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  • 1.
    Ahmed, Hamzah
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Relationship Between Crystal Structure and Mechanical Properties in Cocrystals and Salts of Paracetamol2014Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    Oral tablets are convenient and widely administered drugdosage forms.The mechanical properties of a drug substance such as plasticity, ability to cohere into compacts and friction/adhesion are important in the development of a tablet formulation. Crystal engineering is an interesting and viabletool for improving or optimizing these technical properties of a drug substance.The creation of a lternative polymorphic forms, cocrystals, salts or hydrates of a drug substance can result in structural variations in the molecular packing of the crystals and, thereby, can alter the deformation behavior of the materials.Knowledge of the relationships between crystal modifications and the technical properties in multicomponent systems is limited, but represents a possibility to predict mechanical properties based on crystalstructure that facilitates engineering particles for the optimal processing performance. The overall objective of this thesis is thus to gain better understanding of the relationships between the crystal structure features and the mechanical properties of cocrystals and salts. Paracetamol form I, its cocrystals with oxalic acid and 4,4´-bipyridine, and its hydrochloride salt were selected as model systems in the study.The materials were scaled-up using rational crystallization methods and the physical purity was confirmed. The relevant properties of these powders were determined.Tablets were then made at applied pressures of50-250 MPa under controlled conditions.The tabletability and compactability of the powders were determined. The compression mechanics of the powders were the investigated according to a material classification protocol.Slip planes were identified by visually observing the crystal structures and based on the attachment energies calculated using different force fields in the materialsstudio.The tensile strengths of the powders increased with increasing pressure and the tabletability decreased in the order oxalic acid>paracetamol-hydrochloride salt≈paracetamol-oxalic acid>4,4´-bipyridine>paracetamol-4,4´-bipyridine.The tensile strength of the tablets decreased exponentially with increasing porosity,with some exceptions.Ingeneral, the cocrystals and the salt displayed intermediate compression characteristics as compared to the reference substances.The elastic recovery of the cocrystal and salt forms of paracetamol was not markedly different from that of paracetamol.It was found that slip plane prediction based on the attachment energies was not reliable. While it was possible to explain the improved tableting properties of powders based on the crystal features (i.e. the presence of slip planes and flat layers), no clear relationship was found with yield pressure. This may be attributed to possible brittle material characteristics and the surface energies of the crystals,which need to be further studied.Thus, cocrystallization and salt formation introduced structural features that were responsible for changes in the compaction and compression properties of drug substances. In future work, we intend to extend these studies to provide a clear picture of structure-mechanical property relationships in organic molecular crystals over multiple length scales;molecules to crystals to bulk powder.Key words Crystal engineering, solid forms, cocrystals, salts, tableting, crystal structure, mechanical properties, compression analysis

  • 2.
    Ahmed, Hamzah
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Shimpi, Manishkumar R.
    Luleå University of Technology, Department of Civil, Environmental and Natural Resources Engineering, Chemical Engineering.
    Velaga, Sitaram P.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Relationship between mechanical properties and crystal structure in cocrystals and salt of paracetamol2017In: Drug Development and Industrial Pharmacy, ISSN 0363-9045, E-ISSN 1520-5762, Vol. 43, no 1, p. 89-97Article in journal (Refereed)
    Abstract [en]

    Objectives were to study mechanical properties of various solid forms of paracetamol and relate to their crystal structures. Paracetamol Form I (PRA), its cocrystals with oxalic acid (PRA-OXA) and 4,4-bipyridine (PRA-BPY) and hydrochloride salt (PRA-HCL) were selected. Cocrystals and salt were scaled-up using rational crystallization methods. The resulting materials were subjected to differential scanning solid-state characterization. The powders were sieved and 90-360 µm sieve fraction was considered. These powders were examined by scanning electron microscopy (SEM) and densities were determined. Tablets were made at applied pressures of 35-180 MPa under controlled conditions and the tablet height, diameter and hardness were measured. Tensile strength and porosity of the tablets were estimated using well known models. Crystal structures of these systems were visualized and slips planed were identified. Cocrystal and salt of PRA were physically pure. Sieved powders had comparable morphologies and particle size. The apparent and theoretical densities of powders were similar but no clear trends were observed. The tensile strengths of these compacts were increased with increasing pressure whereas tabletability decreased in the order oxalic acid > PRA-HCL ≈ PRA-OXA > BPY > PRA-BPY. Tablet tensile strength decreases exponentially with increasing porosity with the exception of PRY-BPY and BPY. Slip plane prediction based on attachment energies may not be independently considered. However, it was possible to explain the improved mechanical properties of powders based on the crystal structure. Cocrystallization and salt formation have introduced structural features that are responsible for improved tableting properties of PRA.

  • 3.
    Alhalaweh, Amjad
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Pharmaceutical cocrystals: formation mechanisms, solubility behaviour and solid-state properties2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The primary aim of pharmaceutical materials engineering is the successful formulation and process development of pharmaceutical products. The diversity of solid forms available offers attractive opportunities for tailoring material properties. In this context, pharmaceutical cocrystals, multicomponent crystalline materials with definite stoichiometries often stabilised by hydrogen bonding, have recently emerged as interesting alternative solid forms with potential for improving the physical and biopharmaceutical properties of a drug substance. There are, however, gaps in our understanding of the screening, scale-up and formulation operations required for effective use of cocrystals in drug product development. The objective of this thesis was to improve fundamental understanding of the formation mechanisms, solution behaviour and solid-state properties of pharmaceutical cocrystals. The solution chemistry and solubility behaviour of a diverse set of cocrystals were studied. It was found that the thermodynamic stability regions of the cocrystals and their components were defined by the phase solubility diagrams. Spray drying was introduced as a new method of preparing cocrystals; the formation mechanisms are illustrated. The cocrystals were more soluble than the respective drugs alone and the solubility-pH profiles were able to be predicted by mathematical models using a eutectic point determination approach. The cocrystal solubility was pH-dependent and could be engineered by the choice of coformers; this is valuable information for designing robust formulations. The solubility advantage of cocrystals was retained by the use of excipients that imparted kinetic and thermodynamic stability. The retention of drug-coformer association in processed cocrystals has been revealed, introducing a novel concept with potential implications for solid dosage form development. The final study demonstrated that the structure of the crystals and the particle engineering processes affected the solidstate and bulk particle properties of the cocrystals.This thesis contributes to the field of pharmaceutical science by advancing our understanding of crystallization processes and formulation development, thus enabling pharmaceutical cocrystals into drug products.

