| 1. |
- Adane, M., et al.
(författare)
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The use of extragranular disintegrants in multiple-unit tablet formulations : effect on compressibility, compactibility and disintegration
- 2007
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Ingår i: Journal of drug delivery science and technology. - 1773-2247. ; 17:4, s. 279-284
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Tidskriftsartikel (refereegranskat)abstract
- Multiple-unit tablets formed from mixtures of microcrystalline cellulose pellets and disintegrants (Ac-Di-Sol, Primojel or Kollidon CL) by compaction were investigated with the aim of controlling tablet tensile strength and disintegration time. The effects of pellet porosity, compaction pressure, and type and amount of disintegrant were studied. Primojel made the pellets less prone to deformation during compression, while the other two disintegrants had very minor effects on the compression behavior. Ac-Di-Sol and Primojel generally increased the tablet tensile strength, whereas the effect of Kollidon CL was dependent on the initial pellet porosity. Kollidon CL was found to significantly reduce the disintegration time, but the other two disintegrants had variable efficacy, and for the low-porosity pellets significantly increased the disintegration time. These results are interpreted as resulting from the interplay between the mechanical characteristics of the pellets and the mechanisms of action of the disintegrants.
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| 2. |
- Alderborn, Göran, et al.
(författare)
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Mechanical strength of tablets
- 2008. - 3
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Ingår i: Pharmaceutical Dosage Forms. - New York : Informa Healthcare. - 9780849390166 - 0849390168
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 3. |
- Andersson, Sara B. E., et al.
(författare)
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Determination of Intrinsic Drug Dissolution and Solute Effective Transport Rate during Laminar Fluid Flow at Different Velocities
- 2021
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Ingår i: Pharmaceutics. - : MDPI. - 1999-4923. ; 13:6
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to determine the intrinsic drug dissolution rate (IDR) and the solute effective transport rate of some drugs, using a single particle dissolution technique, satisfying qualified dissolution conditions. The IDR of three poorly water-soluble compounds was measured in milli-Q water using four different fluid velocities. The enveloped surface area of the particles was calculated from the projected area and the perimeter of the particle observed in the microscope. Furthermore, computational fluid dynamics (CFD) simulations were used to theoretically investigate the flow conditions and dissolution rate, comparing box shaped particles and spherical particles with similar dimensions and surface area as the particles used the experiments. In this study, the IDR measurement of the single particles was determined within 5-60 min using particles with an initial projected area diameter (Dp) between 37.5-104.6 mu m. The micropipette-assisted microscopy technique showed a good reproducibility between individual measurements, and the CFD simulations indicated a laminar flow around the particles at all flow velocities, even though there were evident differences in local particle dissolution rates. In conclusion, the IDR and solute effective transport rate were determined under well-defined fluid flow conditions. This type of approach can be used as a complementary approach to traditional dissolution studies to gain in-depth insights into the dissolution process of drug particles.
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| 4. |
- Andersson, Sara B. E., et al.
(författare)
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Effect of fluid velocity and particle size on the hydrodynamic diffusion layer thickness
- 2022
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier. - 0939-6411 .- 1873-3441. ; 180, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to determine the thickness of the hydrodynamic diffusion layer (h(HDL)) of three poor water-soluble compounds under laminar fluid flow using a single particle dissolution technique. The single particle dissolution experiments were performed in a flowing aqueous medium using four different fluid velocities (v), ranging from 46 to 103 mm/s. The particles used had an initial radius (r) of 18.8 to 52.3 mu m. The determined h(HDL) values were calculated from both dissolution experiments and computational fluid dynamics (CFD) simulation. In this study, single particle dissolution experiments gave, with one exception, h(HDL) values in the range of 2.09 to 8.85 mu m and corresponding simulations gave h(HDL) values in the range of 2.53 to 4.38 mu m. Hence, we found a semi-quantitative concordance between experimental and simulated determined h(HDL) values. Also, a theoretical relation between the dependence of hHDL on particle radius and flow velocity of the medium was established by a series of CFD simulations in a fluid velocity range of 10-100 mm/s and particle size (radius) range of 5-40 mu m. The outcome suggests a power law relation of the form h(HDL)alpha r(3/5)v(-2/5). In addition, the h(HDL) seems to be independent of the solubility, while it has a diffusion coefficient dependence. In conclusion, the hHDL values were determined under well-defined conditions; hence, this approach can be used to estimate the h(HDL) under different conditions to increase the understanding of the mass transfer mechanisms during the dissolution process.
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| 5. |
- 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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| 6. |
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| 7. |
- Fichtner, Frauke, et al.
(författare)
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Drug release from compacted single inert matrix agglomerates
- 2007
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Ingår i: Journal of Drug Delivery Science and Technology. - 1773-2247. ; 17:4, s. 273-277
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Tidskriftsartikel (refereegranskat)abstract
- The effect of compaction on the drug release from single, sodium chloride loaded, microcrystalline cellulose agglomerates of different porosities was investigated in this study. The drug release from uncompacted agglomerates and from agglomerates regained from tablets compacted at a range of different compaction pressures was monitored measuring the conductivity of the dissolution medium in a recirculation flow-through system. The drug release profiles were described using the mean dissolution time (MDT), the variation of dissolution time (VDT) and the relative dispersion coefficient (RD). It was found that depending on physical structure changes of the matrix, the drug release rate of compacted agglomerates could be enhanced or retarded in comparison with uncompacted agglomerates. The retardation is suggested to be due to a densification of the matrix and the enhancement due to a crack formation in the external surface of the matrix.
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| 8. |
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| 9. |
- Frenning, Göran, et al.
(författare)
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An effective-medium analysis of confined compression of granular materials
- 2009
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Ingår i: Powder Technology. - : Elsevier BV. - 0032-5910 .- 1873-328X. ; 194:3, s. 228-232
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Tidskriftsartikel (refereegranskat)abstract
- A simplified model for confined compression of granular materials is considered, which idealizes the collection of particles as a (central) force network. Applying an effective-medium procedure, an equation with micromechanically well-defined parameters is derived, which relates the applied pressure to the engineering strain of the powder during uniaxial compression. Despite the simplicity of the model, comparison with experimental data for mm-sized spherical granules indicates that this equation is able to satisfactorily predict the overall compression profile from single-particle data.
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| 10. |
- Frenning, Göran, et al.
