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Jonsson, H., Öhman-Mägi, C., Alderborn, G., Isaksson, P. & Frenning, G. (2019). Crack nucleation and propagation in microcrystalline-cellulose based granules subject to uniaxial and triaxial load. International Journal of Pharmaceutics, 559, 130-137
Open this publication in new window or tab >>Crack nucleation and propagation in microcrystalline-cellulose based granules subject to uniaxial and triaxial load
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2019 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 559, p. 130-137Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
Granule, Uniaxial, Triaxial, Cracking, Fragmentation
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutics
Identifiers
urn:nbn:se:uu:diva-347457 (URN)10.1016/j.ijpharm.2018.12.064 (DOI)000459871500012 ()30599228 (PubMedID)
Funder
Vinnova, 2017-02690
Note

Title in thesis list of papers: Crack nucleation and propagation in microcrystalline cellulose-based granules subject to uniaxial and triaxial load

Available from: 2018-04-03 Created: 2018-04-03 Last updated: 2019-03-21Bibliographically approved
Jonsson, H., Alderborn, G. & Frenning, G. (2019). Evaluation of bulk compression using a discrete element procedure calibrated with data from triaxial experiments on single particles. Powder Technology, 345, 74-81
Open this publication in new window or tab >>Evaluation of bulk compression using a discrete element procedure calibrated with data from triaxial experiments on single particles
2019 (English)In: Powder Technology, ISSN 0032-5910, E-ISSN 1873-328X, Vol. 345, p. 74-81Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Elsevier, 2019
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-347458 (URN)10.1016/j.powtec.2018.12.090 (DOI)000463122300008 ()
Funder
Vinnova
Note

List of authors in thesis manuscript: Henrik Jonsson, Göran Frenning

Available from: 2018-04-03 Created: 2018-04-03 Last updated: 2019-05-10Bibliographically approved
Rudén, J., Frenning, G., Bramer, T., Thalberg, K., An, J. & Alderborn, G. (2019). Linking carrier morphology to the powder mechanics of adhesive mixtures for dry powder inhalers via a blend-state model. International Journal of Pharmaceutics, 561, 148-160
Open this publication in new window or tab >>Linking carrier morphology to the powder mechanics of adhesive mixtures for dry powder inhalers via a blend-state model
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2019 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 561, p. 148-160Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
Adhesive mixture, Ordered mixture, Inhalation powder, Powder mechanics, Blend state, Powder packing, Powder flow
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-382248 (URN)10.1016/j.ijpharm.2019.02.038 (DOI)000462468700015 ()30825556 (PubMedID)
Available from: 2019-05-15 Created: 2019-05-15 Last updated: 2019-05-15Bibliographically approved
Nordström, J., Alderborn, G. & Frenning, G. (2018). Compressibility and tablet forming ability of bimodal granule mixtures: Experiments and DEM simulations. International Journal of Pharmaceutics, 540(1-2), 120-131
Open this publication in new window or tab >>Compressibility and tablet forming ability of bimodal granule mixtures: Experiments and DEM simulations
2018 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 540, no 1-2, p. 120-131Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV, 2018
Keywords
Mixture, Compressibility, Compactibility, Tensile strength, Discrete element method
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-351563 (URN)10.1016/j.ijpharm.2018.02.006 (DOI)000427584900013 ()29425765 (PubMedID)
Available from: 2018-05-30 Created: 2018-05-30 Last updated: 2018-08-20
Rudén, J., Frenning, G., Bramer, T., Thalberg, K. & Alderborn, G. (2018). Relationships between surface coverage ratio and powder mechanics of binary adhesive mixtures for dry powder inhalers. International Journal of Pharmaceutics, 541(1-2), 143-156
Open this publication in new window or tab >>Relationships between surface coverage ratio and powder mechanics of binary adhesive mixtures for dry powder inhalers
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2018 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 541, no 1-2, p. 143-156Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV, 2018
Keywords
Powder flowability, Adhesive mixture, Ordered mixture, Inhalation, Dry powder inhaler, Powder mechanics
National Category
Materials Chemistry
Identifiers
urn:nbn:se:uu:diva-353103 (URN)10.1016/j.ijpharm.2018.02.017 (DOI)000428249100016 ()29454905 (PubMedID)
Available from: 2018-06-11 Created: 2018-06-11 Last updated: 2018-06-11Bibliographically approved
Frenning, G., Ahnfelt, E., Sjögren, E. & Lennernäs, H. (2017). Computational fluid dynamics (CFD) studies of a miniaturized dissolution system. International Journal of Pharmaceutics, 521(1-2), 274-281
Open this publication in new window or tab >>Computational fluid dynamics (CFD) studies of a miniaturized dissolution system
2017 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 521, no 1-2, p. 274-281Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV, 2017
Keywords
Computational fluid dynamics, Miniaturized dissolution testing, Drug-release mechanisms
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-320019 (URN)10.1016/j.ijpharm.2017.01.072 (DOI)000397613700031 ()28189856 (PubMedID)
Funder
Swedish Research Council, 521-2011-3773
Available from: 2017-04-13 Created: 2017-04-13 Last updated: 2018-01-13Bibliographically approved
Jonsson, H., Gråsjö, J. & Frenning, G. (2017). Mechanical behaviour of ideal elastic-plastic particles subjected to different triaxial loading conditions. Powder Technology, 315, 347-355
Open this publication in new window or tab >>Mechanical behaviour of ideal elastic-plastic particles subjected to different triaxial loading conditions
2017 (English)In: Powder Technology, ISSN 0032-5910, E-ISSN 1873-328X, Vol. 315, p. 347-355Article in journal (Refereed) Published
Abstract [en]

The contact force development for two types of polymeric elastoplastic particles subjected to different triaxial loading conditions was studied experimentally utilising a unique triaxial testing apparatus. In order to evaluate the experimental results, a finite element analysis was performed. The experimental findings highlighted the importance of contact dependence, which manifested itself in two principally different ways. Firstly, a reduced stiffness was observed when plastic deformation ceased to be fully contained, which, depending on the loading conditions, occurred at an engineering strain of about 5-10%. Secondly, a markedly increased stiffness was observed when particle confinement inhibited further plastic deformation, making elastic volume reduction the predominant deformation mode. The experimental results could be well reproduced by the numerical simulations, provided that isotropic hardening was included in the elastoplastic model. In an attempt to invariantly describe the data, a nominal contact pressure was determined as a function of the volumetric constraint of the particle. This resulted in an adequate collapse of results obtained for different loading conditions onto a single master curve at large volumetric constraint. In summary, this paper should be considered as a step along the pathway towards our long term goal of introducing novel and improved contact models.

Keywords
Particle mechanics, Triaxial, Compression, Spatial confinement, Contact dependence
National Category
Applied Mechanics
Identifiers
urn:nbn:se:uu:diva-323755 (URN)10.1016/j.powtec.2017.04.005 (DOI)000401593600041 ()
Funder
Swedish Research Council, 621-2011-4049
Available from: 2017-06-13 Created: 2017-06-13 Last updated: 2018-04-12Bibliographically approved
Nyström, L., Nordström, R., Frenning, G., Saunders, B., Alvarez-Asencio, R., Rutland, M. & Malmsten, M. (2017). Peptide loaded microgels as antimicrobial surface coatings. Paper presented at 253rd National Meeting of the American-Chemical-Society (ACS) on Advanced Materials, Technologies, Systems, and Processes, APR 02-06, 2017, San Francisco, CA. Abstract of Papers of the American Chemical Society, 253
Open this publication in new window or tab >>Peptide loaded microgels as antimicrobial surface coatings
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2017 (English)In: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 253Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
American Chemical Society (ACS), 2017
National Category
Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-377531 (URN)000430568506389 ()
Conference
253rd National Meeting of the American-Chemical-Society (ACS) on Advanced Materials, Technologies, Systems, and Processes, APR 02-06, 2017, San Francisco, CA
Available from: 2019-02-25 Created: 2019-02-25 Last updated: 2019-02-25Bibliographically approved
Persson, A.-S., Nordström, J., Frenning, G. & Alderborn, G. (2016). Compression analysis for assessment of pellet plasticity: Identification of reactant pores and comparison between Heckel, Kawakita, and Adams equations. Paper presented at 7th International Granulation Workshop, JUN 29-JUL 03, 2015, Sheffield, ENGLAND. Chemical engineering research & design, 110, 183-191
Open this publication in new window or tab >>Compression analysis for assessment of pellet plasticity: Identification of reactant pores and comparison between Heckel, Kawakita, and Adams equations
2016 (English)In: Chemical engineering research & design, ISSN 0263-8762, E-ISSN 1744-3563, Vol. 110, p. 183-191Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
Compression, Heckel equation, Effective porosity, Plasticity, Kawakita equation, Adams equation
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-300565 (URN)10.1016/j.cherd.2016.01.028 (DOI)000379106600020 ()
Conference
7th International Granulation Workshop, JUN 29-JUL 03, 2015, Sheffield, ENGLAND
Available from: 2016-08-09 Created: 2016-08-09 Last updated: 2018-08-20
Jonsson, H. & Frenning, G. (2016). Investigations of single microcrystalline cellulose-based granules subjected to confined triaxial compression. Powder Technology, 289, 79-87
Open this publication in new window or tab >>Investigations of single microcrystalline cellulose-based granules subjected to confined triaxial compression
2016 (English)In: Powder Technology, ISSN 0032-5910, E-ISSN 1873-328X, Vol. 289, p. 79-87Article in journal (Refereed) Published
Abstract [en]

Confined triaxial compression of single granules was performed in order to assess the contact force development and modes of granule deformation under these conditions. In the study, four microcrystalline cellulose-based granule types of different characteristics were investigated. Results from triaxial single-granule compression experiments were evaluated using an analytical model as well as by comparison to unconfined single-granule compression and to confined bulk compression experiments. It was observed that single granules deform and densify, but tend to keep their integrity during confined triaxial compression, as evident from both compression data and from morphological analysis. Results from confined single granule compression were well represented by the analytical model. These results also largely reflected those from bulk compression experiments, including features of the force-displacement curves as well as rank order between the granule types in terms of contact stiffness. Furthermore, it was shown that intragranular porosity to a high extent governs the onset of plastic incompressibility.

Keywords
Compression, Triaxial, Hydrostatic, Single granules, Confined conditions, Contact mechanics
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-280895 (URN)10.1016/j.powtec.2015.11.051 (DOI)000370095400012 ()
Funder
Swedish Research Council, 621-2011-4049
Available from: 2016-03-16 Created: 2016-03-16 Last updated: 2018-04-12Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-4013-9704

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