  • 4. Alhalaweh, Amjad
    et al.
    Ali, Hassan
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Effects of polymer and surfactant on the dissolution and transformation profiles of cocrystals in aqueous media2014In: Crystal Growth & Design, ISSN 1528-7483, E-ISSN 1528-7505, Vol. 14, no 2, p. 643-648Article in journal (Refereed)
    Abstract [en]

    Capturing solubility advantages of cocrystals is of great interest, and thus to understand the mechanism by which different excipients could maintain the supersaturation generated by cocrystals at the course of absorption in aqueous media is essential. To achieve this aim, the impact of different excipients on dissolution behavior of indomethacin-saccharin (IND-SAC) were monitored by measuring the concentrations of cocrystal components in the absence and presence of various concentration of excipients by HPLC, and solid phases were analyzed by differential scanning calorimetry after each experiment and the potential of Raman spectroscopy for monitoring phase transformations in situ was tested. No dissolution advantage was offered by cocrystals in the absence of any solution additive. The polymer and surfactant used in the study increased the solubility of IND but not SAC. This differential solubilization effect is believed to have stabilized the cocrystals for a relevant period for the absorption to take place. This could be attributed to either decreased gap between supersaturation and saturation of the drug or drug interaction with the additives. Understanding the effects of excipients type and concentration on the transformation profile is vital for designing enabling formulations for cocrystals. The eutectic constant may be useful in selecting excipients for stabilizing cocrystals.

  • 5.
    Alhalaweh, Amjad
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Alzghoul, Ahmad
    Luleå University of Technology, Department of Engineering Sciences and Mathematics, Product and Production Development.
    Kaialy, Waseem
    Chemistry and Drug Delivery Group, Medway School of Pharmacy, University of Kent.
    Data mining of solubility parameters for computational prediction of drug–excipient miscibility2014In: Drug Development and Industrial Pharmacy, ISSN 0363-9045, E-ISSN 1520-5762, Vol. 40, no 7, p. 904-909Article in journal (Refereed)
    Abstract [en]

    Computational data mining is of interest in the pharmaceutical arena for the analysis of massive amounts of data and to assist in the management and utilization of the data. In this study, a data mining approach was used to predict the miscibility of a drug and several excipients, using Hansen solubility parameters (HSPs) as the data set. The K-means clustering algorithm was applied to predict the miscibility of indomethacin with a set of more than 30 compounds based on their partial solubility parameters [dispersion forces , polar forces and hydrogen bonding ]. The miscibility of the compounds was determined experimentally, using differential scanning calorimetry (DSC), in a separate study. The results of the K-means algorithm and DSC were compared to evaluate the K-means clustering prediction performance using the HSPs three-dimensional parameters, the two-dimensional parameters such as volume-dependent solubility and hydrogen bonding , and selected single (one-dimensional) parameters. Using HSPs, the prediction of miscibility by the K-means algorithm correlated well with the DSC results, with an overall accuracy of 94%. The prediction accuracy was the same (94%) when the two-dimensional parameters or the hydrogen-bonding (one-dimensional) parameter were used. The hydrogen-bonding parameter was thus a determining factor in predicting miscibility in such set of compounds, whereas the dispersive and polar parameters had only a weak correlation. The results show that data mining approach is a valuable tool for predicting drug–excipient miscibility because it is easy to use, is time and cost-effective, and is material sparing.

  • 6.
    Alhalaweh, Amjad
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Andersson, Staffan
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Preparation of Zolmitriptan-Chitosan microparticles by spray drying for nasal delivery2009In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 38, no 3, p. 206-214Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to use spray drying to prepare mucoadhesive dry powders of the antimigraine drug, zolmitriptan, in combination with the natural polymer, chitosan, for nasal administration. The effect of type, molecular weight, and proportion of chitosan on the powder and particle characteristics was also studied. Solutions containing different proportions of chitosans were prepared and spray dried. The chemical stability and content of the drug were determined by HPLC. The morphology and size range of the microparticles were also determined. Solid-state analysis was undertaken using thermal methods (DSC/MDSC and TGA), powder X-ray diffraction (PXRD), and Fourier transform infra-red spectroscopy (FT-IR). The drug release profiles were investigated and the time required to reach maximum solution concentrations (Tmax) was used for comparison. The drug was chemically stable, with a 93-105% loading in the microparticles. The microparticles were spherical with a narrow size distribution, irrespective of the formulation. Phase separation was observed for formulations containing less than 90% (w/w) chitosan, irrespective of the type. In contrast, in the formulation containing 90% (w/w) chitosan, the drug was molecularly dispersed. FT-IR studies showed that the bands corresponding to intermolecular hydrogen bonding were broader and more diffuse when zolmitriptan was amorphous. The formation of a hydrogen bond between drug and chitosans was also observed. Tmax increased as the proportion of chitosan decreased, and was proportional to the molecular weight of the chitosan in the formulation containing 90% (w/w) chitosan. Spray drying is a suitable technique for making mucoadhesive dry powders of zolmitriptan and chitosan for nasal application. The dispersion and release of the drug was affected by the properties and composition of the chitosan.

