL-lactide(PDLLA) and tricalcium phosphate(TCP) ceramic particles as orthopaedic application. The TCP particles in a range of 0-60wt%(with 5wt% increment) were doped into the PDLLA matrix for the reinforcement, which were prepared by the melting and hot pressing technique. The basic mechanical strength, biodegradable behavior, and bio- logical response of the composites will be investigated in the study. Various techniques, such as pH meter, UV, FTIR, XRD etc., were used to examine and record the degradable process of the composites soaked in the Ringer''s solution for 1-12 weeks. The cell culture, rats subcutaneous implant and rabbit femur con- dyle fracture fixation test were used to evaluatethe cytotocity , tissue compatability, and effects of bone fracture fixation of the composites, respectively, The histological observation and x-ray photography were applied for investigating assistance. The mechanical strength of the composites initially with TCP additions upto 50wt%, thgereafter, showed no significant differ- ence(p>0.05). The composite with 50wt% TCP addition showed high mechanical strength and had a great agreement with cortical bone in elastic modulus of 37MPa. The weight loss of the pure PDLLA soaked in the Ringer''s solution was started at 4 weeks and reac- hed to 80wt% after 12 weeks. The composites compared with pure PDLLA, however, showed no apparent evidence for degradation after soaked for 12 weeks.

Microorganisms have been known to play a major role in human health since early times. The ingestion of microorganisms as probiotics to restore and/or maintain health is a widely accepted and common practice. The challenge in industry is to ensure viability of probiotics until their ingestion to their site of action, the colon, for health benefits to be realised. Microencapsulation is one of the techniques used to protect probiotic bacteria and ensure viability. A method that does not involve the use of extreme temperatures and/or solvents which would otherwise adversely affect viable cells was developed and patented. The method is solventless and is based on complexation of Food and Drug Administration-approved polymers, poly (vinylpyrrolidone) and poly (vinylacetate-co-crotonic acid) in supercritical carbon dioxide. The use of this method of encapsulation was found to be suitable in target release in earlier studies. Microparticles produced were found to have pH-dependent swellability, protecting bioactives, in this case probiotic bifidobacteria, in acid (simulated gastric acid) and only releasing them in an alkaline environment (simulated intestinal fluid). Further studies were, however, needed to investigate the suitability of the microparticles for food and pharmaceutical applications. The current study therefore aimed to characterize these microparticles in terms of size range, distribution of bacteria within the microparticles, and particle size distribution. The average size of the Bifidobacterium lactis Bb12-encapsulating microparticles was found to be within the acceptable size in food applications. High encapsulation efficiency was obtained, with live bacteria distributed evenly within the microparticles, demonstrating the potential of the microparticles to deliver high numbers of probiotic cultures as required for this type of microorganisms to deliver purpoted benefits to the consumer. Probiotic products are normally kept under refrigerated storage, yet the viability of bacterial cells still decreases. An additional benefit of encapsulation within microparticles would be protection of the encapsulated probiotics from the detrimental factors to which the probiotic products are exposed during storage. In order to investigate this for the microparticles in this study, the shelf life of encapsulated B. lactis Bb 12 powder stored in glass vials was investigated. High temperatures were used for accelerated shelf life studies. Encapsulated B. lactis Bb 12 maintained the viable levels above the therapeutic minimum for the duration of the study (12 weeks), which was 7 weeks more than was the case with unencapsulated probiotic. Thus the microparticles provided protection to the probiotic cultures at temperatures much higher than those normally used for storage of probiotic products. These results further indicate the possibility for storage of the B. lactis Bb12 encapsulated in the tested microparticles, at ambient temperatures for at least two months, without drastic loss of culture viability. Research has recently focused on the development of probiotic foods other than dairy and dairy-based foods. This has been necessitated by increasing vegetarian lifestyle and concerns of allergenicity. A maize-based traditional fermented beverage, mageu, was investigated for use as a vehicle for probiotic delivery. Although no significant difference was noted between survival of encapsulated and unencapsulated probiotic was noted, pH decrease in mageu with encapsulated B. lactis Bb 12 was less than with unencapsulated cells. This suggested that encapsulation would ensure that metabolites produced by encapsulated probiotics, if any, would not negatively affect a product in which they are incorporated. Further studies may be needed for investigation of the effect of the encapsulating microparticles in traditional fermented non-dairy products, using more acid-sensitive probiotic strains as the test strain used in the current study is well-known for its inherent resistance to acidity. This study filled gaps in knowledge in terms of the characteristics of microparticles produced using supercritical technology. The main highlights of the research findings were that the microparticles were suitable for food applications, improved probiotic viability under nonrefrigerated temperatures, and delayed browning of the probiotic powder and minimized drop in pH of the fermented product containing the probiotic encapsulated within. The results showed that microparticles encapsulating B. lactis Bb 12 are appropriate to consumers in areas where refrigeration is absent. Furthermore, the study showed that mageu is a suitable alternative vehicle to dairy-based products, for delivery of probiotic B. lactis Bb 12. This possibility extends accessibility of probiotic products to consumers who do not take dairy products for various reasons. There is also a potential increase of probiotic products on the market. Copyright
Dissertation (MSc)--University of Pretoria, 2012.
Microbiology and Plant Pathology
unrestricted

碩士
國立嘉義大學
動物科學系碩士班
93
The objective of this study was to investigate quality characteristics of Ba-Tseng fresh pork sausage as affected by acid-induced gelled egg white powders and sodium lactate. Firstly, it was to investigate the gel characteristics and dynamic rheological behaviors of lactic acid-induced gelled egg white gel and it’s powder as affected by different concentrations of soaked lactic acid solution (6%, 7%, 8%, 9% and 10%). The results were shown that the pH value of 6% lactic acid-induced gelled egg white gel was lower than 10% lactic acid-induced gelled egg white gel. The viscosity value of 10% lactic acid-induced gelled egg white gel was higher than 6%, 7% and 8% lactic acid-induced gelled egg white gel, moreover, the 6% lactic acid-induced gelled egg white gel had the lowest values. The conalbuim (84kDa), ovalbumin (45kDa) and lysozyme (14.2kDa) molecular protein of fresh egg white were not significantly difference compared with 6%, 7%, 8%, 9% and 10% lactic acid-induced gelled egg white gel, but the lysozyme protein content of egg white gel by different concentrations of soaked lactic acid had higher than fresh egg white by SDS-PAGE measurement. The storage modulus (G’) and loss modulus (G”) of egg white gel were decreased and the onset temperatures were affected by lactic acid treatments. The pH values of 8%, 9% and 10% lactic acid-induced egg white powder were lower than 6% lactic acid-induced gelled egg white powder. The moisture content of 6%, 7%, 8% and 9% lactic acid-induced gelled egg white powder were lower than 10%. The emulsifying capacity and crude protein of 6% lactic acid-induced gelled egg white powder was higher than other groups. The total plate counts of all samples were lower than 1 log CFU/g. By the characteristics of SDS-PAGE, the 84kDa, 45kDa and 14.2kDa molecular protein were shown on 6%, 7%, 8%, 9% and 10% lactic acid-induced gelled egg white powders. The proteins density of lactic acid-induced gelled egg white powder on SDS-PAGE bands had not significantly difference (p>0.05) by protein density analyzer but the density of 7% and 10% lactic acid-induced egg white powder were lower than the others. The lysozyme content of all samples was between 8.22% and 9.42%, and the sample of 10% lactic acid-induced egg white powder was the lowest. Secondly, it was to study the effects of different concentrations of soaked lactic acid (6%, 8% and 10%), additions of acid-induced egg white powder (1%, 1.5% and 2%) and sodium lactate (0%, 1% and 2%) on antioxidant ability, physicochemical and sensory properties of Ba-Tseng fresh pork sausage by response surface methodology (RSM) with a three-variable and three-level design on 0th, 7th and 14th days storage at 4℃. The results showed that the 2-thiobarbituric acid value of all samples increased with the increased storage time, and the samples of 1.0~1.1% acid-induced egg white powder additions had lower values. The pH values of all samples were maintained between 5.0~5.6 during storage periods. The optimal combined conditions for the inhibited growth of TPC and Coliform of Ba-Tseng fresh pork sausage were 6~10% concentrations of soaked lactic acid solution, 1~2% additions of acid-induced egg white powder and 0~2% sodium lactated. The color stability and water holding capacity of Ba-Tseng fresh pork sausage were increased with the lower concentrations of soaked lactic acid solution and addition of acid-induced egg white powder. The metmyoglobin content was clearly affected by storage time and the additions of acid-induced egg white powder, moreover, the 6~7% concentrations of soaked lactic acid and additions of 1.0~1.7% acid-induced egg white powder had lower values. In addition, the 6~8.5% concentrations of soaked lactic acid and addition of 1.0~2.0% acid-induced egg white powder had lower values of shear value. And the lower concentrations of soaked lactic acid and addition of acid-induced egg white powder, the sample had better overall acceptance of sensory properties.