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  • 1.
    Andersson, I. M.
    et al.
    Lund University, Sweden.
    Bergenståhl, B.
    Lund University, Sweden.
    Millqvist-Fureby, Anna
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Alexander, M.
    Arla Foods Ingredients Group P/S, Denmark.
    Paulsson, M.
    Lund University, Sweden.
    Glantz, M.
    Lund University, Sweden.
    Particle morphology and rehydration properties of spray-dried microgels and fractal aggregates with varying fractions of native milk serum proteins2021In: International Dairy Journal, ISSN 0958-6946, E-ISSN 1879-0143, Vol. 112, article id 104862Article in journal (Refereed)
    Abstract [en]

    To keep their functional properties, it is crucial that protein aggregates maintain their structure after spray drying and that the powders can be fully rehydrated. In this study, microgels and fractal aggregates were prepared by heating a mixture of milk serum protein concentrate and lactose (40/60; %, w/w) at 85 °C for 15 min by varying the pH. Various fractions of native proteins were added to the systems prior to spray drying. This study showed that microgels and fractal aggregates kept their structure after spray drying and reconstitution. The particle morphology could be correlated to the stiffness of the interface of the feed droplet. The forced imbibition rate showed a negative correlation with increasing amount of aggregated proteins in the powders that seems to be a result of denatured/aggregated proteins present at the surface. These findings are of importance for the formulation of spray-dried powders with improved rehydration characteristics. © 2020 The Author(s)

  • 2.
    Andersson, I. M.
    et al.
    Lund University, Sweden.
    Glantz, M.
    Lund University, Sweden.
    Alexander, M.
    Arla Foods Ingredients Group P/S, Denmark.
    Millqvist-Fureby, Anna
    RISE - Research Institutes of Sweden, Bioscience and Materials, Surface, Process and Formulation.
    Paulsson, M.
    Lund University, Sweden.
    Bergenståhl, B.
    Lund University, Sweden.
    Impact of surface properties on morphology of spray-dried milk serum protein/lactose systems2018In: International Dairy Journal, ISSN 0958-6946, E-ISSN 1879-0143, Vol. 85, p. 86-95Article in journal (Refereed)
    Abstract [en]

    This study investigated milk serum protein concentrate/lactose systems with varying ratios and how the morphology of the spray-dried particles of these systems could be described by the surface properties of the feed as well as the protein surface coverage of the particles. An extrapolation of the surface pressure of the feed to 0.3 s, the approximate time for molecular diffusion in an atomised droplet in the spray-dryer, showed a relationship with the particle morphology. At low protein concentrations (<1%), the particles were almost totally smooth. At higher protein concentrations (≥1%), the particles became dented and ridged, and these tended to become deeper and thicker as the protein concentration increased. It is suggested that the surface pressure of the feed at low protein concentrations is the most prominent surface property, whereas the modulus of elasticity seems to be the most prominent surface property for particle surface deformation at higher protein concentrations.

  • 3.
    Andersson, I. M.
    et al.
    Lund University, Sweden.
    Millqvist-Fureby, Anna
    RISE - Research Institutes of Sweden, Bioscience and Materials, Surface, Process and Formulation.
    Sommertune, Jens
    RISE - Research Institutes of Sweden, Bioscience and Materials, Surface, Process and Formulation.
    Alexander, M.
    Arla Foods Ingredients Group P/S, Denmark.
    Hellström, N.
    Lund University, Sweden.
    Glantz, Maria
    Lund University, Sweden.
    Paulsson, M.
    Lund University, Sweden.
    Bergenståhl, Björn
    Lund University, Sweden.
    Impact of protein surface coverage and layer thickness on rehydration characteristics of milk serum protein/lactose powder particles2019In: Colloids and Surfaces A: Physicochemical and Engineering Aspects, ISSN 0927-7757, E-ISSN 1873-4359, Vol. 561, p. 395-404Article in journal (Refereed)
    Abstract [en]

    Spray-dried powders were produced from milk serum protein concentrate and lactose in varying ratios, and the rehydration characteristics of the powders were evaluated. The dissolution rate was estimated with a flow-cell based technique, and the external and internal distribution of the powder components were evaluated with X-ray photoelectron spectroscopy and confocal Raman microscopy, respectively. The surface of the powder particles is more or less covered by a thin protein layer. A phase segregation between protein and lactose is observed in the interior of the particle resulting in a protein rich layer in the vicinity of the surface. However, the protein layer in the vicinity of the particle surface tends to become thinner as the bulk protein concentration increases in the powders (from 10 to 60% w/w). The time for the spontaneous imbibition to occur show a linear correlation with the protein surface coverage. The dissolution rate of powders containing 0.1% w/w protein is around 60 times faster than for a powder containing 1% w/w protein but the dissolution rate of powders containing 1% and 100% w/w differ only by a factor of 2. Thus, it is suggested that the outer protein layer becomes denser at the interface as the protein content increases in the powders, thereby causing poorer rehydration characteristics of the powders (especially for low protein concentrations 0.1–1% w/w). This insight has relevance for the formulation of whey protein powders with improved rehydration characteristics. © 2018 Elsevier B.V.

  • 4.
    Badal Tejedor, Maria
    et al.
    RISE Research Institutes of Sweden. NexBioForm Competence Center Vinnova, Sweden.
    Fransson, Jonas
    Swedish Orphan Biovitrum AB, Sweden; NexBioForm Competence Center Vinnova, Sweden.
    Millqvist-Fureby, Anna
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development. NexBioForm Competence Center Vinnova, Sweden.
    Freeze-dried cake structural and physical heterogeneity in relation to freeze-drying cycle parameters2020In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 590, article id 119891Article in journal (Refereed)
    Abstract [en]

    Freeze-drying is the preferred method to manufacture proteins in their solid state thus the understanding of the relationship between cycle parameters and cake properties remains of great interest. The present study aims to investigate the influence of the freezing conditions in the material properties at different layers throughout the dried structure, in the presence and absence of a protein. Placebo and protein formulations were dried applying different cooling rates: slow, fast and fast cooling with annealing. Non-uniform visual cake appearance, different pore sizes and endothermic events for release of structural water were observed throughout the cake at different freezing rates indicating heterogeneous properties of the dried material likely due to heating gradients during freezing. However, annealing increased the crystallinity and eliminated material inhomogeneities across the cake. The crystalline phase was mainly comprised of δ and hemihydrate mannitol (MHH) distributed at different ratios and influenced by the presence of the protein. The undesired formation of MHH is associated to currently used freezing temperatures or amorphous to crystalline material ratios. Thus, the correlation between the freezing step parameters and resulting material structure is a step forward to provide a better understanding of the freeze-dried cake formation and product quality improvement. 

  • 5.
    Badal Tejedor, Maria
    et al.
    RISE - Research Institutes of Sweden (2017-2019), Bioscience and Materials, Surface, Process and Formulation. KTH Royal Institute of Technology, Sweden.
    Niklas, Nordgren
    RISE - Research Institutes of Sweden (2017-2019), Bioscience and Materials, Surface, Process and Formulation.
    Schuleit, Michael
    Novartis Pharma AG, Switzerland.
    Millqvist-Fureby, Anna
    RISE - Research Institutes of Sweden (2017-2019), Bioscience and Materials, Surface, Process and Formulation.
    Rutland, Mark W.
    RISE - Research Institutes of Sweden (2017-2019), Bioscience and Materials, Surface, Process and Formulation. KTH Royal Institute of Technology, Sweden.
    AFM Colloidal Probe Measurements Implicate Capillary Condensation in Punch-Particle Surface Interactions during Tableting2017In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 33, no 46, p. 13180-13188Article in journal (Refereed)
    Abstract [en]

    Adhesion of the powders to the punches is a common issue during tableting. This phenomenon is known as sticking and affects the quality of the manufactured tablets. Defective tablets increase the cost of the manufacturing process. Thus, the ability to predict the tableting performance of the formulation blend before the process is scaled-up is important. The adhesive propensity of the powder to the tableting tools is mostly governed by the surface-surface adhesive interactions. Atomic force microscopy (AFM) colloidal probe is a surface characterization technique that allows the measurement of the adhesive interactions between two materials of interest. In this study, AFM steel colloidal probe measurements were performed on ibuprofen, MCC (microcrystalline cellulose), α-lactose monohydrate, and spray-dried lactose particles as an approach to modeling the punch-particle surface interactions during tableting. The excipients (lactose and MCC) showed constant, small, attractive, and adhesive forces toward the steel surface after a repeated number of contacts. In comparison, ibuprofen displayed a much larger attractive and adhesive interaction increasing over time both in magnitude and in jump-in/jump-out separation distance. The type of interaction acting on the excipient-steel interface can be related to a van der Waals force, which is relatively weak and short-ranged. By contrast, the ibuprofen-steel interaction is described by a capillary force profile. Even though ibuprofen is not highly hydrophilic, the relatively smooth surfaces of the crystals allow "contact flooding" upon contact with the steel probe. Capillary forces increase because of the "harvesting" of moisture - due to the fast condensation kinetics - leaving a residual condensate that contributes to increase the interaction force after each consecutive contact. Local asperity contacts on the more hydrophilic surface of the excipients prevent the flooding of the contact zone, and there is no such adhesive effect under the same ambient conditions. The markedly different behavior detected by force measurements clearly shows the sticky and nonsticky propensity of the materials and allows a mechanistic description.