  • 7.
    Alhalaweh, Amjad
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    George, Sumod
    Basavoju, Srinivas
    Childs, S.L.
    Renovo Research, Atlanta, GA.
    Rizvi, S.A.A.
    College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Pharmaceutical cocrystals of nitrofurantoin: Screening, characterization and crystal structure analysis2012In: CrystEngComm, ISSN 1466-8033, E-ISSN 1466-8033, Vol. 14, no 15, p. 5078-5088Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to screen and prepare cocrystals of the poorly soluble drug nitrofurantoin (NTF) with the aim of increasing its solubility. Screening for cocrystals of NTF using 47 coformers was performed by high-throughput (HT) screening using liquid assisted grinding (LAG) methods. Raman spectroscopy and powder X-ray diffraction (PXRD) were used as the primary analytical tools to identify the new crystalline solid forms. Manual LAG and reaction crystallization (RC) experiments were carried out to confirm and scale-up the hits. Seven hits were confirmed to be cocrystals. The cocrystals were characterized by PXRD, Raman and IR spectroscopy, thermal analysis (DSC and TGA) and liquid-state NMR or elemental analysis. The solution stability of the scaled-up cocrystals in water was tested by slurrying the cocrystals at 25 °C for one week. NTF forms cocrystals with a 1:1 stoichiometric ratio with urea (1), 4-hydroxybenzoic acid (2), nicotinamide (3), citric acid (4), l-proline (5) and vanillic acid (6). In addition, NTF forms a 1:2 cocrystal with vanillin (7). All but one of the NTF cocrystals transformed (dissociated) in water, resulting in NTF hydrate crystalline material or NTF hydrate plus the coformer, which indicates that the transforming cocrystals have a higher solubility than the NTF hydrate under these conditions. The crystal structures of 1:1 NTF-citric acid (4) and 1:2 NTF-vanillin (7) were solved by single-crystal X-ray diffraction. The crystal structures of these two cocrystals were analyzed in terms of their supramolecular synthons.

  • 8.
    Alhalaweh, Amjad
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    George, Sumod
    Boström, Dan
    Department of Energy Technology and Thermal Process Chemistry, Umea University.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    1:1 and 2:1 urea-succinic acid cocrystals: structural diversity, solution chemistry, and thermodynamic stability2010In: Crystal Growth & Design, ISSN 1528-7483, E-ISSN 1528-7505, Vol. 10, no 11, p. 4847-4855Article in journal (Refereed)
    Abstract [en]

    The aim of this work was to study the crystal structures of 1:1 and 2:1 urea-succinic acid (U-SA) cocrystals and to investigate the role of solution chemistry in the formation and stability of different stoichiometric cocrystals. The structural diversity of other urea-dicarboxylic acid cocrystals is also discussed. The 1:1 U-SA cocrystal was stabilized by an acid-amide heterosynthon while acid-amide heterosynthons and amide-amide homosynthons stabilized the 2:1 cocrystals. The hydrogen bonding motifs in 1:1 and 2:1 U-SA cocrystals were consistent with other urea-dicarboxylic acid systems with similar stoichiometries. The 1:1 cocrystals were transformed to 2:1 cocrystals upon slurrying in various solvents at 25 °C. The phase solubility diagram was used to define the stability regions of different solid phases in 2-propanol at 25 °C. While no phase stability region for 1:1 cocrystal could be found, the stable regions for the 2:1 cocrystals and their pure components were defined by eutectic points. The solubility of the 2:1 cocrystals was dependent on the concentration of the ligand in the solution and explained by the solubility product and 1:1 solution complexation. The mathematical models predicting the solubility of the 2:1 cocrystals were evaluated and found to fit the experimental data

  • 9.
    Alhalaweh, Amjad
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Kaialy, Waseem
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Buckton, Graham
    Department of Pharmaceutics, School of Pharmacy, University College London.
    Gill, Hardyal
    Chemistry and Drug Delivery Group, Medway School of Pharmacy, University of Kent.
    Nokhodchi, Ali
    Chemistry and Drug Delivery Group, Medway School of Pharmacy, University of Kent.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Theophylline cocrystals prepared by spray drying: physicochemical properties and aerosolization performance2013In: AAPS PharmSciTech, ISSN 1530-9932, E-ISSN 1530-9932, Vol. 14, no 1, p. 265-276Article in journal (Refereed)
    Abstract [en]

    The purpose of this work was to characterize theophylline (THF) cocrystals prepared by spray drying in terms of the physicochemical properties and inhalation performance when aerosolized from a dry powder inhaler. Cocrystals of theophylline with urea (THF-URE), saccharin (THF-SAC) and nicotinamide (THF-NIC) were prepared by spray drying. Milled THF and THF-SAC cocrystals were also used for comparison. The physical purity, particle size, particle morphology and surface energy of the materials were determined. The in vitro aerosol performance of the spray-dried cocrystals, drug-alone and a drug-carrier aerosol, was assessed. The spray-dried particles had different size distributions, morphologies and surface energies. The milled samples had higher surface energy than those prepared by spray drying. Good agreement was observed between multi-stage liquid impinger and next-generation impactor in terms of assessing spray-dried THF particles. The fine particle fractions of both formulations were similar for THF, but drug-alone formulations outperformed drug-carrier formulations for the THF cocrystals. The aerosolization performance of different THF cocrystals was within the following rank order as obtained from both drug-alone and drug-carrier formulations: THF-NIC > THF-URE > THF-SAC. It was proposed that micromeritic properties dominate over particle surface energy in terms of determining the aerosol performance of THF cocrystals. Spray drying could be a potential technique for preparing cocrystals with modified physical properties.