(författare)
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Aspects of pharmaceutical physics
- 2009. - 5
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Ingår i: Modern Pharmaceutics, Volume 2. - New York : Informa Healthcare USA. - 9781420065688
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 11. |
- Frenning, Göran, et al.
(författare)
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Effective Kawakita parameters for binary mixtures
- 2009
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Ingår i: Powder Technology. - : Elsevier BV. - 0032-5910 .- 1873-328X. ; 189:2, s. 270-275
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Tidskriftsartikel (refereegranskat)abstract
- Despite the fact that many industrial processes use mixtures of powders with different physical and mechanical properties, most fundamental studies of powder compression have focused on single-component systems. There is thus an obvious need for an improved understanding of the compression behaviour of mixtures of particulate and granular solids. In this contribution, we show that the Kawakita equation may be particularly useful in this regard. The reason for this is that the degree of compression (i.e., the ratio between the volume reduction and the initial powder volume) for sufficiently high compression pressures P is a linear function of I I P. For ideal mixtures, for which the volume of each component may be determined independently of the others, this linearity implies that effective Kawakita parameters for the mixture may be readily expressed in terms of the parameters of its components. In order to validate the proposed approach, binary mixtures of mm-sized spherical agglomerates prepared by wet granulation followed by extrusion and spheronization were investigated experimentally. Predicted and measured Kawakita parameters were generally in good agreement, indicating that the assumption of ideal mixing behaviour is valid for this type of systems.
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| 12. |
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| 13. |
- Frenning, Göran, et al.
(författare)
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Spectral analysis of force fluctuations during probe penetration into cohesive powders
- 2008
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Ingår i: Powder Technology. - : Elsevier BV. - 0032-5910 .- 1873-328X. ; 187:1, s. 62-67
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Tidskriftsartikel (refereegranskat)abstract
- We investigate force fluctuations during probe penetration into cohesive powders consisting of ∼5 μm lactose particles with varying surfaceproperties prepared by spray drying. The results obtained for the more cohesive powders were remarkably similar to those previously reported fororders of magnitude larger noncohesive particles. For the less cohesive powders, the spectral densities were instead found to exhibit two distinctpower-law regions. Furthermore, the spectra were found to be independent of the geometry of the penetrating probe and dimensions of the diecavity. These findings suggest that the response is dominated by particle aggregate or agglomerate movement for the more cohesive powders,whereas the behaviour of the less cohesive ones is consistent with a response dominated by relatively weak force chains, with the fluctuations resulting from the recurring creation and collapse of jammed states being damped for length scales N0.1 mm.
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| 14. |
- Jonsson, Henrik, 1987-
(författare)
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Confined Compression of Single Particles : Development of a Novel Triaxial Testing Instrument and Particle-Scale Modelling
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- When predicting the performance of a powder compaction process, assessing the behaviour of the particles comprising the powder bed is of central relevance. Currently, however, no experimental methods are available for mimicking the multiaxial loading conditions imposed on the individual particles in a powder bed during compaction, and such analyses are therefore usually performed in silico. Thus, the purpose of this thesis is to introduce a novel experimental method that enables experimental evaluation of confined triaxial loading conditions on individual particles in the mm-scale.The work underlying the thesis consists of three major parts. Firstly, the triaxial instrument was designed and developed, after which its performance was evaluated using nominally ideal elastic-plastic spheres as model materials. These initial experiments showed that the instrument was able to successfully impose confined triaxial conditions on the particles, something that was verified by finite element method (FEM) simulations.Secondly, the triaxial instrument was used to investigate differences in deformation characteristics under uniaxial and triaxial loading conditions for four different microcrystalline cellulose (MCC)-based granules. It was shown that fragmentation, associated with unconfined uniaxial compression, was impeded under confined triaxial conditions, despite the emergence of cracks. In addition, it was observed that the primary crack always occurs in a plane parallel to the most deformed direction, and that the location of the largest pore has a pronounced influence on the path of the crack.Thirdly, the influence of different triaxial loading ratios were evaluated on polymer spheres, after which a unified description of contact pressure development was devised. Data from these experiments were then successfully used to calibrate a contact model for simulating bulk powder compression with the discrete element method (DEM).All in all, a novel experimental method has been established, which has proven useful as an alternative and complement to numerical studies when studying single particle deformation under confined triaxial conditions.
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| 15. |
- Jonsson, Henrik, 1987-, et al.
(författare)
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Crack nucleation and propagation in microcrystalline-cellulose based granules subject to uniaxial and triaxial load
- 2019
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Ingår i: International Journal of Pharmaceutics. - : Elsevier BV. - 0378-5173 .- 1873-3476. ; 559, s. 130-137
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Tidskriftsartikel (refereegranskat)abstract
- Cracking patterns in four kinds of granules, based on the common pharmaceutical excipient microcrystalline cellulose (MCC) and subject to compressive load, were examined. The initial pore structure and the location of initial failure under uniaxial compression were assessed using X-ray micro-computed tomography, whereas contact force development and onset of cracking under more complex compressive load were examined using a triaxial testing apparatus. Smoothed particle hydrodynamics (SPH) simulations were employed for numerical analysis of the stress distributions prior to cracking. For granules subject to uniaxial compression, initial cracking always occurred along the meridian and the precise location of the crack depended on the pore structure. Likewise, for granules subject to triaxial compression, the fracture plane of the primary crack was generally parallel to the dominant loading direction. The occurrence of cracking was highly dependent on the triaxiality ratio, i.e. the ratio between the punch displacements in the secondary and dominant loading directions. Compressive stresses in the lateral directions, induced by triaxial compression, prevented crack opening and fragmentation of the granule, something that could be verified by simulations. These results provide corroboration as well as further insights into previously observed differences between confined and unconfined compression of granular media.
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| 16. |
- Jonsson, Henrik, 1987-, et al.
(författare)
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Evaluation of bulk compression using a discrete element procedure calibrated with data from triaxial experiments on single particles
- 2019
-
Ingår i: Powder Technology. - : Elsevier. - 0032-5910 .- 1873-328X. ; 345, s. 74-81
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Tidskriftsartikel (refereegranskat)abstract
- Confined compression of bimodal mixtures of ideal spherical cellulose acetate (CA) particles (diameters 1.5 and 2.0 mm) was studied numerically with the discrete element method (DEM) and experimentally using a materials tester equipped with suitable tablet tooling. An extended truncated sphere contact model was used in the simulations, enabling them to be carried out to high relative densities (approaching and sometimes exceeding unity). In order to calibrate this model, the contact pressure development was extracted from prior experimental investigations on single 2.0-mm large CA particles. Results from the simulations were evaluated with the Kawakita and Heckel compression equations and compared to the corresponding data obtained from bulk compression experiments. Generally, a high degree of similarity between experiments and simulations was observed, showing the usefulness of combining confined single particle compression experiments with a suitable numerical model when predicting the performance of powder compression to high relative densities.
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| 17. |
- Mahmoodi, Foad, et al.
(författare)
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A comparison between two powder compaction parameters of plasticity : The effective medium A parameter and the Heckel 1/K parameter
- 2013
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Ingår i: International Journal of Pharmaceutics. - : Elsevier BV. - 0378-5173 .- 1873-3476. ; 453:2, s. 295-299
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of the research was to introduce a procedure to derive a powder compression parameter (EM A) representing particle yield stress using an effective medium equation and to compare the EM A parameter with the Heckel compression parameter (1/K). 16 pharmaceutical powders, including drugs and excipients, were compressed in a materials testing instrument and powder compression profiles were derived using the EM and Heckel equations. The compression profiles thus obtained could be sub-divided into regions among which one region was approximately linear and from this region, the compression parameters EM A and 1/K were calculated. A linear relationship between the EM A parameter and the 1/K parameter was obtained with a strong correlation. The slope of the plot was close to 1 (0.84) and the intercept of the plot was small in comparison to the range of parameter values obtained. The relationship between the theoretical EM A parameter and the 1/K parameter supports the interpretation of the empirical Heckel parameter as being a measure of yield stress. It is concluded that the combination of Heckel and EM equations represents a suitable procedure to derive a value of particle plasticity from powder compression data.
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| 18. |
- Mahmoodi, Foad, et al.
(författare)
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An experimental evaluation of an effective medium based compaction equation
- 2012
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 46:1-2, s. 49-55
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Tidskriftsartikel (refereegranskat)abstract
- Tablet production involves compression of free flowing powder in an enclosed cavity of defined geometry. The complexity of the powder bed system necessitates that a way be found to better understand what occurs during compression. One such approach is by means of compaction equations, of which, the Heckel and Kawakita equations are the best known. This work attempts to experimentally evaluate the applicability of the effective medium (EM) equation introduced by Frenning et al. (2009) to powder systems. Two powder types (sodium chloride and lactose monohydrate), each consisting of three size fractions (<40, 125-212 and 212-300 mu m) were characterised and compressed to a pressure of 500 MPa. These powders were chosen because of their differing mechanical properties. An invariance which is inherent in the EM equation is exposed by varying the starting points of compression, and can yield insights into compression mechanisms. Such invariant regions were observed once plastic particle deformation started to dominate the compression behaviour, and enabled the determination of the point where particle rearrangement stops.
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| 19. |
- Mahmoodi, Foad, et al.
(författare)
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Effect of lubrication on the distribution of force between spherical agglomerates during compression
- 2010
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Ingår i: Powder Technology. - : Elsevier BV. - 0032-5910 .- 1873-328X. ; 198:1, s. 69-74
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Tidskriftsartikel (refereegranskat)abstract
- We employ the carbon paper technique to aid the understanding of in die force and spatial distributions, upon compression of approximately I mm sized spherical agglomerates (pellets) of microcrystalline cellulose (MCC). The aim in this study was to test for the effect of lubricant film on force and spatial distributions. Pellets of MCC were formed via granulation and extrusion/spheronisation. Investigation of pellet bed compression was performed on a materials tester. Prior to compression studies the pellets were characterised for bulk density. size and deformability. Two pellet types were investigated; MCC and MCC lubricated with magnesium stearate. The carbon paper technique relies upon carbon paper as the medium for transferring imprints from compressed pellets onto photo quality paper. The digitised images of these imprints form the basis of analysis through the use of image processing software. Using the carbon paper technique within the range of 10-30 MPa indicates that lubrication does not have a significant effect on the distribution of forces between spherical agglomerates during uniaxial compression. Spatial analysis of the imprints revealed that the lubricated pellets exhibited a higher packing order than the unlubricated ones at low applied pressures (10 and 20 MPa), a difference that could not be observed at 30 MPa. Hence interparticle friction and/or cohesion appear to influence the initial particle rearrangement, whereas confinement is suggested to dominate at higher pressures.
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| 20. |
- Mahmoodi, Foad, et al.
(författare)
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Effect of spherical-agglomerate strength on the distribution of force during uniaxial compression
- 2011
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Ingår i: Powder Technology. - : Elsevier BV. - 0032-5910 .- 1873-328X. ; 206:3, s. 283-290
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Tidskriftsartikel (refereegranskat)abstract
- We employ the carbon paper technique with the aim of investigating the effect of spherical-agglomerate (pellet) strength on force distributions, through confined compression of approximately 1 mm sized pellets formed from microcrystalline cellulose and polyethylene glycol. The carbon paper technique relies on the transference of imprints from compressed pellets onto white photo quality paper, which are digitised and processed via image processing software. The investigated pellets can both deform plastically and develop localised cracks in response to an applied stress, while remaining largely intact during confined compression. Our results indicate that such crack formation - henceforth referred to as fracture - has a decisive influence on force distributions. Previous work on non-fracturing systems has found that the distribution of normalized forces tends to narrow with increasing particle deformation. No narrowing is observed after the point of fracture in this study and the width of the distributions - as quantified by the standard deviation of non-normalized forces - is found to increase with the difference between non-normalized mean force and fracture force. Additional corroborative results show that spatial force-force correlations typically exhibit a marked change once the fracture force is exceeded.
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| 21. |
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| 22. |
- Nilsson, Martin, et al.
(författare)
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Conductivity percolation in loosely compacted microcrystalline cellulose : An in situ study by dielectric spectroscopy during densification
- 2006
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Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 110:41, s. 20502-20506
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Tidskriftsartikel (refereegranskat)abstract
- The present study aims at contributing to a complete understanding of the water-induced ionic charge transport in cellulose. The behavior of this transport in loosely compacted microcrystalline cellulose (MCC) powder was investigated as a function of density utilizing a new type of measurement setup, allowing for dielectric spectroscopy measurement in situ during compaction. The ionic conductivity in MCC was found to increase with increasing density until a leveling-out was observed for densities above similar to 0.7 g/cm(3). Further, it was shown that the ionic conductivity vs density followed a percolation type behavior signifying the percolation of conductive paths in a 3D conducting network. The density percolation threshold was found to be between similar to 0.2 and 0.4 g/cm(3), depending strongly on the cellulose moisture content. The observed percolation behavior was attributed to the forming of interparticulate bonds in the MCC and the percolation threshold dependence on moisture was linked to the moisture dependence of particle rearrangement and plastic deformation in MCC during compaction. The obtained results add to the understanding of the density-dependent water-induced ionic transport in cellulose showing that, at given moisture content, the two major parameters determining the magnitude of the conductivity are the connectedness of the interparticluate bonds and the connectedness of pores with a diameter in the 5-20 nm size range. At densities between similar to 0.7 and 1.2 g/cm(3) both the bond and the pore networks have percolated, facilitating charge transport through the MCC compact.
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| 23. |
- Nordström, Josefina, et al.
(författare)
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Compressibility and tablet forming ability of bimodal granule mixtures : Experiments and DEM simulations
- 2018
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Ingår i: International Journal of Pharmaceutics. - : Elsevier. - 0378-5173 .- 1873-3476. ; 540:1-2, s. 120-131
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Tidskriftsartikel (refereegranskat)abstract
- Compressibility and tablet forming ability (compactibility) of bimodal mixtures of differently sized granules formed from microcrystalline cellulose were studied experimentally and numerically with the discrete element method (DEM). Compression data was analysed using the Kawakita equation. A multi-body contact law that accounts for contact dependence resulting from plastic incompressibility/geometric hardening was used in the DEM simulations. The experimental Kawakita a and 1/b parameters both depended non-monotonically on composition (weight fraction of large particles). For the a parameter, this dependence was explained by variations in the porosity of the initial granule beds; for the 1/b parameter, other factors were found to be of importance as well. The numerical results generally compared favourably with the experiments, demonstrating the usefulness of the DEM at high relative densities, provided that a suitable multi-particle contact model is used. For all mixtures, the tensile strength of the formed tablets increased with increasing applied pressure. The tensile strength generally decreased with increasing fraction of large particle, and this decrease was more rapid for large differences in particle size. A possible interpretation of these findings was proposed, in terms of differences in lateral support of small particles in the vicinity of large particles.
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| 24. |
- Nordström, Josefina, et al.
(författare)
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On the physical interpretation of the Kawakita and Adams parameters derived from confined compression of granular solids
- 2008
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Ingår i: Powder Technology. - : Elsevier BV. - 0032-5910 .- 1873-328X. ; 182:3, s. 424-435
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this paper was to investigate the physical significance of the Kawakita and Adams parameters derived from the compressionof some granular solids. Four model granules of different expected deformation behaviour were prepared by varying the composition and porosityof the granules. The granules were nearly spherical and of similar size and showed a variation in mechanical properties in terms of their elasticity,plasticity, fracture strength and brittleness. Due to the size and shape of the granules, compression due to granule rearrangement was generallylimited. The Kawakita a parameter approximated the maximal engineering strain of the granular solids and both the Kawakita a and b−1parameter reflected the plasticity of the granules. The Adams parameter τ0 seemed to reflect the initial cracking of granules. Thus, the combineduse of the Kawakita parameters a and b−1 and the Adams parameter τ0 may give a comprehensive representation of the compression behaviour ofgranular solids.
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| 25. |
- Nordström, Josefina, et al.
(författare)
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On the role of granule yield strength for the compactibility of granular solids
- 2008
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Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549 .- 1520-6017. ; 97:11, s. 4807-4814
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this article was to explore the relationship between mechanical properties of single granules and the evolution in tensile strength and tablet micro-structure. Granules of different expected deformation behavior were used as model materials. It is suggested that the role of plasticity in this context is twofold: firstly, to affect the rate of compactibility and thus the pressure range needed to reach the maximal attained tablet strength and, secondly, to affect the mode of deformation of the granules and thus the maximal attained tablet strength. A decrease in yield pressure of single granules increased the tablet tensile strength at a given compaction pressure. The yield pressure can be controlled by the granule composition and porosity.
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| 26. |
- Persson, Ann-Sofie, et al.
(författare)
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Compression analysis for assessment of pellet plasticity : Identification of reactant pores and comparison between Heckel, Kawakita, and Adams equations
- 2016
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Ingår i: Chemical engineering research & design. - : Elsevier BV. - 0263-8762 .- 1744-3563. ; 110, s. 183-191
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Tidskriftsartikel (refereegranskat)abstract
- The issue of accurate derivation of a granule yield stress by the traditional procedure using the Heckel equation in addition to the Kawakita and Adams equations has been addressed. The accuracy of the derived parameters was assessed from comparison of single-particle yield pressures from uniaxial compressions. The single-particle yield pressure was nearly four-fold higher for microcrystalline pellets of low (LP) compared to of high (HP) porosity. Heckel profiles were derived using in situ (in-die) and ex situ (out-of-die) global porosities and ex situ voidage porosities derived from mercury porosimetry of pellets and retrieved pellets from tablets. The voidage Heckel profiles enabled a clear distinction between the LP and HP pellets in contrast to the global Heckel profiles. Thus, the voidage was concluded as a better descriptor of the effective porosity of the reactant pore system than the global porosity for calculations of the Heckel numbers. Due to the challenging and tedious work of deriving precise voidage data, derivation of Kawakita b(-1) and Adams parameters remains an interesting approach for assessing granule plasticity. These clearly differentiated between the HP and LP plasticity, thus suggesting that both parameters can be used as a descriptor of pellet plasticity in analytical powder compression analysis.
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| 27. |
- Persson, Ann-Sofie
(författare)
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Flow and Compression of Granulated Powders : The Accuracy of Discrete Element Simulations and Assessment of Tablet Microstructure
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Simulations are powerful and important tools for gaining insight into powder processes. Ultimately, simulations have the potential to replace experiments. Thus, accurate models and insight into the essential factors for descriptions of powder behaviour are required. In this thesis, discrete element method (DEM) simulations of granule flow and compression were evaluated to deduce parameters and potential models essential for the experimental and numerical correspondence. In addition, the evolution in tablet microstructure during compression was studied using mercury porosimetry.Granule flow was measured using angle of repose, discharge rate, and shear. The granular flow depended primarily on particle shape and surface texture due to the mutual influence of these two parameters on the inter-particle forces. Rolling friction stabilised both the heap formation and promoted shear in the elastic quasi-static flow regime. Thus, rolling friction was established to be an essential simulation parameter for the correspondence to experiments.Current compression models often neglect the elastic compact deformation during particle loading. In this thesis, two fundamentally different models were evaluated with focus of including the elastic deformation. The first model comprised a maximal particle overlap, where elastic deformation commences. The second model accounted for the contact dependence and impingement at high relative densities. This model was based on a truncated-sphere followed by a Voronoi extension. The validity of the models was demonstrated by the elastic qualitative correspondence to experimental compressions for ductile materials.In tablets, the void (inter-granular pore) diameter was dependent on the degree of compression. Thus, the degree of compression provides an indication of the tablet microstructure. The microstructure was subsequently observed to be related to the tablet tensile strength as inferred from a percolation threshold required for formation of coherent tablets.In summary, this thesis has shed light onto the potential of simulating flow and compression of granulated pharmaceutical powders using DEM. Continuous work in the area are required to further improve the models to increase the experimental and numerical correspondence.
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| 28. |
- Persson, Ann-Sofie, et al.
(författare)
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Flowability of surface modified pharmaceutical granules : A comparative experimental and numerical study
- 2011
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 42:3, s. 199-209
-
Tidskriftsartikel (refereegranskat)abstract
- Flowability - as measured by hopper discharge rate, angle of repose and Carr's index (CI) - of surface modified microcrystalline cellulose granules was investigated experimentally. Three-dimensional simulations of the granule flow were performed, using the discrete element method (DEM), including either sliding and rolling friction or sliding friction and cohesion in the model. Granule surface modification with polymer coating and lubrication was found to have a significant effect on the sliding friction coefficient. This effect was also reflected in the ensuing flow behaviour, as quantified by the experimental discharge rate and angle of repose, whereas the results for the Cl were inconclusive. The numerical results demonstrated that granular flow was qualitatively different for non-cohesive and cohesive granules, occurring in the form of individual particles for the former and in larger clusters for the latter. Rolling friction and cohesion nevertheless affected the simulated discharge rate in a similar manner, producing results comparable to those observed experimentally and calculated with the Beverloo equation. The numerical results for the cohesive granules demonstrated that cohesion alone was sufficient to produce stable heaps. However, the agreement with experimental data was satisfactory only for the non-cohesive granules, demonstrating the importance of rolling friction.
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| 29. |
- Rudén, Jonas, et al.
(författare)
-
Effect of pressure drop on blend state-dispersibility relationships of adhesive mixtures for inhalation
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The blend state model, describing the spatial distribution of fine particles within an adhesive mixture, was investigated by varying the pressure drop (airflow) used to disperse and aerosolize budesonide containing mixtures. The dispersibility was assessed using a ScreenHaler device with a Turbuhaler mouthpiece and a next generation impactor. The pressure drop was set to 0.5, 2 or 4 kPa during the experiments. It can be concluded that in the S1 state, where the fines are situated in the cavities, the formulation disperses linearly with increased pressure drop. However, when an adhesion layer has formed on the carrier surface (i.e., the S2 state and above) a critical pressure drop must be reached to properly aerosolize the powder. Above the S2 transition, the structure of the adhesion layer, is thus more important than the pressure drop. A mixture containing inert lactose fines to saturate the S1 state, followed by addition of budesonide displayed an increase in the fine particle fraction as compared to the S1 only budesonide mixture. This provides support that the blend state model can be used as a tool to improve the optimization of adhesive mixtures for dry powder inhalers.
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| 30. |
- Rudén, Jonas, et al.
(författare)
-
Effect of pressure drop on the in vitro dispersion of adhesive mixtures of different blend states for inhalation
- 2022
-
Ingår i: International Journal of Pharmaceutics. - : Elsevier. - 0378-5173 .- 1873-3476. ; 617
-
Tidskriftsartikel (refereegranskat)abstract
- In this study, the effect of pressure drop (Delta P) on the in vitro dispersion of a series of carrier-based adhesive mixtures of different fines-to-carrier proportions, corresponding to the four different blend states of the blend state model, i.e. S1 to S3, was investigated. Four binary and one ternary adhesive mixture consisting of lactose carrier and budesonide fines and lactose fines were prepared. The dispersion was assessed using a next generation impactor (NGI) at Delta P of 0.5, 2 and 4 kPa. For the S1 mixture, where the fines were located in surface cavities of the carrier, the fine particle fraction (FPF) increased nearly linearly with Delta P. For S2 and S3 mixtures, with adhesion layers on the enveloped carrier surface, the FPF-Delta P relationships were bended and approached a plateau. Examination of powder captured in the pre-separator of the NGI led to the conclusion that the dispersion of these adhesive mixtures occurred by erosion of the adhesion layer, i.e. budesonide was liberated as single particles or micro-agglomerates. It is concluded that the FPF-Delta P relationships were dependent on the blend state and for the S2 and S3 mixtures, a critical pressure drop was identified above which the pressure drop had a limited effect on the FPF.
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| 31. |
- Rudén, Jonas, et al.
(författare)
-
Linking carrier morphology to the powder mechanics of adhesive mixtures for dry powder inhalers via a blend-state model
- 2019
-
Ingår i: International Journal of Pharmaceutics. - : Elsevier BV. - 0378-5173 .- 1873-3476. ; 561, s. 148-160
-
Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to investigate how the carrier morphology affects the expression of blend states in adhesive mixtures as a function of surface coverage ratio (SCR) and to identify where transitions between the different states occur. Adhesive mixtures of five lactose carriers with varying contents of lactose fines, corresponding to blends with different SCR ranging from 0 to 6, were produced by low-shear mixing. The powder mechanics of the mixtures were characterized by bulk density, compressibility and permeability. The appearance of the carriers and blends was studied by scanning electron microscopy, light microscopy and atomic force microscopy. The size and morphology of the carriers had a crucial impact on the evolution of the blend state, and affected the powder mechanical properties of the mixtures. It was found that smaller carriers with little or no surface irregularities were more sensitive to additions of fines resulting in self-agglomeration of fines at relatively low SCR values. On the contrary, carriers with irregular surface structures and larger sizes were able to reach higher SCR values before self-agglomeration of fines occurred. This could be attributed to an increased deagglomeration efficiency of irregular and larger carriers and to fines predominantly adhering to open pores.
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| 32. |
- Rudén, Jonas, et al.
(författare)
-
On the relationship between blend state and dispersibility of adhesive mixtures containing active pharmaceutical ingredients
- 2021
-
Ingår i: International Journal of Pharmaceutics. - : Elsevier. - 2590-1567. ; 3
-
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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| 33. |
- Rudén, Jonas
(författare)
-
Powder mechanics and dispersion properties of adhesive mixtures for dry powder inhalers : Conceptualized as a blend state model
- 2021
-
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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| 34. |
- Rudén, Jonas, et al.
(författare)
-
Relationships between surface coverage ratio and powder mechanics of binary adhesive mixtures for dry powder inhalers
- 2018
-
Ingår i: International Journal of Pharmaceutics. - : ELSEVIER SCIENCE BV. - 0378-5173 .- 1873-3476. ; 541:1-2, s. 143-156
-
Tidskriftsartikel (refereegranskat)abstract
- The aim of this paper was to study relationships between the content of fine particles and the powder mechanics of binary adhesive mixtures and link these relationships to the blend state. Mixtures with increasing amounts of fine particles (increasing surface coverage ratios (SCR)) were prepared using Lactopress SD as carrier and micro particles of lactose as fines (2.7 mu m). Indicators of unsettled bulk density, compressibility and flowability were derived and the blend state was visually examined by imaging. The powder properties studied showed relationships to the SCR characterised by stages. At low SCR, the fine particles predominantly gathered in cavities of the carriers, giving increased bulk density and unchanged or improved flow. Thereafter, increased SCR gave a deposition of particles at the enveloped carrier surface with a gradually more irregular adhesion layer leading to a reduced bulk density and a step-wise reduced flowability. The mechanics of the mixtures at a certain stage were dependent on the structure and the dynamics of the adhesion layer and transitions between the stages were controlled by the evolution of the adhesion layer. It is advisable to use techniques based on different types of flow in order to comprehensively study the mechanics of adhesive mixtures.
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| 35. |
- Sarangi, Sohan
(författare)
-
Understanding Adhesive Mixtures for Inhalation : Particle Dynamics Modelling and Segregation Experiments
- 2022
-
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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| 36. |
- An, Junxue, et al.
(författare)
-
Nanoscale characterization of PEGylated phospholipid coatings formed by spray drying on silica microparticles
- 2020
-
Ingår i: Journal of Colloid and Interface Science. - : Elsevier BV. - 0021-9797 .- 1095-7103. ; 577, s. 92-100
-
Tidskriftsartikel (refereegranskat)abstract
- Phospholipids constitute biocompatible and safe excipients for pulmonary drug delivery. They can retard the drug release and, when PEGylated, also prolong the residence time in the lung. The aim of this work was to assess the structure and coherence of phospholipid coatings formed by spray drying on hydrophilic surfaces (silica microparticles) on the nanoscale and, in particular, the effect of addition of PEGylated lipids thereon. Scanning electron microscopy showed the presence of nanoparticles of varying sizes on the microparticles with different PEGylated lipid concentrations. Atomic force microscopy confirmed the presence of a lipid coating on the spray-dried microparticles. It also revealed that the lipid-coated microparticles without PEGylated lipids had a rather homogenous coating whereas those with PEGylated lipids had a very heterogeneous coating with defects, which was corroborated by confocal laser scanning microscopy. All coated microparticles had good dispersibility without agglomerate formation, as indicated by particle size measurements. This study has demonstrated that coherent coatings of phospholipids on hydrophilic surfaces can be obtained by spray drying. However, the incorporation of PEGylated lipids in a one-step spray-drying process to prepare lipid coated microparticles with both controlled-release and stealth properties is very challenging.
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| 37. |
- Bramer, Tobias, et al.
(författare)
-
Implications of regular solution theory on the release mechanism of catanionic mixtures from gels
- 2009
-
Ingår i: Colloids and Surfaces B. - : Elsevier BV. - 0927-7765 .- 1873-4367. ; 71:2, s. 214-225
-
Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to apply the regular solution theory of mixed micelles to gain new insights on the drug release mechanism, when using catanionic mixtures as a method of obtaining prolonged release from gels. Synergistic effects were investigated at equilibrium and quantified in terms of regular solution theory interaction parameters. The drug release from catanionic aggregates was studied both in a polymer free environment, using dialysis membranes, and in gels, using a modified LISP paddle method. The drug release kinetics was modelled theoretically by combining the regular solution theory with Fick's diffusion laws assuming a contribution to the transport only from monomeric species (stationary aggregates). The theoretical predictions were found to be in reasonably good agreement with experiments. An analysis of the calculated distribution of species between aggregated and monomeric states was shown to provide further insights into the release mechanism.
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| 38. |
- Brohede, Ulrika, et al.
(författare)
-
Characterization of the drug release process by investigation of its temperature dependence
- 2004
-
Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549 .- 1520-6017. ; 93:7, s. 1796-1803
-
Tidskriftsartikel (refereegranskat)abstract
- Temperature-dependent drug release from disintegrating tablets made of NaCl-containing agglomerated micronized cellulose (AMC) granules has been studied to characterize the release process. Release measurements on tablets compacted at three different compaction pressures; 50, 100, and 200 MPa, were performed at seven different temperatures; 6, 23, 33, 43, 50, 55, and 63°C using the recently developed alternating ionic current method. Tablets compacted at different compaction pressures showed similar release rates. The release process was found to be diffusion-controlled, and the activation energy of the diffusion coefficient was comparable to that obtained for diffusion in pure water. The results show that the AMC granules in contact with water swell to a size and shape that is only slightly affected by their compaction history and the ion diffusion operates mainly within liquid-filled pores within the AMC granules. By using the temperature dependence of the release process, it was possible to reach this conclusion without any assumptions concerning the number and radii of the granules into which the tablets disintegrated. Further, the magnitude of the effective diffusion coefficient was found to be ∼7.5 · 10−10 cm2/s, which is ∼four orders of magnitude lower than for unhindered diffusion of Na+ and Cl− in water but similar to the diffusion coefficient for protons and OH− ions in microcrystalline cellulose.
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| 39. |
- Brohede, Ulrika, 1969-
(författare)
-
Drug Diffusion and Nano Excipient Formation Studied by Electrodynamic Methods
- 2007
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- New smart drugs demand new smart drug delivery systems and also new smart analysis methods for the drug delivery process and material characterization. This thesis contributes to the field by introducing a new electrodynamic approach for studying the drug diffusion proc-esses as well as the formation of a new type of drug delivery systems, the so called mesoporous nano excipients.Drug diffusion processes from different pharmaceutical materials were examined. The transport of charged drug substances was investigated by electrodynamic methods; either as a release process governed by diffusion using the alternating ionic current method or by applying a voltage, sinusoidal or dc, to force the drug ions to move in an electric field.Temperature-dependent drug release from microcrystalline cellulose tablets was examined in order to extract information about the diffu-sion process. Percolation theory was also employed to binary mixtures of an insoluble and electrically insulating matrix material together with a soluble and ionic conducting drug. Further, dielectric spectros-copy was proven to be a powerful method for examining the state of vesicle formation of drug and surfactant molecules in a carbopol gel. Finally, a new potential class of pharmaceutical materials were exam-ined, namely the AMS-n mesoporous materials, showing that the al-ternating ionic current method is powerful both in the study of the synthesis of and in the release process from these.
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| 40. |
- Brohede, Ulrika, et al.
(författare)
-
Percolative drug diffusion from cylindrical matrix systems with unsealed boundaries
- 2007
-
Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549 .- 1520-6017. ; 96:11, s. 3087-3099
-
Tidskriftsartikel (refereegranskat)abstract
- Release of NaCl in both the axial and radial directions from cylindrical ethyl cellulose tablets were investigated by the alternating ionic current method. The pore structure of the investigated binary mixtures was examined by mercury porosimetry and scanning electron microscopy, and the nm range fractal surface dimension of tablet pore walls was extracted from krypton gas adsorption isotherms. The drug release was shown to consist of two overlapping processes of which the first was ascribed to dissolution of NaCl close to the tablet boundary followed by subsequent diffusion through a thin ethyl cellulose layer and a second from which a porosity percolation threshold of 0.22 could be extracted. As well, a cross-over to effective-medium behaviour at a porosity of 0.44 was observed. The presented findings showed that drug release from matrix tablets with unsealed tablet walls substantially differs from earlier investigated release processes for which the drug has only been allowed to escape through one of the flat tablet surfaces. Thus, the present study brings forward knowledge important for the tailoring of controlled drug delivery vehicles with optimum release patterns.
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| 41. |
- Frenning, Göran, et al.
(författare)
-
A new method for characterizing the release of drugs from tablets in low liquid surroundings
- 2002
-
Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549 .- 1520-6017. ; 91:3, s. 776-784
-
Tidskriftsartikel (refereegranskat)abstract
- The purpose of this article is to introduce a method capable of determining early drug dissolution in small amounts of liquid. The method is based on the measurement of the alternating ionic current through a cell containing the dissolution medium and the substance to be dissolved. Both the initial and more prolonged absorption of liquid into tablets can also be determined by using the same technique. The method has been tested on two tablet formulations containing agglomerated micronized cellulose and NaCl as a model drug. Release of NaCl was delayed from both formulations; the extent of the delay was strongly formulation-dependent only when the surrounding liquid was in short supply. This finding shows that new drug dissolution phenomena may be encountered in small liquid volumes; these phenomena would not have been seen with the large volume methods normally used in in vitro dissolution tests. Hence, for formulations intended for sublingual, buccal, or rectal administration, i.e., in areas where liquid is scarce, in vitro dissolution tests should be performed in small volumes of dissolution medium.
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| 42. |
- Frenning, Göran
(författare)
-
A Voronoi strain-based method for granular materials and continua
- 2023
-
Ingår i: Computational particle mechanics. - : Springer Nature. - 2196-4378 .- 2196-4386. ; 10:3, s. 427-443
-
Tidskriftsartikel (refereegranskat)abstract
- In a recent article (Frenning in Comp Part Mech 24:1-4, 2021), we demonstrated that a Delaunay-based strain estimate could be used as a starting point for the development of a particle-based method for continua. In this article, we argue that the Voronoi diagram, dual to the previously used Delaunay tetrahedralization, provides a more natural description of the underlying particulate system. For this reason, a Voronoi-based estimate of the deformation gradient is derived and used to the same effect. Although the gradient vectors cease to be antisymmetric, sums over nearest neighbors vanish, which results in a formulation that not only is linearly complete but also satisfies the patch test irrespective of initial particle placement. Pairwise forces, inferred from the local (nonaffine) deformation of each bond or contact, impart a physical stabilization. Forces are obtained from a discrete Lagrangian, thus ensuring that linear and angular momenta are conserved in the absence of external forces and torques. Methods to enforce different types of boundary conditions are described; these are exact for linear displacements, for constant stresses and for free surfaces. The performance of the method is assessed in a number of numerical tests.
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| 43. |
- Frenning, Göran
(författare)
-
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
-
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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| 44. |
- Frenning, Göran
(författare)
-
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
-
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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| 45. |
- Frenning, Göran, 1970-
(författare)
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Charged Particle Transport: As Information Source about Ion Conductors, Dielectric Materials, and Drug Delivery Systems
- 2002
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis treats charged particle transport, mostly in solid materials but also, to some extent, in aqueous media. Three major types of materials have been investigated; dielectric materials, ion conductors, and drug-delivery systems.The frequency-dependent dielectric permittivity of sputtered amorphous thin film tantalum oxide (Ta2O5) has been determined by using impedance spectroscopy. A new interpolation formula has been derived, that interpolates between the two power-law regions at low and high frequencies usually observed in the dielectric spectrum. This formula is based on a regular-singular-point (RSP) analysis of the conduction process, and the power-laws in the dielectric spectrum are interpreted in terms of RSPs of the underlying rate equation for the corresponding polarization-current response function.Lithium transport properties of Ta2O5 have been analyzed by using the galvanostatic intermittent titration technique and by isothermal transient ionic current measurements. Chemical and component diffusion coefficients for intercalated lithium have been extracted. Moreover, the ion conduction process has been analyzed theoretically, and expressions for transient ionic currents derived, both for single ion-conducting layers and for three-layered structures of ion conductors.Electrical measurement techniques have also been applied to pharmaceutical systems. The alternating ionic current technique has been developed as a tool for determining the release of electrically charged drug substances in aqueous media. Tablets made of agglomerated micronized cellulose have been investigated, and sodium chloride has been used as a model drug. An attempt has been made to describe the combined drug dissolution and drug release processes in mathematical terms.
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| 46. |
- Frenning, Göran
(författare)
-
Compression mechanics of granule beds : A combined finite/discrete element study
- 2010
-
Ingår i: Chemical Engineering Science. - : Elsevier BV. - 0009-2509 .- 1873-4405. ; 65:8, s. 2464-2471
-
Tidskriftsartikel (refereegranskat)abstract
- Compression of three-dimensional beds comprising 1000 plastically deforming initially spherical granules is investigated by using the combined finite/discrete element (FE/DE) method. The material model is formulated within the framework of multiplicative plasticity, and utilizes a density-dependent elliptic yield surface that allows porous particles to both deform and to densify plastically, whereas only volume-preserving plastic deformation is possible for nonporous ones. Granules with different characteristics (yield stress and initial porosity) are studied, and the relationship between the single-granule properties and the global compression behaviour of the granule bed is investigated. It is demonstrated that the FE/DE method may shed light on the deformation and densification behaviour of individual granules, since the size and shape of each granule are continually determined as an integral part of the solution procedure, and that the method thus provides a comprehensive picture of the processes occurring during confined compression of granular materials. (C) 2010 Elsevier Ltd. All rights reserved.
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| 47. |
- Frenning, Göran, et al.
(författare)
-
Computational fluid dynamics (CFD) studies of a miniaturized dissolution system
- 2017
-
Ingår i: International Journal of Pharmaceutics. - : Elsevier BV. - 0378-5173 .- 1873-3476. ; 521:1-2, s. 274-281
-
Tidskriftsartikel (refereegranskat)abstract
- Dissolution testing is an important tool that has applications ranging from fundamental studies of drugrelease mechanisms to quality control of the final product. The rate of release of the drug from the delivery system is known to be affected by hydrodynamics. In this study we used computational fluid dynamics to simulate and investigate the hydrodynamics in a novel miniaturized dissolution method for parenteral formulations. The dissolution method is based on a rotating disc system and uses a rotating sample reservoir which is separated from the remaining dissolution medium by a nylon screen. Sample reservoirs of two sizes were investigated (SR6 and SR8) and the hydrodynamic studies were performed at rotation rates of 100, 200 and 400 rpm. The overall fluid flow was similar for all investigated cases, with a lateral upward spiraling motion and central downward motion in the form of a vortex to and through the screen. The simulations indicated that the exchange of dissolution medium between the sample reservoir and the remaining release medium was rapid for typical screens, for which almost complete mixing would be expected to occur within less than one minute at 400 rpm. The local hydrodynamic conditions in the sample reservoirs depended on their size; SR8 appeared to be relatively more affected than SR6 by the resistance to liquid flow resulting from the screen.
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| 48. |
- Frenning, Göran, et al.
(författare)
-
Dielectric and Li transport properties of electron conducting and non-conducting sputtered amorphous Ta2O5 films
- 2001
-
Ingår i: Electrochimica Acta. - 0013-4686 .- 1873-3859. ; 46:13-14, s. 2041-2046
-
Tidskriftsartikel (refereegranskat)abstract
- Two types of sputtered thin film amorphous tantalum oxide (Ta2O5) were studied: one electron conducting Ta2O5 (ec-Ta2O5) and the other non-conducting Ta2O5 (nc-Ta2O5). The as-deposited films were characterized by impedance spectroscopy (IS) and isothermal transient ionic current (ITIC) measurements. From IS, the dc conductivity 2×10−14 S/cm was obtained for the ec-Ta2O5 film at an applied ac potential of 50 mV whereas a value ≤1×10−17 S/cm was obtained for the nc-Ta2O5 film. Li conducting properties were studied using the galvanostatic intermittent titration technique and ITIC measurements on the intercalated samples. Despite the very dissimilar dc conductivities of the as-deposited films, the two Ta2O5 samples showed surprisingly similar Li ion conducting properties for small Li/Ta2O5 ratios. The Li ion mobility was in the range 1.1×10−9–3.0×10−9 cm2/V s for both films. However, the Li storage behaviour as well as the chemical diffusion coefficient differed. For the nc-Ta2O5 film a plateau was observed in the equilibrium potential vs. composition curve for Li/Ta2O5 ratios between 7×10−5 and 2×10−3. This plateau was likely to have been caused by attractive interactions between the intercalated ions, possibly large enough to cause phase separation. The attractive interactions were shown to suppress the chemical diffusion coefficient in this composition range.
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| 49. |
- Frenning, Göran, et al.
(författare)
-
Drug release modeled by dissolution, diffusion, and immobilization
- 2003
-
Ingår i: International Journal of Pharmaceutics. - 0378-5173 .- 1873-3476. ; 250:1, s. 137-145
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Tidskriftsartikel (refereegranskat)abstract
- This article presents a novel drug release model that combines drug dissolution, diffusion, and immobilization caused by adsorption of the drug to the tablet constituents. Drug dissolution is described by the well-known Noyes–Whitney equation and drug adsorption by a Langmuir–Freundlich adsorption isotherm, and these two processes are included as source and sink terms in the diffusion equation. The model is applicable to tablets that disintegrate into a number of approximately spherical fragments. In order to simplify the analysis it is assumed that liquid absorption, matrix swelling, and tablet disintegration are much faster than drug dissolution and subsequent drug release. The resulting model is shown to yield release characteristics in good agreement with those observed experimentally.
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- Frenning, Göran
(författare)
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Efficient Voronoi volume estimation for DEM simulations of granular materials under confined conditions
- 2015
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Ingår i: MethodsX. - : Elsevier BV. - 1258-780X .- 2215-0161. ; 2, s. 79-90
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Tidskriftsartikel (refereegranskat)abstract
- When the discrete element method (DEM) is used to simulate confined compression of granular materials, the need arises to estimate the void space surrounding each particle with Voronoi polyhedra. This entails recurring Voronoi tessellation with small changes in the geometry, resulting in a considerable computational overhead. To overcome this limitation, we propose a method with the following features: A local determination of the polyhedron volume is used, which considerably simplifies implementation of the method. A linear approximation of the polyhedron volume is utilised, with intermittent exact volume calculations when needed. The method allows highly accurate volume estimates to be obtained at a considerably reduced computational cost.
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