  • 6.
    Badal Tejedor, Maria
    et al.
    RISE - Research Institutes of Sweden (2017-2019), Bioscience and Materials, Chemistry and Materials. KTH Royal Institute of Technology, Sweden.
    Niklas, Nordgren
    RISE - Research Institutes of Sweden (2017-2019), Bioscience and Materials, Chemistry and Materials.
    Schuleit, Michael
    Novartis Pharma AG, Switzerland.
    Pazesh, Samaneh
    Uppsala University, Sweden.
    Alderborn, Göran
    Uppsala University, Sweden.
    Millqvist-Fureby, Anna
    RISE - Research Institutes of Sweden (2017-2019), Bioscience and Materials, Chemistry and Materials.
    Rutland, Mark W.
    RISE - Research Institutes of Sweden (2017-2019), Bioscience and Materials, Chemistry and Materials. KTH Royal Institute of Technology, Sweden.
    Determination of interfacial amorphicity in functional powders2017In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 33, no 4, p. 920-926Article in journal (Refereed)
    Abstract [en]

    The nature of the surfaces of particles of pharmaceutical ingredients, food powders, and polymers is a determining factor for their performance in for example tableting, powder handling, or mixing. Changes on the surface structure of the material will impact the flow properties, dissolution rate, and tabletability of the powder blend. For crystalline materials, surface amorphization is a phenomenon which is known to impact performance. Since it is important to measure and control the level of amorphicity, several characterization techniques are available to determine the bulk amorphous content of a processed material. The possibility of characterizing the degree of amorphicity at the surface, for example by studying the mechanical properties of the particles' surface at the nanoscale, is currently only offered by atomic force microscopy (AFM). The AFM PeakForce QNM technique has been used to measure the variation in energy dissipation (eV) at the surface of the particles which sheds light on the mechanical changes occurring as a result of amorphization or recrystallization events. Two novel approaches for the characterization of amorphicity are presented here. First, since particles are heterogeneous, we present a methodology to present the results of extensive QNM analysis of multiple particles in a coherent and easily interpreted manner, by studying cumulative distributions of dissipation data with respect to a threshold value which can be used to distinguish the crystalline and amorphous states. To exemplify the approach, which is generally applicable to any material, reference materials of purely crystalline α-lactose monohydrate and completely amorphous spray dried lactose particles were compared to a partially amorphized α-lactose monohydrate sample. Dissipation data are compared to evaluations of the lactose samples with conventional AFM and SEM showing significant topographical differences. Finally, the recrystallization of the surface amorphous regions in response to humidity was followed by studying the dissipation response of a well-defined surface region over time, which confirms both that dissipation measurement is a useful measure of surface amorphicity and that significant recrystallization occurs at the surface in response to humidity.

  • 7.
    Badal Tejedor, Maria
    et al.
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor. KTH Royal Institute of Technology, Sweden.
    Niklas, Nordgren
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor.
    Schuleit, Michael
    Novartis Pharma AG, Switzerland.
    Rutland, Mark W.
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor. KTH Royal Institute of Technology, Sweden.
    Millqvist-Fureby, Anna
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor.
    Tablet mechanics depend on nano and micro scale adhesion, lubrication and structure2015In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 486, no 1-2, p. 315-323Article in journal (Refereed)
    Abstract [en]

    Tablets are the most convenient form for drug administration. However, despite the ease of manufacturing problems such as powder adhesion occur during the production process. This study presents surface and structural characterization of tablets formulated with commonly used excipients (microcrystalline cellulose (MCC), lactose, mannitol, magnesium (Mg) stearate) pressed under different compaction conditions. Tablet surface analyses were performed with scanning electron microscopy (SEM), profilometry and atomic force microscopy (AFM). The mechanical properties of the tablets were evaluated with a tablet hardness test. Local adhesion detected by AFM decreased when Mg stearate was present in the formulation. Moreover, the tablet strength of plastically deformable excipients such as MCC was significantly decreased after addition of Mg stearate. Combined these facts indicate that Mg stearate affects the particle-particle bonding and thus elastic recovery. The MCC excipient also displayed the highest hardness which is characteristic for a highly cohesive material. This is discussed in the view of the relatively high adhesion found between MCC and a hydrophilic probe at the nanoscale using AFM. In contrast, the tablet strength of brittle materials like lactose and mannitol is unaffected by Mg stearate. Thus fracture occurs within the excipient particles and not at particle boundaries, creating new surfaces not previously exposed to Mg stearate. Such uncoated surfaces may well promote adhesive interactions with tools during manufacture.

  • 8.
    Badal Tejedor, Maria
    et al.
    RISE - Research Institutes of Sweden (2017-2019), Bioscience and Materials, Surface, Process and Formulation. KTH Royal Institute of Technology, Sweden.
    Pazesh, Samaneh
    Uppsala University, Sweden.
    Niklas, Nordgren
    RISE - Research Institutes of Sweden (2017-2019), Bioscience and Materials, Surface, Process and Formulation.
    Schuleit, Micheal
    Novartis Pharma AG, Switzerland.
    Rutland, Mark W.
    RISE - Research Institutes of Sweden (2017-2019), Bioscience and Materials, Surface, Process and Formulation. KTH Royal Institute of Technology, Sweden.
    Alderborn, Göran
    Uppsala University, Sweden.
    Millqvist-Fureby, Anna
    RISE - Research Institutes of Sweden (2017-2019), Bioscience and Materials, Surface, Process and Formulation.
    Milling induced amorphisation and recrystallization of α-lactose monohydrate2018In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 537, no 1-2, p. 140-147Article in journal (Refereed)
    Abstract [en]

    Preprocessing of pharmaceutical powders is a common procedure to condition the materials for a better manufacturing performance. However, such operations may induce undesired material properties modifications when conditioning particle size through milling, for example. Modification of both surface and bulk material structure will change the material properties, thus affecting the processability of the powder. Hence it is essential to control the material transformations that occur during milling. Topographical and mechanical changes in surface properties can be a preliminary indication of further material transformations. Therefore a surface evaluation of the α-lactose monohydrate after short and prolonged milling times has been performed. Unprocessed α-lactose monohydrate and spray dried lactose were evaluated in parallel to the milled samples as reference examples of the crystalline and amorphous lactose structure. Morphological differences between unprocessed α-lactose, 1 h and 20 h milled lactose and spray dried lactose were detected from SEM and AFM images. Additionally, AFM was used to simultaneously characterize particle surface amorphicity by measuring energy dissipation. Extensive surface amorphicity was detected after 1 h of milling while prolonged milling times showed only a moderate particle surface amorphisation. Bulk material characterization performed with DSC indicated a partial amorphicity for the 1 h milled lactose and a fully amorphous thermal profile for the 20 h milled lactose. The temperature profiles however, were shifted somewhat in the comparison to the amorphous reference, particularly after extended milling, suggesting a different amorphous state compared to the spray-dried material. Water loss during milling was measured with TGA, showing lower water content for the lactose amorphized through milling compared to spray dried amorphous lactose. The combined results suggest a surface-bulk propagation of the amorphicity during milling in combination with a different amorphous structural conformation to that of the amorphous spray dried lactose. The hardened surface may be due to either surface crystallization of lactose or to formation of a low-water glass transition.

  • 9.
    Bogdanova, E.
    et al.
    Malmö University, Sweden.
    Lages, S.
    Malmö University, Sweden; Lund University, Sweden.
    Phan-Xuan, T.
    Malmö University, Sweden; Lund University, Sweden: NovoNordiskA/S, Denmark.
    Kamal, M. A.
    Malmö University, Sweden; Lund University, Sweden.
    Terry, A.
    Lund University, Sweden.
    Millqvist-Fureby, Anna
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Kocherbitov, V.
    Malmö University, Sweden.
    Lysozyme-Sucrose Interactions in the Solid State: Glass Transition, Denaturation, and the Effect of Residual Water2023In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 20, no 9, p. 4664-Article in journal (Refereed)
    Abstract [en]

    The freeze-drying of proteins, along with excipients, offers a solution for increasing the shelf-life of protein pharmaceuticals. Using differential scanning calorimetry, thermogravimetric analysis, sorption calorimetry, and synchrotron small-angle X-ray scattering (SAXS), we have characterized the properties at low (re)hydration levels of the protein lysozyme, which was freeze-dried together with the excipient sucrose. We observe that the residual moisture content in these samples increases with the addition of lysozyme. This results from an increase in equilibrium water content with lysozyme concentration at constant water activity. Furthermore, we also observed an increase in the glass transition temperature (Tg) of the mixtures with increasing lysozyme concentration. Analysis of the heat capacity step of the mixtures indicates that lysozyme does not participate in the glass transition of the sucrose matrix; as a result, the observed increase in the Tg of the mixtures is the consequence of the confinement of the amorphous sucrose domains in the interstitial space between the lysozyme molecules. Sorption calorimetry experiments demonstrate that the hydration behavior of this formulation is similar to that of the pure amorphous sucrose, while the presence of lysozyme only shifts the sucrose transitions. SAXS analysis of amorphous lysozyme-sucrose mixtures and unfolding of lysozyme in this environment show that prior to unfolding, the size and shape of lysozyme in a solid sucrose matrix are consistent with its native state in an aqueous solution. The results obtained from our study will provide a better understanding of the low hydration behavior of protein-excipient mixtures and support the improved formulation of biologics. © 2023 The Authors. 