  • 10.
    Alhalaweh, Amjad
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Roy, Lilly
    Department of Pharmaceutical Sciences, University of Michigan.
    Rodriguez-Hornedo, Nair
    Department of Pharmaceutical Sciences, University of Michigan.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    pH-dependent solubility of indomethacin-saccharin and carbamazepine-saccharin cocrystals in aqueous media2012In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 9, no 9, p. 2605-2612Article in journal (Refereed)
    Abstract [en]

    Cocrystals constitute an important class of pharmaceutical solids for their remarkable ability to modulate solubility and pH dependence of water insoluble drugs. Here we show how cocrystals of indomethacin-saccharin (IND-SAC) and carbamazepine-saccharin (CBZ-SAC) enhance solubility and impart a pH-sensitivity different from that of the drugs. IND-SAC exhibited solubilities 13 to 65 times higher than IND at pH values of 1 to 3, whereas CBZ-SAC exhibited a 2 to 10 times higher solubility than CBZ dihydrate. Cocrystal solubility dependence on pH predicted from mathematical models using cocrystal K(sp), and cocrystal component K(a) values, was in excellent agreement with experimental measurements. The cocrystal solubility increase relative to drug was predicted to reach a limiting value for a cocrystal with two acidic components. This limiting value is determined by the ionization constants of cocrystal components. Eutectic constants are shown to be meaningful indicators of cocrystal solubility and its pH dependence. The two contributions to solubility, cocrystal lattice and solvation, were evaluated by thermal and solubility determinations. The results show that solvation is the main barrier for the aqueous solubility of these drugs and their cocrystals, which are orders of magnitude higher than their lattice barriers. Cocrystal increase in solubility is thus a result of decreasing the solvation barrier compared to that of the drug. This work demonstrates the favorable properties of cocrystals and strategies that facilitate their meaningful characterization.

  • 11.
    Alhalaweh, Amjad
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Sokolowski, Anders
    Department of Pharmaceutical Chemistry, Uppsala University.
    Rodriguez-Hornedo, Nair
    Department of Pharmaceutical Sciences, University of Michigan.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Solubility behavior and solution chemistry of indomethacin cocrystals in organic solvents2011In: Crystal Growth & Design, ISSN 1528-7483, E-ISSN 1528-7505, Vol. 11, no 9, p. 3923-3929Article in journal (Refereed)
    Abstract [en]

    The main objective of this study was to investigate the solubility behavior and solution chemistry of indomethacin-saccharin (IND-SAC) cocrystals in organic media. We also evaluated previously proposed models of cocrystal solubility in organic solvents. In addition, the solubility behavior of IND-SAC cocrystals was compared with that of indomethacin-nicotinamide (IND-NIC) cocrystals using the eutectic constant approach. Phase solubility diagrams of IND-SAC cocrystals in various solvents were generated and the transition concentrations, at which drug and cocrystals are in equilibrium with the solvents, were determined. The solubility of IND-SAC cocrystals was explained by the solubility product and solution complexation. The tested models were found to fit the experimental data and to adequately explain the solubility behavior of the cocrystals. The solution complexation of IND and SAC is negligible in ethyl acetate and low in methanol and ethanol. The IND-NIC cocrystals were more soluble than the IND-SAC cocrystals in all the solvents studied. The eutectic constants predicted both the solubility and the stability of the cocrystals. Understanding the solubility behavior and solution chemistry of cocrystals has important implications for the screening, scale-up, and formulation development of this solid form. Further, the determination of eutectic constants is a simple and resource sparing means of obtaining key information on cocrystal stability and solution behavior

  • 12.
    Alhalaweh, Amjad
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Formation of cocrystals by spray drying2010In: Journal of Pharmacy and Pharmacology (JPP), ISSN 0022-3573, E-ISSN 2042-7158, Vol. 62, no 10 - Special issue, p. 1332-1333Article in journal (Other academic)
    Abstract [en]

    Spray drying is a widely used technique for material processing and scale-up. The cocrystals formation by spray drying is studied. In contrast to solvent evaporation method, spray drying of stiochiometric solutions of incongruently saturating cocrystals had generated pure cocrystals. The formation phenomena in spray drying could be kinetically controlled or mediated by glassy state.

  • 13.
    Alhalaweh, Amjad
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Formation of cocrystals from stoichiometric solutions of incongruently saturating systems by spray drying2010In: Crystal Growth & Design, ISSN 1528-7483, E-ISSN 1528-7505, Vol. 10, no 8, p. 3302-3305Article in journal (Refereed)
    Abstract [en]

    Spray drying is a well established technique for material processing and scale-up. This study investigated the formation of pharmaceutical cocrystals by spray drying. The cocrystal formation mechanisms in spray-drying and solution methods, based on triangular phase diagrams, are discussed. The solvent evaporation of stoichiometric solutions of incongruently saturating cocrystals resulted in a mixture of phases, as dictated by the thermodynamic phase diagram. In contrast, spray drying of similar solutions of incongruently saturating systems generated pure cocrystals. It is thus suggested that the formation of cocrystals by spray drying could be kinetically controlled and/or mediated by the glassy state of the material.

  • 14.
    Alhalaweh, Amjad
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Vilinska, Annamaria
    Luleå University of Technology, Department of Civil, Environmental and Natural Resources Engineering, Sustainable Process Engineering.
    Gavini, Elisabetta
    University of Sassari.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Rassu, Giovanna
    University of Sassari.
    Surface thermodynamics of mucoadhesive dry powder formulation of zolmitriptan2011In: AAPS PharmSciTech, ISSN 1530-9932, E-ISSN 1530-9932, Vol. 12, no 4, p. 1186-1192Article in journal (Refereed)
    Abstract [en]

    Microparticle powders for nasal delivery were formulated to contain the model drug, zolmitriptan, and varying proportions of different polymers. The objective of the study was to investigate the effects of these formulative parameters on the surface chemistry of the spray-dried microparticles and their potential for adhesion to the tested substrates, porcine mucin, and nasal tissue. The polymers used were chitosans of varying ionization states and molecular weights and hydroxypropyl methyl cellulose. The surface energies of the surfaces of the microparticles were determined using contact angle measurements and the van Oss model. The theory of surface thermodynamics was applied to determine the theoretical potential for the different materials to adhere to the substrates. It was found that the drug or polymers alone, as well as the various formulations, were more likely to adhere to mucin than to nasal tissue. Further, there was a trend for higher molecular weight chitosans to adhere better to the substrates than lower molecular weight chitosans. Similarly, adhesion was improved for formulations with a higher content of polymers. These theoretical predictions may be compared with further experimental results and be of use in making informed decisions on the choice of formulations for future expensive bio-studies.

  • 15.
    AlHayali, Amani
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    In vitro-solubility and supersaturation behavior of supersaturating drug delivery systems2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The development of new pharmaceutical products has been challenged by the growing number of poorly water-soluble drugs, which often lead to suboptimal bioavailability. Various approaches, such as the use of amor-phous solid dispersions and cocrystals, have been used to improve the solu-bility, and subsequent bioavailability, of these drug molecules. Supersaturat-ing drug delivery systems (SDDSs) have potential for achieving adequate oral drug bioavailability by increasing the drug solubility and creating a su-persaturated state in the gastrointestinal tract. However, there is a need for better understanding of the supersaturation behavior in SDDSs and of the factors affecting supersaturation. The main objective of this thesis was to improve understanding of the supersaturation solubility behavior in SDDSs with a particular focus on rapidly dissolving solid forms (amorphous forms/cocrystals).

    In the course of the work, a new formulation for ezetimibe using an amorphous solid dispersion was prepared, cocrystals of tadalafil were pre-pared, and oral films of silodosin were formulated for the first time. These new formulations were thoroughly characterized using a number of solid-state and pharmaceutical characterization techniques.

    The dissolution and supersaturation behavior of the prepared SDDSs were studied. The effects of various factors on the supersaturation and precipita-tion characteristics were investigated. These factors included the preparation method, the temperature of the dissolution medium, the type of dissolution biorelevant medium (gastric/intestinal) used, the permeability of the relevant gastrointestinal membranes, the addition of polymers, and the addition of surfactants. The amorphous solid dispersions, cocrystals and oral films that were prepared represent new drug formulations that provide significantly higher dissolution rates and supersaturated solubility than crystalline drug forms. Solid dispersions prepared by the melting method had better super-saturation properties than those prepared by spray drying. The precipitation kinetics of the solid dispersion were faster at 37 ̊C than at 25 ̊C in bio-relevant media. Implementation of an absorption tool during in vitro evalua-tion of supersaturation levels could improve the prediction accuracy of su-persaturation and precipitation. A better understanding of the effects of ex-cipients on the supersaturation and precipitation behavior of these types of formulation was obtained in this thesis. The improvement in supersaturation solubility obtained by adding polymers and surfactants was not proportional to the amounts of excipient used.

    This thesis has made notable contributions to the field of pharmaceutical science by advancing our understanding of the supersaturation solubility behavior of the newly prepared SDDSs.

  • 16.
    Al-Hayali, Amani Ibraheem Younis
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Tavelin, Staffan
    Umeå university.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Dissolution and precipitation behavior of ternary solid dispersions of Ezetimibe in biorelevant media: AAPS annual meeting and Exposition2014 USA2014Conference paper (Other academic)
    Abstract [en]

    PurposeTo prepare ternary solid dispersions of Ezetimibe (EZ) and investigate their powder dissolution and precipitation behavior(supersaturation) in simulated gastric and intestinal fluidsMethodsTernary solid dispersions of EZ were prepared with PVPK30 and Poloxamer 188 at different ratios. Spray drying and meltquenching methods were used for the preparation of these solid dispersions. The solid dispersions were characterized bybasic to advanced solid-state tools including Modulated differential scanning calorimetry (MDSC), Powder X-ray diffractionand Fourier transform infrared spectroscopy .Biorelevant simulated media (FaSSIF pH 6.5 and FaSSGF pH1.6) were used tostudy the supersaturating solubility of the ternary solid dispersions. HPLC was used to determine the drug concentrationsResultsTernary solid dispersions were successfully prepared by spray drying and melt quench methods. All prepared soliddispersions showed broadening of the XRD peaks indicating amorphous nature. MDSC analysis revealed disappearance ofthe melting peak of Ezetimibe indicating that molecular dispersion of the drug in polymer matrix. The solid dispersions withhigher PVPK30 content showed single Tg at 158.54 °C (spray drying) and 169.32 °C (melt quench). About 10 folds increasein the apparent solubility was observed for solid dispersions prepared by both methods. However, melt quenched soliddispersions had maintained the supersaturation solubility in FaSSIF longer than spray dried solid dispersions. Dissolutionstudies in FaSSGF are ongoingConclusionAmorphous ternary solid dispersions of Ezetimibe containing PVP K30 and Poloxamer 188 could be prepared by spraydrying and melt quenching methods. These solid dispersions showed improved solubility and prolonged supersaturation inbiorelevant media

  • 17.
    Al-Hayali, Amani Ibraheem Younis
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Tavellin, Staffan
    Departments of Pharmacology and Clinical Neuroscience, Umeå university.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Dissolution and precipitation behavior of ternary solid dispersions of ezetimibe in biorelevant media2017In: Drug Development and Industrial Pharmacy, ISSN 0363-9045, E-ISSN 1520-5762, Vol. 43, no 1, p. 79-88Article in journal (Refereed)
    Abstract [en]

    The effects of different formulations and processes on inducing and maintaining the supersaturation of ternary solid dispersions of ezetimibe (EZ) in two biorelevant media fasted-state simulated intestinal fluid (FaSSIF) and fasted-state simulated gastric fluid (FaSSGF) at different temperatures (25˚C and 37˚C) were investigated in this work. Ternary solid dispersions of EZ were prepared by adding polymer PVP-K30 and surfactant poloxamer 188 using melt-quenching and spray-drying methods. The resulting solid dispersions were characterized using scanning electron microscopy, differential scanning calorimetry, modulated differential scanning calorimetry, powder X-ray diffraction and Fourier transformation infrared spectroscopy. The dissolution of all the ternary solid dispersions was tested in vitro under non-sink conditions. All the prepared solid dispersions were amorphous in nature. In FaSSIF at 25˚C, the melt-quenched (MQ) solid dispersions of EZ were more soluble than the spray-dried solid (SD) dispersions and supersaturation was maintained. However, at 37˚C, rapid and variable precipitation behavior was observed for all the MQ and SD formulations. In FaSSGF, the melting method resulted in better solubility than the spray-drying method at both temperatures. Ternary solid dispersions show potential for improving solubility and supersaturation. However, powder dissolution experiments of these solid dispersions of EZ at 25˚C may not predict the supersaturation behavior at physiologically relevant temperatures.  

  • 18.
    AlHayali, Amani
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Selo, Mohammed Ali
    School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College Dublin; Faculty of Pharmacy, University of Kufa, Al-Najaf, Iraq.
    Ehrhardt, Carsten
    School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College Dublin.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Investigation of supersaturation and in vitro permeation of the poorly water soluble drug ezetimibe2018In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 117, p. 147-153Article in journal (Refereed)
    Abstract [en]

    The interplay between supersaturation, precipitation and permeation characteristics of the poorly water-soluble drug ezetimibe (EZ) was investigated. Supersaturation and precipitation characteristics of EZ in the presence of Caco-2 cells were compared to those in a cell-free environment. The effect of the water-soluble polymer polyvinyl pyrrolidone (PVP-K30) on the supersaturation, precipitation and transport of EZ was also investigated and the amount of drug taken up by Caco-2 cells was quantified.

    A one-compartment setup without Caco-2 cells (i.e. in the wells of cell-culture plates) was used to mimic a non-sink in vitro dissolution chamber. The two-compartment Caco-2 cell monolayer setup (with apical and basolateral compartments) was used to investigate how the absorption of EZ affects supersaturation. EZ in varying degrees of supersaturation (DS; 10, 20, 30 and 40) was introduced into the one-compartment setup or the apical chamber of the two-compartment setup. Samples were collected at specific times to determine supersaturation, precipitation and permeation. At the end of the study, Caco-2 cells were lysed and the intracellular amount of EZ was quantified.

    In the one-compartment setup, a high DS was associated with rapid precipitation. Supersaturation was maintained for longer time periods and precipitation was lower in the presence of Caco-2 cells. There were no significant differences in the absorption rate of the drug, even at high concentrations on the apical side. Permeability coefficients for all supersaturated solutions (i.e. DS 10–40) were significantly (p < 0.05) different from those when EZ was present in crystalline form. Both concentrations of PVP-K30 (i.e. 0.05% and 0.1% w/v) improved solubility and supersaturation of EZ when added to the apical side, however, the increase in absorption at the higher concentration was not proportional. The amount of intracellular EZ increased with increasing DS in the apical side, until the saturation limit was reached in the cells (i.e. at DS 30 and higher).

    This study demonstrated that precipitation of EZ could be overestimated when supersaturation was investigated without the implementation of an absorption compartment in vitro, both in the absence and in the presence of polymer.

  • 19.
    Al-Hayali, Amani
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Selo, Mohammed Ali
    School of Pharmacy and Pharmaceutical Sciences , Trinity College Dublin .
    Ehrhardt, Carsten
    School of Pharmacy and Pharmaceutical Sciences , Trinity College Dublin .
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Investigation of supersaturation and permeation of a poorly water soluble drug Ezetimibe: Systems approaches to drug discovery, development and clinical usage2017In: Future Medicines For One World, 2017Conference paper (Refereed)
  • 20.
    Ali, Hassan
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Alhalaweh, Amjad
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Mendes, N.F.C.
    Ribeiro-Claro, Paulo
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Solid-state vibrational spectroscopic investigation of cocrystals and salt of indomethacin2012In: CrystEngComm, ISSN 1466-8033, E-ISSN 1466-8033, Vol. 14, no 20, p. 6665-6674Article in journal (Refereed)
    Abstract [en]

    Knowledge and control of the solid forms of active pharmaceutical ingredients are important aspects of drug development in the pharmaceutical industry. In this paper, the process of the molecular self-assembly of saccharin cocrystals and the 2-amino-5-methylpyridine salt of indomethacin, in terms of the hydrogen bonding patterns, has been studied in the solid-state using vibrational spectroscopy (Raman and infrared). Interaction patterns in the respective crystalline states were obtained from the single crystal data. The effects of cocrystal and salt formation on the frequencies of the vibrational modes of motion were explained by vibrational spectroscopy and supported by quantum chemical calculations at the density functional theory level, leading to unambiguous assignment of the vibrational spectra of the starting materials and their respective products. Both Raman and infrared spectroscopies were useful, reliable tools for characterizing and distinguishing the indomethacin cocrystals and salt.

  • 21.
    Ali, Hassan
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Alhalaweh, Amjad
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Vibrational spectroscopic investigation of polymorphs and cocrystals of indomethacin2013In: Drug Development and Industrial Pharmacy, ISSN 0363-9045, E-ISSN 1520-5762, Vol. 39, no 5, p. 625-634Article in journal (Refereed)
    Abstract [en]

    Context:Identification of optimal solid form of an active pharmaceutical ingredient and form control are very important in drug development. Thus, the structural information of these forms and in-depth insight on the modes of molecular interactions are necessary, and vibrational spectroscopic methods are well suited for this purpose.Objective:In-depth structural analysis of different solid forms of indomethacin (IND) using Raman and infrared (IR) spectroscopy is the objective. We have investigated the modes of molecular interactions in polymorphs (α and γ), amorphous and discovered cocrystals of IND with nicotinamide (NIC) and trans-cinnamic acid (CIN) coformers.Materials and methods: The solid forms of IND have been prepared; their purity has been verified by differential scanning calorimetry and powder X-ray diffractometry and then studied in the solid-state by Raman and IR spectroscopy. The modes of the interactions were closely investigated from the vibrational data.Results: The key vibrational features of IND solid forms have been specified. The IR (C=O) band at 1713 cm−1 attributed to cyclic acid dimer of γ IND has disappeared in IND–NIC/CIN whilst retained in IND–SAC cocrystal.Discussion:IND cocrystallizes in different conformations and crystal lattices with different coformers. The cyclic acid dimer of IND has been kept on its cocrystallization with saccharin and it could have been broken with NIC and CIN.Conclusions: The complementary nature of Raman and IR spectroscopy allowed unambiguous investigation of the chemical composition of pharmaceutical materials which is of particular importance in the absence of detailed structural information, as in the case of IND–NIC and IND–CIN.

  • 22.
    Alleso, Morten
    et al.
    Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, and Department of Food Science, Faculty of Life Sciences, University of Copenhagen.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Alhalaweh, Amjad
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Cornett, Claus
    Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, and Department of Food Science, Faculty of Life Sciences, University of Copenhagen.
    Rasmussen, Morten A.
    Department of Food Science, Faculty of Life Sciences, University of Copenhagen.
    Berg, Frans van den
    Department of Food Science, Faculty of Life Sciences, University of Copenhagen.
    Diego, Heidi Lopez de
    Analytical R and D, H. Lundbeck A/S.
    Rantanen, Jukka
    Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen.
    Near-infrared spectroscopy for cocrystal screening: a comparative study with Raman spectroscopy2008In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 80, no 20, p. 7755-7764Article in journal (Refereed)
    Abstract [en]

    Near-infrared (NIR) spectroscopy is a well-established technique for solid-state analysis, providing fast, noninvasive measurements. The use of NIR spectroscopy for polymorph screening and the associated advantages have recently been demonstrated. The objective of this work was to evaluate the analytical potential of NIR spectroscopy for cocrystal screening using Raman spectroscopy as a comparative method. Indomethacin was used as the parent molecule, while saccharin and L-aspartic acid were chosen as guest molecules. Molar ratios of 1:1 for each system were subjected to two types of preparative methods. In the case of saccharin, liquid-assisted cogrinding as well as cocrystallization from solution resulted in a stable 1:1 cocrystalline phase termed IND-SAC cocrystal. For L-aspartic acid, the solution-based method resulted in a polymorphic transition of indomethacin into the metastable a form retained in a physical mixture with the guest molecule, while liquid-assisted cogrinding did not induce any changes in the crystal lattice. The good chemical peak selectivity of Raman spectroscopy allowed a straightforward interpretation of sample data by analyzing peak positions and comparing to those of pure references. In addition, Raman spectroscopy provided additional information on the crystal structure of the IND-SAC cocrystal. The broad spectral line shapes of NIR spectra make visual interpretation of the spectra difficult, and consequently, multivariate modeling by principal component analysis (PCA) was applied. Successful use of NIR/PCA was possible only through the inclusion of a set of reference mixtures of parent and guest molecules representing possible solid-state outcomes from the cocrystal screening. The practical hurdle related to the need for reference mixtures seems to restrict the applicability of NIR spectroscopy in cocrystal screening.

  • 23.
    Alomari, Mustafa
    et al.
    UCL School of Pharmacy, University College London.
    Vuddanda, Parameswara Rao
    Luleå University of Technology, Department of Health Sciences, Medical Science. UCL School of Pharmacy, University College London.
    Trenfield, Sarah J.
    UCL School of Pharmacy, University College London.
    Dodoo, Cornelius C.
    UCL School of Pharmacy, University College London.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Basit, Abdul W.
    UCL School of Pharmacy, University College London.
    Gaisford, Simon
    UCL School of Pharmacy, University College London.
    Printing of T3 and T4 Oral Drug Combinations as a Novel Strategy for Hypothyroidism2018In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 549, no 1-2, p. 363-369Article in journal (Refereed)
    Abstract [en]

    Hypothyroidism is a chronic and debilitating disease that is estimated to affect 3% of the general population. Clinical experience has highlighted the synergistic value of combining triiodothyronine (T3) and thyroxine (T4) for persistent or recurrent symptoms. However, thus far a platform that enables the simultaneous and independent dosing of more than one drug for oral administration has not been developed. Thermal inkjet (TIJ) printing is a potential solution to enable the dual deposition of T3 and T4 onto orodispersible films (ODFs) for therapy personalisation. In this study, a two-cartridge TIJ printer was modified such that it could print separate solutions of T3 and T4. Dose adjustments were achieved by printing solutions adjacent to each other, enabling therapeutic T3 (15–50 μg) and T4 dosages (60–180 μg) to be successfully printed. Excellent linearity was observed between the theoretical and measured dose for both T3 and T4 (R2 = 0.982 and 0.985, respectively) by changing the length of the print objective (Y-value). Rapid disintegration of the ODFs was achieved (< 45 seconds). As such, this study for the first time demonstrates the ability to produce personalised dose combinations by TIJ printing T3 and T4 onto the same substrate for oral administration.

  • 24.
    Andersen, Anders J.
    et al.
    PolyPeptide Laboratories.
    Frokjaer, Sven
    Danish University of Pharmaceutical Sciences.
    Weert, Marco van de
    Danish University of Pharmaceutical Sciences.
    Yang, Mingshi
    Danish University of Pharmaceutical Sciences.
    Fomsgaard, Jens
    PolyPeptide Laboratories.
    Hovgaard, Lars
    Danish University of Pharmaceutical Sciences.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Characterization of salmon calcitonin in spray-dried powder for inhalation: effect of formulation and process variables2006In: 2006 AAPS Annual Meeting and Exposition, American Association of Pharmaceutical Scientists , 2006Conference paper (Refereed)
    Abstract [en]

    To characterize physicochemical properties of salmon calcitonin in spray-dried powder for inhalation and understand the interplay between stability, formulation and process parametersSalmon calcitonin (sCT) was spray-dried together with mannitol and chitosan that acts as stabiliser and absorption enhancer, respectively. Two process variables, i.e. inlet temperature and atomizing air volumetric flow rate, were investigated. Solid state properties of the spray-dried powders were characterized using SEM, TGA, XRPD and DSC. The physicochemical stability of salmon calcitonin in the dry powder was investigated by FTIR, HPLC and LC-MS techniques.A high yield of up to 80 % spray-dried powder was obtained with an improved cyclone assembled with B-290 Mini Spray Drier. Nevertheless, the yield was markedly reduced when addition of chitosan exceeded a certain proportion in spray drying formulation. XRPD and DSC results indicated that crystallinity of mannitol was inhibited with an increase of chitosan in the formulation. Residual moisture levels in the spray dried powders were 1-2%. As indicated by FTIR analysis, sCT retained its structural integrity under the spray drying conditions studied, i.e. 100-180 ºC inlet temperature and 357-742 L/h atomizing air volumetric flow rate. Addition of mannitol and chitosan in the spray drying formulation did not improve stabilization of sCT, in which around 7 % degraded impurities were found at a condition of 180 ºC inlet temperature. Yet no obvious degraded impurities were found in plain sCT spray-dried powder under the conditions studied. The LC-MS analysis showed that oxidation was the main degradation pathway at high inlet temperature. Other minor impurities originated from deamidation of Asn26, N-O acyl migration on Ser29 and dimerization by cross-linkage of the disulfide bonds. Two fragments, i.e. H-(Cys1-Gly28)-OH and H-(Ser29-Pro32)-NH2, could also be found when the degraded ester bond between Gly28 and Ser29 was further hydrolysed in phosphate buffer.Salmon calcitonin can be spray-dried into dry powders with good physical integrity under certain conditions. Chemical stability of sCT in spray-dried powder could be improved by the optimization of formulation and process variables.

  • 25.
    Andersson, Mikael
    et al.
    Department of Neuroscience, Physiotherapy, Uppsala University.
    Stridsman, Caroline
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Rönmark, Eva
    National Institute for Working Life, Norrbottens Läns Landsting, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine, The OLIN Unit, Umeå University, Karolinska Institutet, Lung and Allergy Research.
    Lindberg, Anne
    Norrbottens Läns Landsting, OLIN studies, Sunderby Hospital, Sunderby sjukhus, Luleå, Department of Public Health and Clinical Medicine, Division of Medicine, Umeå University.
    Emtner, Margareta
    Department of Neuroscience, Physiotherapy, Uppsala University.
    Physical activity and fatigue in chronic obstructive pulmonary disease: A population based study2015In: Respiratory Medicine, ISSN 0954-6111, E-ISSN 1532-3064, Vol. 109, no 8, p. 1048-1057Article in journal (Refereed)
    Abstract [en]

    Background In subjects with chronic obstructive pulmonary disease (COPD), symptoms of fatigue, concomitant heart disease and low physical activity levels are more frequently described than in subjects without COPD. However, there are no population-based studies addressing the relationship between physical activity, fatigue and heart disease in COPD. The aim was to compare physical activity levels among subjects with and without COPD in a population based study, and to evaluate if concomitant heart disease and fatigue was associated to physical activity. Methods In this, 470 subjects with COPD and 659 subjects without COPD (non-COPD) participated in examinations including structured interview and spirometry. A ratio of the forced expiratory volume in one second (FEV1)/best of forced vital capacity (FVC) and vital capacity (VC) < 0.7 was used to define COPD. Physical activity was assessed with the International Physical Activity Questionnaire (IPAQ), and fatigue with the Functional Assessment of Chronic Illness Therapy - Fatigue scale (FACIT-F). Results The prevalence of low physical activity was higher among subjects with FEV1 < 80% predicted compared to non-COPD subjects (22.4% vs. 14.6%, p=0.041). The factors most strongly associated with low physical activity in subjects with COPD were older age, OR 1.52, (95% CI 1.12 – 2.06), a history of heart disease, OR 2.11 (1.10 - 4.08), and clinically significant fatigue, OR 2.33 (1.31 - 4.13); while obesity was the only significant factor among non-COPD subjects, OR 2.26 (1.17 – 4.35). Conclusion Physical activity levels are reduced when lung function is decreased below 80% of predicted, and the factors associated with low physical activity are different among subject with and without COPD. We propose that the presence of fatigue and heart disease are useful to evaluate when identifying subjects for pulmonary rehabilitation.

  • 26.
    Andersson, Staffan
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Långtidsregistrering av fysiologiska mätsignaler: igår idag och i morgon2005In: Klinisk fysiologi: dåtid, nutid och framtid, Luleå: Luleå tekniska universitet, 2005, p. 164-170Chapter in book (Other academic)
  • 27.
    Andersson, Staffan
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Sundström, G
    Njurar och urinvägar2005In: Klinisk fysiologi: med nuklearmedicin och klinisk neurofysiologi, Stockholm: College of Liberal Arts and Sciences, 2005, 2. uppl., p. 292-310Chapter in book (Other (popular science, discussion, etc.))
  • 28.
    Andersson, Staffan
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Tigerman, B
    Kvalitetsundersökning av svenska bredbandsnätet med avseende på datatransmission 12-grupplänkar: Analys av mätmetoder1974Report (Other (popular science, discussion, etc.))
  • 29.
    Andersson, Staffan
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Tigerman, B
    Kvalitetsundersökning av svenska bredbandsnätet med avseende på datatransmission över 12-grupplänkar: Mätmetoder och dataunderlag1974Report (Other (popular science, discussion, etc.))
  • 30.
    Antzutkin, Oleg
    et al.
    Luleå University of Technology, Department of Civil, Environmental and Natural Resources Engineering, Sustainable Process Engineering.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Wong, Alan
    Physics Department, University of Warwick, Coventry, UK CV4 7AL.
    Dupree, Ray
    Physics Department, University of Warwick, