| 1. |
- Gernandt, Jonas, 1982-
(författare)
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On the phase behaviour of hydrogels : A theory of macroion-induced core/shell equilibrium
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Colloidal macroions are known to interact very strongly with oppositely charged polyionic hydrogels. Sometimes this results in a non-uniform distribution of the macroions within the gel, a phenomenon that is not fully understood. This thesis is a summary of four papers on the development of a theory of the thermodynamics of macroions interacting with hydrogels, aimed at explaining the phenomenon of core/shell separation in spherical gels. It is the first theory of such interactions to use a rigorous approach to whole-gel mechanics, in which the elastic interplay between different parts of the gel is treated explicitly.The thesis shows that conventional theories of elasticity, earlier used on gels in pure solvent, can be generalised to apply also to gels in complex fluids, and that the general features of the phase behaviour are the same if mapped to corresponding system variables. It is found that the emergence of shells is due to attractions between macroions in the gel, mediated by polyions. Since the shell state is unfavourable from the perspective of the shell itself, being deformed from its preferred state, there will be a hysteresis between the uptake and the release of the macroion, like already known to occur with the uptake and release of pure solvent.Due to the elastic interplay, growth of the shell makes further growth progressively more favourable. Thus, unless there is a limited amount of macroions available the system will not reach equilibrium until complete phase transition has taken place. If the amount is limited the core/shell separation can be in equilibrium, so the volume of the solution that the gel is in contact with plays a very important part in determining the thermodynamic resting point of the system. The ability of a macroion/hydrogel to phase separate thus depends on the molecular properties whereas the ultimate fate of such a separation depends on the proportions in number between the ingoing components.
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| 2. |
- Frenning, Göran
(författare)
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An efficient finite/discrete element procedure for simulating compression of 3D particle assemblies
- 2008
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Ingår i: Computer methods in applied mechanics and engineering. - : Elsevier BV. - 0045-7825. ; 197:49/50, s. 4266-4272
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Tidskriftsartikel (refereegranskat)abstract
- An efficient combined finite/discrete element procedure is developed, which is intended for simulating compression of 3D particle assemblies. Its main ingredients are an explicit solution scheme of the predictor–corrector type, an efficient two-stage contact detection algorithm, and physically stabilized elements that require only one integration point. The algorithm admits a straightforward parallelization, with a reasonable parallel efficiency. Our results indicate that realistic systems comprising 1000 or more particles may successfully be analyzed within a reasonable computation time (not more than about 10–15 h).However, the explicit solution scheme limits the applicability of the algorithm in its present form to systems of fairly soft particles, unless special procedures such as mass scaling are used to increase the critical time step.
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| 3. |
- Frenning, Göran
(författare)
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Analysis of pharmaceutical powder compaction using multiplicative hyperelasto-plastic theory
- 2007
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Ingår i: Powder Technology. - : Elsevier BV. - 0032-5910 .- 1873-328X. ; 172:2, s. 103-112
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Tidskriftsartikel (refereegranskat)abstract
- Single-ended compaction of lactose powder is investigated numerically within the framework of multiplicative hyperelasto-plastic theory. In keeping with previous work in the pharmaceutical field, a slightly modified Drucker–Prager Cap model is described and used in the simulations. Coulomb friction is included on all interfaces. Our results indicate that simulations of this type may be useful not only to determine density and stress distributions within tablets, as has been done hitherto, but also may provide indications of circumstances under which the tableting operation fails due to capping.
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| 4. |
- Unga, Johan, 1976, et al.
(författare)
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Relating solubility data of parabens in liquid PEG 400 to the behaviour of PEG 4000-parabens solid dispersions
- 2009
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier BV. - 0939-6411 .- 1873-3441. ; 73:2, s. 260-268
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Tidskriftsartikel (refereegranskat)abstract
- The solid state behaviour of polyethylene glycol 4000 (PEG 4000) and dispersions of a homologous series of parabens (methyl- (MP), ethyl- (EP), propyl- (PP) and butyl- (BP)) were examined and compared to the paraben solubility in liquid PEG 400. Dispersions were prepared by co-melting different amounts of paraben (5-80% (w/w)) and PEG 4000 and were studied using a combination of differential scanning calorimetry (DSC) and small and wide angle X-ray diffraction (SAXD/WAXD). Depending on the concentration of parabens in the dispersions, DSC showed melting peaks from folded and unfolded forms of PEG, a eutectic melting and melting of pure parabens. The fraction of folded PEG increased and the melting temperatures of both PEG forms decreased with increasing paraben content. In an apparent phase diagram of PP-PEG dispersions a eutectic mixture appeared above 5% PP. In addition, a melting peak corresponding to the paraben appeared for dispersion containing more than 60% PP. Similar phase diagrams were shown for the other parabens. The SAXD data and a 1D correlation function analysis revealed that MP and BP were incorporated into the amorphous domains of the lamellae of solid PEG to a higher degree than EP and PP. In addition, the lamellae thickness of PEG and the fraction of amorphous domains increased more for MP and BP compared to EP and PP. BP showed the highest solubility of the parabens followed by MP, EP and PP in both liquid and solid PEG. Furthermore, the thickness of the amorphous domains of the PEG in the different parabens-PEG dispersions could be correlated to the solubility in liquid PEG 400.
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| 5. |
- Nikjoo, Dariush, 1977-, et al.
(författare)
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Hyaluronic Acid Hydrogels for Controlled Pulmonary Drug Delivery—A Particle Engineering Approach
- 2021
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Ingår i: Pharmaceutics. - : MDPI. - 1999-4923. ; 13:11
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Tidskriftsartikel (refereegranskat)abstract
- Hydrogels warrant attention as a potential material for use in sustained pulmonary drug delivery due to their swelling and mucoadhesive features. Herein, hyaluronic acid (HA) is considered a promising material due to its therapeutic potential, the effect on lung inflammation, and possible utility as an excipient or drug carrier. In this study, the feasibility of using HA hydrogels (without a model drug) to engineer inhalation powders for controlled pulmonary drug delivery was assessed. A combination of chemical crosslinking and spray-drying was proposed as a novel methodology for the preparation of inhalation powders. Different crosslinkers (urea; UR and glutaraldehyde; GA) were exploited in the hydrogel formulation and the obtained powders were subjected to extensive characterization. Compositional analysis of the powders indicated a crosslinked structure of the hydrogels with sufficient thermal stability to withstand spray drying. The obtained microparticles presented a spherical shape with mean diameter particle sizes from 2.3 ± 1.1 to 3.2 ± 2.9 μm. Microparticles formed from HA crosslinked with GA exhibited a reasonable aerosolization performance (fine particle fraction estimated as 28 ± 2%), whereas lower values were obtained for the UR-based formulation. Likewise, swelling and stability in water were larger for GA than for UR, for which the results were very similar to those obtained for native (not crosslinked) HA. In conclusion, microparticles could successfully be produced from crosslinked HA, and the ones crosslinked by GA exhibited superior performance in terms of aerosolization and swelling.
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| 6. |
- Andersson, Sara B. E., 1987-
(författare)
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Novel and refined small-scale approaches to determine the intrinsic dissolution rate of drugs
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Many drugs are administered as crystalline particles compressed into tablets and taken orally. When the tablet reaches the gastrointestinal tract, it disintegrates and the drug particles dissolve in the gastrointestinal fluid. The dissolved molecules are absorbed across the intestinal membranes into the bloodstream to reach their target sites. Only dissolved molecules can be absorbed, and if a drug has low solubility and/or dissolution rate in gastrointestinal fluid, the drug absorption might be insufficient. Hence, knowing the solubility and dissolution behaviour of a potential drug candidate is necessary early in the drug development process. The aim of this thesis was to evaluate and refine different approaches for measuring and determining dissolution rate, as well as to develop novel in vitro small-scale dissolution methods. First, interlaboratory variability in determination of intrinsic dissolution rate (IDR) and apparent solubility (Sapp) was investigated using a miniaturized dissolution instrument. To minimize the interlaboratory variability, standardized protocols for both the experimental design and the data analyses were required, and a flow chart for performing standardized powder and disc IDR measurements was established. Next, as an alternative to the powder and disc methods, carefully dispersed suspensions were used to determine the IDR, and rapid and more controlled IDR measurements were obtained using suspensions with dispersed primary particles. From the suspension measurements, an IDR/Sapp ratio of the compounds were determined. This ratio can potentially be used to identify whether a compound is likely to show dissolution rate-limited absorption and hence is sensitive to particle size reduction. The final experiments used a single particle dissolution approach to determine the IDR at four different fluid velocities. Computational fluid dynamics (CFD) simulations were used to theoretically investigate the flow conditions and dissolution rates. Single particle dissolution measurements under well-defined conditions gave high-quality dissolution data. An IDR was determined within 5-60 minutes using particles with initial diameters of 37.5-104.6 μm. The single particle dissolution experiments were used to determine the thickness of the effective hydrodynamic boundary layer (heff). The heff values were also assessed by CFD simulations, and a good concordance between experimental and simulated heff values was obtained. The approaches presented in this thesis can be used to derive qualified knowledge about the dissolution properties of drugs with several potential applications in drug development, such as profiling of solid drugs, informed formulation decisions, assisting the modelling of drug dissolution and providing improved understanding of the in vivo-dissolution behaviour
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| 7. |
- Rudén, Jonas, et al.
(författare)
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On the relationship between blend state and dispersibility of adhesive mixtures containing active pharmaceutical ingredients
- 2021
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Ingår i: International Journal of Pharmaceutics. - : Elsevier. - 2590-1567. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- The objectives of this investigation were to study the evolution in blend state of adhesive mixtures containing the active pharmaceutical ingredients (APIs) salbutamol, budesonide and AZD5423 and to study the relationship between blend state and dispersibility of the mixtures, as assessed by the fine particle fraction (FPF). A series of adhesive mixtures of varied fines concentration were prepared for each API using the same type of carrier. Based on visual examination and powder mechanics, blend states were identified and summarized as blend state maps for each API. The dispersibility of the mixtures was studied using a Fast Screening Impactor (FSI) equipped with a ScreenHaler. The evolution in blend state differed between the APIs in terms of the width of the blend states. The structure of the adhesion layer also differed between the APIs, from relatively uniform to a heterogeneous layer with small agglomerates dispersed on the carrier surface. All three APIs expressed a similar type of bended relationship between FPF and fines concentration. However, the initial rate of increase and the fines concentration of the plateau differed between the APIs. The adhesive mixtures of all APIs followed the three main states in terms of structural evolution and the overall shape of the FPF-fines concentration profiles could be explained by the evolution in blend state. It is proposed that the structure of the adhesion layer is an important factor explaining the differences in blend state - blend dispersibility relationships between the APIs.
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| 8. |
- Rudén, Jonas
(författare)
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Powder mechanics and dispersion properties of adhesive mixtures for dry powder inhalers : Conceptualized as a blend state model
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Inhaled medicines is a therapy that dates back several thousands of years. Nowadays, using various types of inhaler devices to deliver active pharmaceutical ingredients (APIs) to treat respiratory diseases has become common practice. One such device is the dry powder inhaler (DPI) which often contains an adhesive powder mixture consisting of micron-sized API particles and larger inert particles (carriers). The general goal of a DPI formulation is to reach as high inhalable dose (dispersibility) as possible while maintaining a low dose variability. In addition, the formulation has to be stable during manufacturing and handling to avoid segregation. In this thesis, critical properties of adhesive mixtures for DPIs have been identified and summarized in a blend state model that describes the spatial distribution of API- and carrier particles in a mixture. The model consists of four distinct states, which are identified using a combination of powder mechanical analysis and imaging techniques. In the first state, denoted S1, the drug deposits at the open pores of the carriers resulting in a denser powder packing but a low dispersibility. At the second state, S2a, the drug will adhere to the outer carrier surfaces, which results in a more porous powder packing and increased dispersibility. Following further increases in drug load, reaching the S2b state, the adhering drug layer grows in complexity resulting in further reductions in powder density but with additional increases in dispersibility. At the final state, S3, the mixture is oversaturated with fines, which results in segregation and large self-agglomerates that are poorly dispersed during an inhalation experiment. The evolution of the blend state was found to be dependent on the carrier and API properties such as size and shape. Irregular carriers could handle higher drug loads before segregation occurred, while irregular API particles formed more porous adhesion layers resulting in lower drug loads. In terms of dispersibility, it was found that porous adhesion layers were more easily dispersed than coherent adhesion layers. When varying the pressure drop (airflow rate), the dispersibility of the S1 state increased linearly with higher pressure drops. However, S2a-S3 were more or less insensitive to increased pressure drops above a certain critical pressure drop. With the blend state model and the mapping of the evolution in blend state with increased drugs loads, the formulation work can ideally be improved leading to more effective treatments for patients.
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| 9. |
- Sarangi, Sohan
(författare)
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Understanding Adhesive Mixtures for Inhalation : Particle Dynamics Modelling and Segregation Experiments
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Pulmonary route has been used as a source of drug delivery to lungs for centuries. Drugformulation decides the type of inhaler devices such as pressurized metered-dose inhalers(pMDIs), nebulizers and dry powder inhalers (DPIs). The most commonly used formulationin DPI consists of an ordered unit consisting of smaller drug particles (3 to 5 μm) (activepharmaceutical ingredient, API) attached to larger inert particles (carrier particles, 100 μm)called adhesive mixtures. APIs are highly cohesive in nature due to high surface to volume ratio.The adhesive mixture prevents self-agglomeration of APIs and helps deliver it to the deep lungs.In the manufacturing of adhesive mixtures, the focus has been on mixing and release insideinhaler. The research work in this thesis focuses on unaddressed issues on mixture stability andsegregation using modeling and experimental techniques. The Discrete Element Method (DEM)was used to investigate the mechanics of adhesive units, formed by randomized distributionof APIs on the surface of carrier particle. Binary collisions (head on and oblique) betweenadhesive units were simulated for different number density of fines on the carrier (surfacecoverage ratio, SCR), surface energy (interfacial adhesion/cohesion energy), shape of APIs(spherical, triangular bipyramidal and tetrahedral), size of carrier particles (50, 100, 200 μm),type of carrier particle (lactose and mannitol) and the angle of impact. To account for variationthree different initial randomized distributions of API on the carrier were considered. The dataobtained was analysed in terms of effective mechanical properties (coefficient of restitution),effective friction, physical stability of adhesive unit and redistribution of fines on the carriersurface. The coefficient of restitution follows a Kawakita type equation for higher velocity andfor different surface energy. The effect of the fine particle shape was predominant for low SCRs,and adhesive units formed from tetrahedral fines exhibited the largest physical stability andlargest friction during oblique collisions. In terms of carrier size and properties it was observedthat mannitol particles are more stable than lactose with similar dispersion performance andthe200 μm carrier is the most stable among the sizes investigated. To complement the modeling,segregation of adhesive mixture (consisting of budesonide and salbutamol sulphate as APIand Inhalac 70 as carrier) was studied. Experiments showed significant loss of APIs and selfagglomeration at higher SCR. The micro mechanical models and experiments lay a foundationtowards a better understanding of the adhesive mixture dynamics.
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| 10. |
- Sarangi, Sohan, et al.
(författare)
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Effect of carrier size and mechanical properties on adhesive unit stability for inhalation : A numerical study
- 2021
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Ingår i: Powder Technology. - : Elsevier. - 0032-5910 .- 1873-328X. ; 390, s. 230-239
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Tidskriftsartikel (refereegranskat)abstract
- The Discrete Element Method (DEM) was used to investigate the micromechanics of adhesive units, the building blocks of adhesive mixtures, comprising a carrier particle with attached micronised fine particles. Binary head-on collisions between adhesive units was performed in the handling and dispersion velocity regimes, with variations in carrier mechanical properties (mannitol or lactose) and size (50, 100, 200 μm). The system was modeled with spherical particles with interactions represented by Hertz-Mindlin and Johnson-Kendall-Roberts contact models. The results were analysed in terms of stability ratios (retention, loss and transfer) and mechanical properties (restitution coefficient). It was observed that mannitol particles are more stable than lactose with similar dispersion performance and that the 200 μm carrier is the most stable among the particles investigated. The results provide a parametric knowledge about the performance of carrier particles and could be used for development of macro models for particle engineering and optimization of formulations.
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