  • 10.
    Bogdanova, Ekaterina
    et al.
    Biofilms research center for Biointerfaces, Sweden; Malmö University, Sweden.
    Millqvist-Fureby, Anna
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Kocherbitov, Vitaly
    Biofilms research center for Biointerfaces, Sweden; Malmö University, Sweden.
    Hydration enthalpies of amorphous sucrose, trehalose and maltodextrins and their relationship with heat capacities.2021In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 23, no 26, p. 14433-14448Article in journal (Refereed)
    Abstract [en]

    The mechanisms of glass transitions and the behavior of small solute molecules in a glassy matrix are some of the most important topics of modern thermodynamics. Water plays an important role in the physical and chemical stability of lyophilized biologics formulations, in which glassy carbohydrates act as cryoprotectants and stabilizers. In this study, sorption calorimetry was used for simultaneous measurements of water activity and the enthalpy of water sorption by amorphous sucrose, trehalose and maltodextrins. Moreover, the heat capacity of these carbohydrates in mixtures with water was measured by DSC in a broad range of water contents. The hydration enthalpies of glassy sucrose, trehalose and maltodextrins are exothermic, and the enthalpy change of water-induced isothermal glass transitions is higher for small molecules. The partial molar enthalpy of mixing of water in slow experiments is about -18 kJ mol-1, but less exothermic in the case of small molecules at fast hydration scan rates. By measuring the heat capacities of disaccharides and maltodextrins as a function of water content, we separated the contributions of carbohydrates and water to the total heat capacities of the mixtures. The combination of these data allowed testing of thermodynamic models describing the hydration-induced glass transitions. The heat capacity changes calculated by the fitting of the hydration enthalpy data for disaccharides are in good agreement with the heat capacity data obtained by DSC, while for maltodextrins, the effect of sub-Tg transitions should be taken into account. Combining the data obtained by different techniques, we found a distinct difference in the behavior of water in glassy polymers compared to that in glassy disaccharides. By understanding the behavior of water in glassy carbohydrates, these results can be used to improve the design of freeze-dried formulations of proteins and probiotics.

  • 11.
    Bogdanova, Ekaterina
    et al.
    Malmö University, Sweden; Biofilms research center for Biointerfaces, Sweden; NextBioForm Competence Centre, Sweden.
    Millqvist-Fureby, Anna
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Kocherbitov, Vitaly
    Malmö University, Sweden; Biofilms research center for Biointerfaces, Sweden; NextBioForm Competence Centre, Sweden.
    Influence of Cooling Rate on Ice Crystallization and Melting in Sucrose-Water System2022In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 111, no 7, p. 2030-2037Article in journal (Refereed)
    Abstract [en]

    The ice crystallization and melting in systems where the equilibrium state is difficult to reach is one of the growing areas in pharmaceutical freeze-drying research. The quality of the final freeze-dried product depends on the parameters of the cooling step, which affect the ice nucleation and growth. In this paper, we present a DSC study of ice crystallization and melting in a sucrose-water system. Using two different types of thermal cycles, we examine the influence of cooling and heating rates on the thermal behavior of sucrose-water solutions with water contents between 50 and 100 wt%. The DSC results show that low cooling rates provide crystallization at higher temperatures and lead to lower amount of non-freezing water. Consequently, the glass transition and ice melting properties observed upon heating depend on the cooling conditions in the preceding step. Based on the experimental results, we investigate the reasons for the existence of the two steps on DSC heating curves in sucrose-water systems: the glass transition step and the onset of ice melting. We show that diffusion of water can be the limiting factor for ice growth and melting in the sucrose-water system when the amorphous phase is in a liquid state. In particular, when the diffusion coefficient drops below 10−14 m2/sec, the ice crystals growth or melting becomes strongly suppressed even above the glass transition temperature. Understanding the diffusion limitations in the sucrose-water system can be used for the optimization of the freeze-drying protocols for proteins and probiotics. © 2022 The Authors

  • 12.
    Boge, Lukas
    et al.
    RISE - Research Institutes of Sweden (2017-2019), Bioscience and Materials, Surface, Process and Formulation. Chalmers University of Technology, Sweden.
    Västberg, Amanda
    RISE - Research Institutes of Sweden (2017-2019), Bioscience and Materials, Surface, Process and Formulation.
    Umerska, Anita
    Université Bretagne Loire, France.
    Bysell, Helena
    RISE - Research Institutes of Sweden (2017-2019), Bioscience and Materials, Surface, Process and Formulation.
    Eriksson, Jonny
    Uppsala University, Sweden.
    Edwards, Katarina
    Uppsala University, Sweden.
    Millqvist-Fureby, Anna
    RISE - Research Institutes of Sweden (2017-2019), Bioscience and Materials, Surface, Process and Formulation.
    Andersson, Martin
    Chalmers University of Technology, Sweden.
    Freeze-dried and re-hydrated liquid crystalline nanoparticles stabilized with disaccharides for drug-delivery of the plectasin derivative AP114 antimicrobial peptide2018In: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 522, p. 126-135Article in journal (Refereed)
    Abstract [en]

    Liquid crystalline nanoparticles (LCNPs), e.g. cubosomes and hexosomes, are receiving more and more attraction as drug delivery vehicles. Dry powder formulation that forms LCNPs upon hydration can be advantageous to make new routes of administration accessible. In this work, we investigate use of three disaccharides (lactose, trehalose and sucrose) as protective matrices for glycerol monooleate based LCNP forming powders produced by freeze-drying. Phase behavior, particle size and size distributions at the different preparation steps were monitored by small angle x-ray scattering (SAXS) and dynamic light scattering (DLS). Particle appearance was imaged by cryogenic transmission electron microscopy (cryo-TEM). Moreover, the therapeutic relevant antimicrobial peptide AP114 (plectasin derivative) was incorporated in the formulations. Peptide encapsulation and release as well as in vitro antibacterial effect were investigated. Results showed that all freeze-dried powders did form particles with liquid crystalline structure upon hydration. However, a phase transition from the bicontinuous cubic Pn3m to the reversed hexagonal was observed, as a consequence of sugar addition and the freeze-drying procedure. Data indicates that trehalose is the preferred choice of lyo-protectant in order to maintain a mono-modal particle size distribution. In addition, antimicrobial activity of AP114-containing formulations was found to be highest for the formulation containing trehalose. The release kinetics of AP114 from the nanoparticles was strongly affected by the dimensions of the hexagonal phase. Larger dimension of the hexagonal phase, significantly improved the release of AP114 and antimicrobial activity of the formulation.

  • 13.
    Both, E M
    et al.
    Wageningen University and Research, The Netherlands.
    Nuzzo, Marine
    RISE - Research Institutes of Sweden, Bioscience and Materials, Surface, Process and Formulation.
    Millqvist-Fureby, Anna
    RISE - Research Institutes of Sweden, Bioscience and Materials, Surface, Process and Formulation.
    Boom, R M
    Wageningen University and Research, The Netherlands.
    Schutyser, M A I
    Wageningen University and Research, The Netherlands.
    Morphology development during single droplet drying of mixed component formulations and milk2018In: Food Research International, ISSN 0963-9969, E-ISSN 1873-7145, Vol. 109, p. 448-454, article id S0963-9969(18)30328-4Article in journal (Refereed)
    Abstract [en]

    We report on the influence of selected components and their mixtures on the development of the morphology during drying of single droplets and extend the results to the morphology of whole milk powder particles. Sessile single droplet drying and acoustic levitation methods were employed to study single droplet drying. The influence of carbohydrates (lactose and maltodextrin DE12) and proteins (micellar casein or whey protein) on morphology development is very different, since upon concentration protein systems will jam and undergo a colloidal glass transition, whereas carbohydrate systems will gradually increase in viscosity as a consequence of the concentration. Whey protein gives relatively rigid shells due to jamming of the "hard sphere" proteins, while casein micelles behave as "soft spheres" that can deform after jamming, which gives flexibility to the shell during drying. The influence of the carbohydrates on the final morphology was found much larger than the influence of the proteins. Caseins influenced morphology only in mixtures with lactose at higher concentrations due to its high voluminosity. Similar observations were done for whole milk, where fat appeared to have no influence. With maltodextrin the influence of the casein was again observed in the shape and smoothness of wrinkles. Both sessile and levitated droplet drying methods provide a similar and consistent view on morphology development.

  • 14. Dahlberg, C
    et al.
    Millqvist-Fureby, Anna
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    Schuleit, M
    Surface composition and contact angle relationships for differently prepared solid dispersions2008In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 70, no 2, p. 478-485Article in journal (Refereed)
    Abstract [en]

    Solid dispersions are promising drug delivery forms which offer the possibility to disperse a hydrophobic drug in a hydrophilic matrix and thereby improve the dissolution behavior and the bioavailability of the drug. One important aspect and a prerequisite in understanding the drug dissolution mechanism from solid dispersions is a better analytical monitoring of the solid dispersion surface properties, such as powder surface composition and water adsorption properties. In this paper, we have considered chemical and structural surface analysis data for solid dispersions processed by spray drying or roto-evaporation and compared these data with information obtained by contact angle measurements. Firstly, we establish the usefulness and suitability of X-ray photoelectron spectroscopy (XPS) for determination of surface chemical composition and scanning electron microscopy (SEM) for determining the structure of solid dispersions composed of different types of carriers, drugs and drug concentrations. Secondly, we measure contact angles of solid dispersions to describe wettability, to finally establish a link between the surface chemical composition, the powder structure and the wetting behavior. These experimental methods offer a rapid screening tool for the selection of carrier, drug concentration and/or process in early development. In addition, they provide a useful tool for investigating structural aspects of solid dispersions which have intrinsic relevance for drug dissolution and stability.

  • 15. Dahlberg, C
    et al.
    Millqvist-Fureby, Anna
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    Schuleit, M
    Dvinskikh, SV
    Furó, I
    Polymer mobilization and drug release during tablet swelling. A 1H NMR and NMR microimaging study2007In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 122, p. 199-205Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to investigate the swelling characteristics of a hydroxypropyl methylcellulose (HPMC) matrix incorporating the hydrophilic drug antipyrine. We have used this matrix to introduce a novel analytical method, which allows us to obtain within one experimental setup information about the molecular processes of the polymer carrier and its impact on drug release. Nuclear magnetic resonance (NMR) imaging revealed in situ the swelling behavior of tablets when exposed to water. By using deuterated water, the spatial distribution and molecular dynamics of HPMC and their kinetics during swelling could be observed selectively. In parallel, NMR spectroscopy provided the concentration of the drug released into the aqueous phase. We find that both swelling and release are diffusion controlled. The ability of monitoring those two processes using the same experimental setup enables mapping their interconnection, which points on the importance and potential of this analytical technique for further application in other drug delivery forms.

  • 16. Dahlberg, Carina
    et al.
    Millqvist-Fureby, Anna
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    Schuleit, Michael
    Furó, Istvan
    Polymer-drug interactions and wetting of solid dispersions2010In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 39, no 1-3, p. 125-133Article in journal (Refereed)
    Abstract [en]

    We demonstrate the ability of drugs to influence the wetting of solid dispersion tablets in unexpected ways. Five model drugs of different water solubility and ability to interact with the involved polymers were incorporated in hydrophilic polymer matrices, made of either hydroxypropyl methylcellulose (HPMC) or polyvinyl pyrrolidone (PVP). The physical mixtures of all combinations of drug and polymer presented Surface hydrophobicities, as measured by the equilibrium advancing contact angle of water, which are expected for materials that do not influence the interactions of each other with water. However, the solid dispersions containing HPMC deviated from this regular behaviour and displayed contact angles below those of the pure compounds involved. either drug or polymer. This behaviour is explained by changed surface exposure of HPMC side groups, as a result of changes in intermolecular hydrogen bonds. In addition to water contact angle measurements, we employed NMR imaging to monitor the time course of water ingress and swelling.

  • 17. Dahlberg, Carina
    et al.
    Millqvist-Fureby, Anna
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    Schuleit, Michael
    Furó, Istvan
    Relationships between solid dispersion preparation process, particle size and drug release - An NMR and NMR microimaging study2010In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 76, no 2, p. 311-319Article in journal (Refereed)
    Abstract [en]

    Solid dispersion tablets prepared by either spray drying or rotoevaporation and exhibiting different grain and pore sizes were investigated under the process of hydration-swelling-gelation. H-2 and H-1 NMR microimaging experiments were used to selectively follow water penetration and polymer mobilization kinetics, respectively, while the drug release kinetics was followed by H-1 NMR spectroscopy. The obtained data, in combination with morphological information by scanning electron microscopy (SEM), reveal a complex process that ultimately leads to release of the drug into the aqueous phase. We find that the rate of water ingress has no direct influence on release kinetics, which also renders air in the tablets a secondary factor. On the other hand, drug release is directly correlated with the polymer mobilization kinetics. Water diffusion into the originally dry polymer grains determines the rate of grain swelling and the hydration within the grains varies strongly with grain size. We propose that this sets the stage for creating homogeneous gels for small grain sizes and heterogeneous gels for large grain sizes. Fast diffusion through water-rich sections of the inhomogeneous gels that exhibit a large mesh size is the factor which yields a faster drug release from tablets prepared by rotoevaporation.

  • 18.
    Dahlenborg, Hanna
    et al.
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Medicinteknik. Lund University, Sweden.
    Millqvist-Fureby, Anna
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor.
    Bergenståhl, Björn
    Lund University, Sweden.
    Effect of particle size in chocolate shell on oil migration and fat bloom development2015In: Journal of Food Engineering, ISSN 0260-8774, E-ISSN 1873-5770, Vol. 146, p. 172-181Article in journal (Refereed)
    Abstract [en]

    The effects of chocolate shell particle size were investigated by means of its influence on rate of oil migration and fat bloom development. The particle size of the non-fat particles in the chocolate, i.e. sugar and cocoa particles was varied between 15, 22 and 40 μm. A novel set of analytical techniques was used and by combining migration results with surface topology results clear differences could be observed between the samples. At 23 °C storage the samples with a particle size of 15 μm showed higher rate of oil migration and further, the earliest development of fat bloom at the surface. This could be observed both macroscopically and microscopically. Thus, it appears as a larger specific surface area of the non-fat particles facilitates migration of filling oil, possibly due to a more heterogeneous and coarser crystal network with higher permeability. Molecular diffusion cannot explain the level of oil migration observed and, thus, convective flow is assumed to be an important contribution in addition to the molecular diffusion.

  • 19.
    Dahlenborg, Hanna
    et al.
    RISE, SP – Sveriges Tekniska Forskningsinstitut. Lund University, Sweden.
    Millqvist-Fureby, Anna
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor.
    Bergenståhl, Björn
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor. Lund University, Sweden.
    Effect of shell microstructure on oil migration and fat bloom development in model pralines2015In: Food Structure, ISSN 2213-3291, Vol. 5, p. 51-65Article in journal (Refereed)
    Abstract [en]

    This study investigated the influence of shell microstructure on oil migration and fat bloom development in chocolate model systems. The microstructure of the model shells was varied by means of tempering or seeding cocoa butter and the addition of non-fat particles. Further, the impact of different storage conditions was studied. By using a set of novel analytical techniques the migration rate could be connected to the development of fat bloom at the surface. The non-seeded cocoa butter samples showed significantly higher rate of migration together with the highest rate of developed fat bloom, whereas the over-seeded cocoa butter samples showed low migration rate and low rate of fat bloom development. Addition of particles (sugar, cocoa powder and defatted cocoa powder) proved to have a significant impact on the microstructure, since these samples showed a substantially higher rate of migration and fat bloom development compared to seeded cocoa butter samples. Molecular diffusion could not explain the migration behaviour, thus, convective flow is suggested as an important contribution in addition to the molecular diffusion.

  • 20. Dahlenborg, Hanna
    et al.
    Millqvist-Fureby, Anna
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    Bergenståhl, Björn
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    Kalnin, Daniel JE
    Investigation of chocolate surfaces using profilometry and low vacuum scanning electron microscopy2011In: Journal of the American Oil Chemists Society, ISSN 0003-021X, E-ISSN 1558-9331, Vol. 88, no 6, p. 773-783Article in journal (Refereed)
    Abstract [en]

    In this study we establish the use of optical non-contact profilometry combined with low vacuum scanning electron microscopy (LV SEM) for the investigation of lipid surfaces. We illustrate, by using profilometry, a methodology for investigation of chocolate surface topology as a function of time, in the same area of interest. Both qualitative and quantitative data analysis has been performed for profilometry data. Further, relating these results to LV SEM images provides complementary topological information and hence a useful toolkit for the study of the chocolate surface prior and post fat bloom formation. For the demonstration of the successful combination of these two analytical techniques, white chocolate pralines were stored at two temperature-controlled conditions (at 18 °C, and cycled between 15 and 25 °C). Surface properties were then investigated during 36 weeks of storage. The surface images and the roughness parameters indicated distinct development of surface characteristics for the two storage conditions. From the results it is suggested that some imperfections, in the form of pores or protrusions, could play a role in fat bloom development and that there may be different main mechanisms of fat migration taking place for the different storage environments. In the present work, a positive correlation of profilometry data to chocolate surface characteristics and early bloom development has been established. There are indications that early prediction of fat bloom can be possible, however further work needs to be done to quantify prediction of fat bloom.

  • 21.
    Dahlenborg, Hanna
    et al.
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet. Lund University, Sweden.
    Millqvist-Fureby, Anna
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    Brandner, Birgit D.
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    Bergenståhl, Björn A.
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet. Lund University, Sweden.
    Study of the porous structure of white chocolate by confocal Raman microscopy2012In: European Journal of Lipid Science and Technology, ISSN 1438-7697, E-ISSN 1438-9312, Vol. 114, no 8, p. 919-926Article in journal (Refereed)
    Abstract [en]

    Confocal Raman microscopy has been shown to be a useful technique for investigation of white chocolate surfaces. The appearance of protrusions and pores, and the distribution of fat, sucrose, and milk powder at and below the surface of white chocolate pralines were investigated using confocal Raman microscopy. Raman horizontal and depth scans showed that the protrusions and pores continue at least 10μm into the chocolate shell and that some protrusions and channels mainly consist of fat, while some consisted of a fat layer, leaving a hollow space underneath. Further, the pores and their continuing channels consisted of nothing but air. These findings indicate that the protrusions might be connected to channels where we suggest a pressure driven convective flow of liquid fat from within the chocolate matrix that, depending on temperature, moves up to the surface or goes back into the matrix, leaving an empty pore with a shell of fat at the surface, which in some cases collapse and leaves a hollow pore and channel. Therefore, these findings support that the protrusions could be connected to oil migration in chocolate and, thus, further to fat bloom development.

  • 22.
    Elofsson, Ulla
    et al.
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    Millqvist-Fureby, Anna
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    Stability of spray-dried protein-stabilized emulsions: Effects of different carbohydrate additives2003In: Food Colloids, Biopolymers and Materials / [ed] Eric Dickinson, Ton van Vliet, Royal Society of Chemistry, 2003, p. 265-274Chapter in book (Refereed)
  • 23.
    Elofsson, Ulla
    et al.
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor.
    Millqvist-Fureby, Anna
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor.
    Gerde, Per
    Inhalation Sciences Sweden AB, Sweden.
    Pulmonary delivery of antimicrobial peptides2015In: ONdrugDelivery, ISSN 2049-145X, Vol. 57, p. 4-7Article in journal (Refereed)
    Abstract [en]

    Anna Fureby, PhD, Group Manager & Senior Scientist, Life Science, and Ulla Elofsson, PhD, Senior Scientist, both of SP Technical Research Institute of Sweden, and Per Gerde, PhD, Chief Scientific Officer, Inhalation Sciences Sweden, discuss the serious problem of antibiotic resistance and the potential role of antimicrobial peptides in the treatment of resistant bacterial strains. For pulmonary infections, optimising the formulation and delivery method is a crucial factor for success.

  • 24. Elversson, J
    et al.
    Andersson, K
    Millqvist-Fureby, Anna
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    An atomic force microscopy approach for assessment of particle density applied to single spray-dried carbohydrate particles2007In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 96, no 4, p. 905-912Article in journal (Refereed)
    Abstract [en]

    To evaluate an atomic force microscopy (AFM) approach for effective density analysis of single spray dried carbohydrate particles in order to investigate the internal structure of the particles. In addition, the AFM method was compared to an established technique, that is gas pycnometry. Resonant frequency AFM analysis was employed for determination of the mass of individual particles of spray-dried lactose, mannitol, and a mixture of sucrose/dextran (4:1). The effective particle density was calculated using the diameter of the spherical particles obtained from light microscopy. The apparent particle density was further analyzed with gas pycnometry. It was observed by microscopy that particles appeared either ‘‘solid’’ or ‘‘hollow.’’ A solid appearance applied to an effective particle density close to the true density of the material, whereas a density around 1 g/cm3 corresponded to a hollow appearance. However, carbohydrates, which crystallized during spray drying, for example, mannitol appeared solid but the average effective particle density was 0.95 g/cm3, indicating a continuous but porous structure. AFM measurements of effective particle density corroborate the suggestion of differences in particle structure caused by the varying propensity of carbohydrates to crystallize during spray drying, resulting in mainly either amorphous hollow orcrystalline porous particles.

  • 25. Elversson, J
    et al.
    Millqvist-Fureby, Anna
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    Aqueous two-phase system as a formulation concept for spray-dried protein2005In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 294, p. 73-87Article in journal (Refereed)
    Abstract [en]

    This study investigates to what extent an aqueous two-phase system (ATPS) can encapsulate and protect the secondary structure of a protein during spray drying. The ATPSs contained polyvinyl alcohol (PVA) and dextran solutions, in different proportions. A model protein, bovine serum albumin (BSA) and, in some experiments, trehalose were added to the ATPS prior to spray drying. Electron spectroscopy for chemical analysis (ESCA), differential scanning calorimetry (DSC), UV spectrophotometry, size exclusion high-performance liquid chromatography (SEC-HPLC) and Fourier transform infrared spectroscopy (FTIR) were used for analysis of solid and reconstituted samples. The anticipated function of the ATPS was to improve the stability of the protein by preventing interactions with the air–liquid interface during drying and by improving the encapsulation of the protein in the dried powder. BSA was found to preferentially partition to the dextran phase and in the absence of PVA, BSA dominated the powder surface. In samples containing PVA, the polymer mainly covered the powder surface, even though the dextran-rich phase was continuous, thus preventing protein surface interactions and providing improved encapsulation. However, PVA was found to cause partial loss of the native structure of BSA although the protein was well encapsulated during spray drying

  • 26. Elversson, J
    et al.
    Millqvist-Fureby, Anna
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    In situ coating - An approach for particle modification and encapsulation of proteins during spray-drying2006In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 323, p. 52-63Article in journal (Refereed)
    Abstract [en]

    In this paper, we present a method for in situ coating of individual protein particles in a respirable size. The aim of the coating was to influence the particle/powder properties, and to reduce or prevent surface-induced conformational changes of the protein, during spray-drying, which was the method used for simultaneously preparing and coating particles. The investigated formulations included bovine serum albumin (BSA), trehalose and either of the two non-ionic polymers, hydroxypropyl methylcellulose (HPMC) and poly(ethylene oxide)–poly(propylene oxide) triblock co-polymer (Poloxamer 188). Complete protein coating as measured by electron spectroscopy for chemical analysis (ESCA) was achieved at a polymer concentration of approximately 1% of the total solids weight, and could be predicted from the dynamic surface tension at the air/water interface, as measured by the pendant drop method. Further, particle properties such as: size, dissolution time, powder flowability, and apparent particle density, as measured by gas pycnometry, were affected by the type and concentration of the polymer. In addition, the particle surface morphology could possibly be correlated to the surface elasticity of the droplet surface during drying. Moreover, an extensive investigation (Fourier transform infrared spectroscopy, circular dichroism and size exclusion chromatography) of the structural effects of protein encapsulated in a polymeric coating suggested that in situ coating provide particulate formulations with preserved native conformation and with a high stability during rehydration

  • 27. Elversson, J
    et al.
    Millqvist-Fureby, Anna
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    Particle size and density in spray drying - effects of carbohydrate properties2005In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 94, p. 2049-2060Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to examine some fundamental aspects of the particle formation during spray drying, related to particle size and density. Particles were prepared in a laboratory spray dryer from carbohydrates with different solubility and crystallization propensity, such as lactose, mannitol and sucrose/dextran 4:1. The feed concentrations ranged from 1% w/w to saturated and the size of droplets and particles were measured by laser diffraction. Particles were also characterized by various microscopy techniques (i.e. scanning electron microscopy, confocal laser scanning microscopy and light microscopy), differential scanning calorimetry, gas adsorption, and gas pycnometry. As demonstrated larger particles could be obtained by either increasing the droplet size during atomization; increasing the concentration of the feed solution; or decreasing the solubility of the solute. The apparent particle density was found negatively correlated to the feed concentration. Due to the non-linear relationship between the feed concentration and the particle size, it was concluded that higher solids load may cause an increase in the effective particle density and that the reduction in the apparent particle density was a result of a gradually less permeable particle surface. Further, the crystallization propensity of the carbohydrate influenced the particle formation and resulted in either hollow or porous particles

  • 28. Elversson, J
    et al.
    Millqvist-Fureby, Anna
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    Alderborn, G
    Elofsson, Ulla
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet. RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Droplet and particle size relationship and shell thickness of inhalable lactose particles during spray drying2003In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 92, p. 900-910Article in journal (Refereed)
    Abstract [en]

    To find means of controlling the size and density of particles intended for inhalation the relationship between droplet and particle size during spray drying was investigated. Lactose solutions were atomized with a two-fluid nozzle and dried in a laboratory spray drier. The effects of nozzle orifice diameter, atomization airflow and feed concentration on droplet and particle size were examined. Mass median diameter of both droplets and particles were analyzed with laser diffraction. In addition, scanning electron microscopy and transmission electron microscopy were used for studies of particle shape and morphology. It was demonstrated that nozzle orifice diameter and airflow, but not feed concentration controlled the droplet size during atomization. Increasing droplet size increased particle size but the effect was also influenced by feed concentration. Particles from solutions of a low concentration (1% w/w) were smaller than those from higher concentrations (5-20% w/w). This may be partly explained by lower yields at higher feed concentrations, but may also be related to differences in drying rate. Spray-dried lactose solutions formed hollow particles, and it was suggested that the shell thickness of the particles increased with increasing feed concentration

  • 29.
    Gidlöf, Zandra
    et al.
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development. Lund University, Sweden.
    Lomstein Pedersen, Betty
    Ferring Pharmaceuticals A/S, SWeden.
    Nilsson, Lars
    Lund University, Sweden.
    Teleman, Anita
    RISE Research Institutes of Sweden.
    Wahlgren, Marie
    Lund University, Sweden.
    Millqvist-Fureby, Anna
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Utilising phase diagram to understand barley starch microsphere preparation in an aqueous two-phase system2023In: Colloids and Surfaces A: Physicochemical and Engineering Aspects, ISSN 0927-7757, E-ISSN 1873-4359, Vol. 658, article id 130652Article in journal (Refereed)
    Abstract [en]

    In this work, a waxy barley starch-PEG aqueous two-phase system (ATPS) phase diagram was constructed, and starch microsphere preparation was explored at different phase diagram positions. The aim was to investigate starch-PEG ATPS phase behaviour and relate this to starch crystallisation and microsphere formation. The hypothesis was that phase diagram position would influence the starch microsphere preparation and the properties of the microspheres. The microsphere formation process was investigated with regard to microsphere development and starch crystallisation kinetics. Microsphere physicochemical properties and their development during different stages of the preparation were studied by examining freshly produced, freeze-dried, and redispersed microspheres. Enzymatic hydrolysis of redispersed microspheres was also investigated. It was possible to produce microspheres from different positions in the phase diagram using 24 h incubation at 25 °C. However, the operational area for the used production conditions was relatively small compared to the biphasic region of the phase diagram. The main findings were that the starch-PEG ATPS phase behaviour can affect the rate of microsphere formation and particle size, but the additional properties of the dried and redispersed microspheres did not differ to a considerable extent. Thus, we have identified a robust production space where production parameters such as time to obtain microspheres can be considerably influenced by the ATPS system phase diagram position.

  • 30.
    Martínez, Claudia
    et al.
    Uppsala University, Sweden; University of Barcelona, Spain.
    Amery, Leanne
    AstraZeneca, UK.
    De Paoli, Giorgia
    University of Dundee, uk.
    Elofsson, Ulla
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Millqvist-Fureby, Anna
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Kwok, Stanley
    AstraZeneca, USA.
    López-Cabezas, Carmen
    Hospital Clínic Barcelona, Spain.
    Rosenberger, Marika
    Sanofi-Aventis Deutschland GmbH, Germany.
    Schoenau, Christian
    Sanofi-Aventis Deutschland GmbH, Germany.
    Wahlgren, Marie
    Lund University,Sweden.
    Paulsson, Mattias
    Uppsala University, Sweden.
    Examination of the Protein Drug Supply Chain in a Swedish University Hospital: Focus on Handling Risks and Mitigation Measures2023In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 112, no 11, p. 2799-Article in journal (Refereed)
    Abstract [en]

    Protein drugs, such as monoclonal antibodies, have proved successful in treating cancer and immune system diseases. The structural complexity of these molecules requires careful handling to ensure integrity and stability of the drug. In this study, a failure mode and effects analysis was performed based on a Gemba Walk method in a Swedish University Hospital. The Gemba Walk is focused on pharmacists observing the actual supply process steps from distributor, pharmacy cleanroom to patient administration. Relevant protein drugs are chosen based on sales statistics within the hospital and the corresponding wards were observed. Further is the Double Diamond design method used to identify major risks and deliver mitigation strategies. The study identified potential stress factors such as temperature, shock by impact, shaking, vibration and light exposure. There were also risks associated with porters’ and healthcare professionals’ lack of awareness and access to information. These risk factors may cause loss of efficacy and quality of the protein drug, potentially leading to patient safety concerns. In this study, a simulation is also performed to list measures that theoretically should be in place to ensure the quality of the protein drug, for example validated and protocol-based compounding in cleanroom, training and validated transports. © 2023 The Authors

  • 31.
    Millqvist-Fureby, Anna
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor.
    Aqueous two-phase systems for microencapsulation in food applications: Chapter 152014In: Microencapsulation in the Food Industry: A Practical Implementation Guide / [ed] A Gaonkar, N Vasisht, A Kare, R Sobel, Elsevier, 2014, p. 157-169Chapter in book (Refereed)
  • 32.
    Millqvist-Fureby, Anna
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    Characterisation of spray-dried emulsions with mixed fat phases2003In: Colloids and Surfaces B: Biointerfaces, ISSN 0927-7765, E-ISSN 1873-4367, Vol. 31, p. 65-79Article in journal (Refereed)
    Abstract [en]

    Fat encapsulation in spray-dried protein-stabilised emulsions is known to depend on the choice of protein, the emulsion droplet size, and the melting point of the fat. However, the fat encapsulation may also depend on the fat crystal habit. Fats may crystallise in three different α, ß' and ß, of which the ß-form is thermodynamically stable. The α-form is obtained in rapidly cooled fats, and it can then transform into the ß'-form during storage, and this crystal form is finally transformed into the ß-form. In order to investigate the effect of different fat phases on the spray-dried emulsions, two solid fats were studied: fully hardened rapeseed oil (ß-stable) and fully hardened palm oil (ß'-stable). The solid fats were used on their own or in mixtures with rapeseed oil, in order to provide fat phases with different properties. The emulsion composition was chosen as to mimic the composition of whole milk, i.e. 40% lactose, 30% sodium caseinate and 30% fat on a dry weight basis. The dried powders were stored under dry conditions at 4 or 37 °C in order to investigate the changes in the fat crystals and surface composition of the powders with time. The surface composition was analysed using electron spectroscopy for chemical analysis. Evaluation of the data showed that surface coverage of fat varied depending on the composition of the fat phase. The ratio of lactose to protein remained constant, which implies that the fat was present as `islands' on a surface composed of lactose and protein. The hardened palm oil crystallised initially in the α- or ß'-form (depending on the ratio of hardened fat to oil), and during storage, the crystal form gradually changed into the ß'-form. In powders containing hardened rapeseed oil only the stable ß-form was found, even in fresh samples. The surface coverage of fat was reduced after storage, whereas the ratio of lactose to protein at the surface remained unchanged. The emulsion droplet size in emulsions prepared at a low homogenisation pressure was considerably increased after spray-drying and reconstitution, whilst the emulsion droplet size was well preserved in emulsions prepared at high homogenisation pressure

  • 33.
    Millqvist-Fureby, Anna
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    Encapsulation approaches for proteins: Chapter 162008In: Delivery and Controlled Release of Bioactives in Foods and Nutraceuticals / [ed] Nissim Garti, Elsevier, 2008, p. 404-425Chapter in book (Refereed)
  • 34.
    Millqvist-Fureby, Anna
    et al.
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    Burns, N
    Surface activity at the air-water interface in relation to surface composition of spray-dried milk protein-stabilized emulsions1999In: Food Emulsions and Foams / [ed] Dickinson, E. & Rodriguez Patino, J.M., Royal Society of Chemistry, 1999, p. 236-245Chapter in book (Refereed)
  • 35.
    Millqvist-Fureby, Anna
    et al.
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    Elofsson, Ulla
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    Bergenståhl, B
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    Surface composition of spray-dried milk protein-stabilised emulsions in relation to pre-heat treatment of proteins2001In: Colloids and Surfaces B: Biointerfaces, ISSN 0927-7765, E-ISSN 1873-4367, Vol. 21, p. 47-58Article in journal (Refereed)
    Abstract [en]

    Several important technical properties of spray-dried food powders depend on particle-liquid interactions (e.g. wettability, dispersability) and particle-particle interactions (e.g. flowability). It can be assumed that the chemical composition of the surface layer of the particles to a large extent determine these properties. The present study has been aimed to investigate the relation between the surface composition of spray-dried milk protein-stabilised emulsions and pre-heat treatment of the proteins. Solutions of WPC were heat-treated at low (60-90°C) and high (140°C) temperature and the degree of denaturation was determined, prior to the preparation of emulsions with rapeseed oil. The surface composition of the dry powders were established by using ESCA (electron spectroscopy of chemical analysis).The emulsions were characterised by droplet size distribution before spray drying and after dissolution of the powders. Also free fat extractions and estimations of wettability (dissolution rates) were performed. The powder surface coverage of protein decreased with increasing degree of protein denaturation before the emulsification, whereas the emulsion droplet size increased both before spray drying and after reconstitution of powders. The free fat extraction as well as the dissolution rate, whereof the latter decreased with increasing surface fat coverage, correlated well with the fat coverage of the powder surface.

  • 36.
    Millqvist-Fureby, Anna
    et al.
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor.
    Larsson, Anders
    Mesoporous solid carrier particles in controlled delivery and release: Chapter 252014In: Microencapsulation in the Food Industry: A Practical Implementation Guide / [ed] A Gaonkar, N Vasisht, A Kare, R Sobel, Elsevier, 2014, p. 299-319Chapter in book (Refereed)
  • 37.
    Millqvist-Fureby, Anna
    et al.
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    Malmsten, M
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    Bergenståhl, B
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    An aqueous polymer two-phase system as carrier in the spray-drying of biological material2000In: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 225, p. 54-61Article in journal (Refereed)
    Abstract [en]

    This investigation describes a novel concept in formulation of carrier systems for spray-drying of biological materials. As carrier materials a system composed of poly (vinyl pyrrolidone) (PVP) and dextran was used. This system yields an aqueous two-phase system in which each phase is enriched in one of the polymers. By varying the composition of the system, the effective structure of a 'stirred' such system can be varied, covering the entire range from dextran continuous to PVP continuous. This facilitates encapsulation of either of these polymers in a spray-drying operation. In an attempt to investigate the spray-drying from such a system, the surface composition of the spray-dried powder obtained from various compositions of the two-phase system was analysed by electron spectroscopy for chemical analysis (ESCA), providing information on the distribution of the polymers in the powder and thus also in the spray droplets. The two-phase system was applied for spray-drying of live bacteria. The survival rate of the bacteria depended on the composition of the two-phase system. The storage stability of the bacteria in these formulations was investigated after storage at room temperature under dry conditions for four weeks, and it was found that the survival rate was 10-45%. The results therefore show that this type of formulation holds promise for future applications for micro-organisms as well as other sensitive biological materials such as proteins.

  • 38.
    Millqvist-Fureby, Anna
    et al.
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    Malmsten, M
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    Bergenståhl, B
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    Spray-drying of trypsin – Surface characterisation and activity preservation1999In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 188, p. 243-253Article in journal (Refereed)
    Abstract [en]

    In the present study trypsin mixed with various carbohydrates, i.e. lactose, sucrose, mannitol, a-cyclodextrin and dextrin, was spray-dried in order to investigate the effects of spray-drying on this enzyme, with particular emphasis on the effects of interactions between trypsin and the surface formed during spray-drying. The protein was strongly over-represented at the surface of the powder particles, the surface coverage ranging from 10 to 65%, depending on the amount of trypsin in the solids (0.2-5%). This indicates that the protein adsorbs at the air/liquid interface of the spray-droplets, and that this surface is largely preserved also after drying. The surface concentration of protein in the spray-dried powders could be controlled by adding a surfactant to the mixture before drying, since the surfactant adsorbs preferentially at the air/liquid interface of the spray droplets, thus expelling protein from the surface. In general, the residual activity of trypsin in these non-optimised formulations was 90% or higher, and in no case less than 82%. It was found that the loss of activity could partly be explained by inactivation of the protein adsorbed at the surface. For mannitol and sucrose, however, the level of inactivation was higher than could be explained by surface inactivation alone, and additional mechanisms must also be considered.

  • 39.
    Millqvist-Fureby, Anna
    et al.
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    Malmsten, M
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    Bergenståhl, B
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    Surface characterisation of freeze-dried protein/carbohydrate mixtures1999In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 191, p. 103-114Article in journal (Refereed)
    Abstract [en]

    In the present investigation freeze-drying of proteins (BSA or trypsin) together with various carbohydrates, i.e. lactose, sucrose, mannitol, a-cyclodextrin and dextrin, has been studied with particular emphasis on the surface composition of the freeze-dried powders. The proteins were found to be over-represented on the powder surface as compared to the bulk concentration of protein. The mechanism behind the surface accumulation is believed to be that proteins adsorb preferentially over carbohydrates to the ice/liquid interface in the frozen sample. The degree of surface accumulation depended on the carbohydrate used, and was increased in annealed samples compared to reference samples. The activity of trypsin was fairly preserved well (58-90%) in the freeze-dried powders, but depended on the carbohydrate excipient, whilst the surface composition had little effect on the activity. The activity preservation was improved when the protein concentration was raised from 1% to 10% in the solids. The surface composition of powders containing mixtures of mannitol and dextrin as excipients depended on the ratio between the two carbohydrates, with the lowest surface coverage of protein obtained in 50/50 mixtures.

  • 40.
    Millqvist-Fureby, Anna
    et al.
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    Smith, P
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    In-situ lecithination of dairy powders in spray-drying for confectionery applications2007In: Food Hydrocolloids, ISSN 0268-005X, E-ISSN 1873-7137, Vol. 21, p. 920-927Article in journal (Refereed)
    Abstract [en]

    Powders are essential ingredients of chocolate. In particular for milk chocolate milk and whey powders are important, together with sucrose, lactose and cocoa solids. During processing to maintain a good flow of the molten chocolate mass, particles with hydrophilic surfaces, such as dairy powders and sugars, are coated with a surface-active compound. Only lecithin and polyglycerol polyricinoleate (PGPR) (at a limited level) are allowed in chocolate, and as these are expensive as little as possible is added, whilst maintaining rheological properties. Conventionally, lecithin is added during conching, and through the intense kneading of the chocolate mass it is distributed throughout the mass. Usually about 0.5% is added, although the level depends upon the composition of the chocolate. Here we present a new approach to lecithination of spray-dried milk and lactose powders, which we call in-situ lecithination. It has been found that the surface of a spray-dried powder is dominated by any surface-active species, and in a competitive situation, the most rapidly adsorbing species dominates. This behaviour is utilised when lecithin is added to the spray-dryer feed, and through the competitive adsorption of surface-active agents during the drying process, it dominates the powder surface composition as measured by X-ray photoelectron spectroscopy (XPS). This is also seen in differences in sedimentation rate when the powders are mixed with cocoa butter to assess the rheological properties of the powder dispersions. The effect was large for lactose powders, but smaller for skim milk powder and whey powder.

  • 41.
    Millqvist-Fureby, Anna
    et al.
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    Smith, P
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    In-situ lecithination of dairy powders in spray-drying for confectionery applications2007In: Food Hydrocolloids, ISSN 0268-005X, E-ISSN 1873-7137, Vol. 21, p. 920-927Article in journal (Refereed)
    Abstract [en]

    A newly developed acoustic emission on-line monitoring technique (Voltaire J. et al. 2004) provides insight into the dynamic interactions occurring between paper, inkfount emulsion, and rubber blanket in offset printing. The technique uses a microphone placed in the vicinity of the exit of the paper-blanket nip. Through digital signal processing of the measured sound pressure it is possible to distinguish between machinery sound and that caused by the tacky ink splitting. In this study, printing of coldset inks on newsprint was carried out on a two-unit sheet-fed offset press. In line with earlier results, an increase in print density was found to correspond to increased sound pressure at the nip exit for higher frequencies (above 15 kHz). Depending on the status of the press at startup, i.e. ink and fount condition and temperature, an increase or decrease towards a more stable value of the sound pressure was detected during the early running of the press, and in both cases this correlated well with the evolution in print density to its target value. This and related results can prove useful for monitoring, and adjusting by feedback, the initial press equilibration before the print-ready stage. Moreover, the acoustic emission can directly reveal destabilised conditions at longer running times that by other means would not be detected until later

  • 42.
    Munoz-Ibanez, Marta
    et al.
    Inria, France; University of Paris-Saclay, France.
    Nuzzo, Marine
    RISE, SP – Sveriges Tekniska Forskningsinstitut. Lund University, Sweden.
    Turchiuli, Christelle
    Inria, France; University of Paris-Saclay, France; University of Paris-Sud, France.
    Bergenståhl, Björn
    Lund University, Sweden.
    Dumoulin, Elisabeth
    Inria, France; University of Paris-Saclay, France.
    Millqvist-Fureby, Anna
    RISE, SP – Sveriges Tekniska Forskningsinstitut.
    The microstructure and component distribution in spray-dried emulsion particles2016In: Food Structure, ISSN 2213-3291, Vol. 8, p. 16-24Article in journal (Refereed)
    Abstract [en]

    Microencapsulation by spray drying of oil-in-water (o/w) emulsions provides a means to encapsulate functional lipophilic ingredients. The active ingredient is dispersed in continuous solid phase providing protection. However, the encapsulation efficiency depends on the microstructure and morphology of the dry particles influenced by several mechanisms occurring during processing such as oil droplet breakup during atomization, ingredient diffusivity, interfacial adsorption of surface active ingredients, and drying kinetics. In this work, sunflower oil (model for lipophilic compounds) was encapsulated in solid particles composed of acacia gum and maltodextrin DE12. Three powders with different initial emulsion size (e.g. about 0.1 and 1 μm) and atomized under high and low shear rate were analysed for the morphology and distribution of oil droplets and matrix constituents within the solid particle (20–100 μm). The microscopic (optical, SEM, LVSEM, confocal Raman), spectroscopic (XPS) and analytical (solvent extraction) techniques used were either qualitative or quantitative. Their combination made it possible to determine both the composition at the surface and inside the particle. The surface differs from the bulk in composition, confirming the constituent segregation during spray drying, and depended on the initial emulsion size and atomization conditions that must be controlled for an efficient encapsulation. Especially, the use of confocal Raman microscopy is promising for the study of processstructure-properties relationship.

  • 43.
    Nuzzo, Marine
    et al.
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Life Science.
    Millqvist-Fureby, Anna
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor.
    Sloth, Jakob
    GEA Process Engineering A/S, Denmark.
    Bergenståhl, Björn
    Lund University, Sweden.
    Surface Composition and Morphology of Particles Dried Individually and by Spray Drying2015In: Drying Technology, ISSN 0737-3937, E-ISSN 1532-2300, Vol. 33, no 6, p. 757-767Article in journal (Refereed)
    Abstract [en]

    This study investigates how the morphology of spray-dried particles is related to the formulation and properties of the components in the formulation. Further, the scale effects in comparisons of levitation-dried single particles and spray-dried particles in a lab-scale spray dryer have been addressed. The Drying Kinetics AnalyzerTM generates single particles from a levitated drop under simulated spray-drying conditions. A set of surface-active polymers (bovine serum albumin, hydroxypropyl methyl cellulose, and triblock co-polymer Poloxamer), in combination with lactose, were analyzed for their dynamic surface properties in solution, and their effect on particle morphology and surface composition were determined by low-vacuum SEM and XPS analyses. The morphology obtained in spray drying was reproduced in the single-particle drying. The surface compositions were also similar, but higher levels of surface-active materials were found at the surface of the single particles as compared to the spray-dried particles. Further, the adsorption rate of surface-active compounds at the drop surface estimated by dynamic surface tension was found to be an important parameter to estimate the surface composition at different drying scales. The particle morphology was primarily determined by the surface rheological properties of the feed solution and, to a lesser extent, by the surface composition.

  • 44.
    Nuzzo, Marine
    et al.
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Life Science. Lund University, Sweden.
    Sloth, Jakob
    GEA Process Engineering A/S, Denmark.
    Bergenstahl, Björn
    Lund University, Sweden.
    Millqvist-Fureby, Anna
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Life Science.
    Phase segregation in individually dried particles composed of biopolymers2015In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 31, no 40, p. 10946-10954Article in journal (Refereed)
    Abstract [en]

    Mixing of two biopolymers can results in phase separation due to their thermodynamically incompatibility under certain conditions. This phenomenon was first reported when the solution was allowed to equilibrate, but it has later been observed also as a consequence of drying. The challenges of this study were to observe phase segregation by confocal Raman microscopy and LV-SEM on dried film, individually dried particles, and spray dried particles. The influence of the solid content and the phase ratio (composition) of a HPMC/maltodextrin mixture on the localization of the ingredients in the individually dried particles was investigated. We observed that phase segregation of HPMC and maltodextrin is induced by solvent evaporation in film drying, single particle drying, as well as spray drying. The phase ratio is an important parameter that influences the localization of the HPMC-enriched phase and maltodextrin-enriched phase, i.e., to the particle surface, to the core, or in a more or less bicontinuous pattern. The drying time, affected by the solids content, was found to control the level of advancement of the phase segregation.

  • 45.
    Nuzzo, Marine
    et al.
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor. Lund University, Sweden.
    Sloth, Jakob
    GEA Process Engineering A/S, Denmark.
    Brandner, Birgit
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor.
    Bergenstahl, Björn
    Lund University, Sweden.
    Millqvist-Fureby, Anna
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor.
    Confocal Raman microscopy for mapping phase segregation in individually dried particles composed of lactose and macromolecules2015In: Colloids and Surfaces A: Physicochemical and Engineering Aspects, ISSN 0927-7757, E-ISSN 1873-4359, Vol. 481, p. 229-236Article in journal (Refereed)
    Abstract [en]

    The quality of powder is determined by its functionality such as dissolution, encapsulation and flowability. The functionality of powder is in turn determined by their primary properties such as morphology and composition which need to be studied. Hence morphology and surface composition has been largely investigated in spray dried powders and individually dried particles. On the contrary, there is only scarce information regarding the internal structure. With the aim of acquiring a better understanding of the localization of different ingredients in spray dried powders we have used confocal Raman microscopy to investigate the internal microstructure of individually dried particles. In this study three different macromolecules have been investigated: bovine serum albumin, hydroxypropyl methyl cellulose, and triblock co-polymer poloxamer in a lactose matrix are compared at various macromolecule to lactose ratios. The surface and internal component distribution in response to the macromolecule concentration has been established. For the first time phase segregation in particles during a short drying time range is shown. Macromolecules were enriched at the surface of the dried particles and a macromolecule depleted layer was observed below the surface. Macromolecule enriched domains were found segregated from the amorphous lactose matrix in the internal part of the particles. Confocal Raman microscopy was found to be a powerful tool for internal mapping in individually dried particles.

  • 46.
    Nuzzo, Marine
    et al.
    RISE - Research Institutes of Sweden, Bioscience and Materials, Chemistry and Materials. Lund University, Sweden.
    Sloth Overgaard, Jakob
    GEA Process Engineering AS, Denmark.
    Bergenståhl, Bjorn
    Lund University, Sweden.
    Millqvist-Fureby, Anna
    RISE - Research Institutes of Sweden, Bioscience and Materials, Chemistry and Materials.
    The morphology and internal composition of dried particles from whole milk—From single droplet to full scale drying2017In: Food Structure, ISSN 2213-3291, Vol. 13, p. 35-44Article in journal (Refereed)
    Abstract [en]

    Powder structure and functionality are expected to be closely linked to the composition and drying process. In order to understand the optimization of the quality of a powder, e.g. encapsulation efficiency, or wetting and dispersion properties, monitoring of the particle microstructure is an attractive concept. However, to study the impact of different parameters in formulation and drying process on full scale is complicated and expensive, hence, studies on smaller scale, even single particle drying, is a potentially useful complement, as long as the results are comparable. The aim of this study is to compare morphology and internal composition of whole milk particles produced at different dryer scales to assess the development of internal structure in powder formed by spray drying. Whole milk was spray dried in the single particle dryer, laboratory dryer, pilot plant dryer and full scale dryer. The morphology and composition of the particles obtained were analyzed by low vacuum-SEM, confocal Raman microscopy and X-ray photoelectron spectroscopy. Phenomena such as adsorption of surface active compounds at the particle surface and phase segregation are observed to different extent, depending on particle size and drying time. The scale of drying influences the internal microstructure and distribution of components in the particles, and to a small extent also the external morphology. These effects are proposed to be related to the drying times for different droplet sizes, although mechanical handling effects and agglomeration in the full scale dryer may also influence the final morphology of these particles, as well as the surface composition.

  • 47.
    Osanloo, Daniel
    et al.
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development. Vinnova, Sweden.
    Fransson, Jonas
    Vinnova, Sweden; Nanexa AB, Sweden.
    Bergenståhl, Björn
    Vinnova, Sweden; Lund University, Sweden.
    Millqvist-Fureby, Anna
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development. Vinnova, Sweden.
    Effects of drying methods on physical properties and morphology of trehalose/mannitol mixtures2023In: Drying Technology, ISSN 0737-3937, E-ISSN 1532-2300, Vol. 41, no 4, p. 503-522Article in journal (Refereed)
    Abstract [en]

    Solid-state properties of dried protein formulations are important for stability and functionality of the product. This study investigates how different drying technologies (freeze-drying with and without annealing, spray drying and spray-freeze drying) affect the structure and solid-state properties of a set of matrix formulations composed of trehalose (glass former) and mannitol (scaffolding agent) in five ratios. The dried materials were characterized using differential scanning calorimetry, thermogravimetric analysis, x-ray diffraction and scanning electron microscopy. The morphology of the dried matrix is determined by the drying technology and the composition. In all mixtures, mannitol partially dissolved in the amorphous trehalose, resulting in reduced glass transition temperature. At least 50% mannitol is required to achieve a scaffolding effect through crystallized mannitol. At 25% mannitol poor structural stability is obtained regardless of drying technology. Despite the vast differences in drying kinetics, all drying technologies resulted in similar amorphous content in the dried material. © 2022 The Author(s). 

  • 48.
    Osanloo, Daniel
    et al.
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development. Lund University, Sweden.
    Mahlin, Denny
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Bjerregaard, Simon
    Ferring Pharmaceuticals A/S, Denmark.
    Bergenståhl, Björn
    Lund University, Sweden.
    Millqvist-Fureby, Anna
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development. Lund University, Sweden.
    Formulation factors affecting foam properties during vacuum foam-drying2024In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 652, article id 123803Article in journal (Refereed)
    Abstract [en]

    This paper explores how vacuum foam-drying of a protein is influenced by formulation parameters by investigating the foam structure, physical properties of the foam, and the stability of the protein. Recombinant human bile salt-stimulated lipase was used as a model of a protein drug. The stability of the lipase was evaluated through activity measurements. Two disaccharides (sucrose and trehalose), strongly tending to an amorphous form, were used as matrix formers, and the physical properties were assessed through residual water content, glass transition temperature, and crystalline state. Moreover, some formulations included surfactants with different sizes and structures of the head group. The alkyl chain length was kept constant to only investigate the impact of the surfactant head group, in the presence of the lipase, on the foamability and surface coverage of the lipase. The study demonstrated that the lipase allowed for a dry, solid foam with a foam overrun of up to 2600 %. The wall thickness of the dry, solid foam was estimated to be 20–50 µm. Clear differences between sucrose and trehalose as matrix former were identified. The lipase showed no tendency to lose activity because of the drying and rehydration, despite a proportion of the lipase covering the surfaces of the dry material. 

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  • 49.
    Palmkron, Shuai Bai
    et al.
    Lund university, Sweden.
    Bergenståhl, Björn
    Lund university, Sweden.
    Håkansson, Sebastian
    Lund university, Sweden; BioGaia AB, Sweden.
    Wahlgren, Marie
    Lund university, Sweden.
    Millqvist-Fureby, Anna
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Larsson, Emanuel
    Lund university, Sweden.
    Quantification of structures in freeze-dried materials using X-ray microtomography2023In: Colloids and Surfaces A: Physicochemical and Engineering Aspects, ISSN 0927-7757, E-ISSN 1873-4359, Vol. 658, article id 130726Article in journal (Refereed)
    Abstract [en]

    The structure of a freeze-dried material is essential for its ability to preserve and protect biologics such as proteins, cells and other sensitive structures. The structure of a typical freeze-dried matrix can be described as pores surrounded by thin walls where the walls are the encapsulating material (for e.g. cells). The objective of this investigation is to evaluate X-ray microtomography (µCT) as a characterization method to quantifying the matrix of a freeze dried material, and compare it to scanning electron microscopy (SEM). The material consists of maltodextrin, freeze-dried below or above the glass transition temperature of the maximal freeze concentration (Tg′) and after applying annealing. The SEM images have high resolution and provide an excellent view of the sample. However, it is challenging to perform any image analysis and to ensure that a representative section is presented. The µCT images provide a rather uniform contrast between material and void, allowing for a simple grey-level thresholding when separating structure from the background. A robust image analysis procedure allows the results extracted from a representative sample volume to be evaluated. Further image analysis has been focused on understanding the thickness of the encapsulating structures by estimations of volume-weighted averages of inscribed spheres within the walls. The results show two types of structures: A large pore structure of around 20–100 µm separated by thin walls around 2–3 µm thick, and a finer structure consisting of smaller pockets of air (< 10 µm) packed in a honeycomb like structure. The structures of the samples dried below and above Tg′ have smaller and thinner structures, while material dried after annealing has larger and thicker structures. The structures display comparably small differences between the different drying protocols despite the quite different drying conditions.

  • 50.
    Palmkron, Shuai
    et al.
    Lunds University, Sweden.
    Gustavsson, Linnea
    RISE Research Institutes of Sweden. Lunds University, Sweden.
    Wahlgren, Marie
    Lunds University, Sweden.
    Bergensthål, Björn
    Lunds University, Sweden.
    Millqvist-Fureby, Anna
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Temperature and Heat Transfer Control During Freeze Drying. Effect of Vial Holders and Influence of Pressure2022In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 39, p. 2597-Article in journal (Refereed)
    Abstract [en]

    Objective: A common issue of freeze drying is the inhomogeneity between samples, both in regards to water content and structure. The purpose of this study is to address this issue, and try to understand the cause of inhomogeneity in the heat transfer and sample temperature. Methods: The temperature and the heat transfer was measured using different setups, both with and without vial holders at various positions at different shelf temperature and chamber pressures. By comparing sublimation rate measurements (water sample) with temperature equilibrium measurements with a non-evaporating liquid (oil sample), the heat transfer contribution from radiation and conduction could be separated and investigated individually. Results: The oil sample temperature increases each time the pressure is decreased; the increase is highest at lower shelf temperatures. Using vial holder reduces the deviation between the samples but have limited effect on the temperature increase. The sublimation rate for water sample is pressure dependent and samples close to the walls have a higher sublimation rate than vials in the center. The sublimation rate increases slightly when using a vial holder but the deviation between vials becomes more random. Conclusions: The heat transfer consists of conduction through rectified vapor and radiation from surrounding walls, about 65–75% of the heat is transferred by conduction and 25–35% by radiation under normal operational conditions. As the vial holder is also influenced by the radiation, the vial inside the holder is indirectly affected by the surrounding radiation. © 2022, The Author(s).

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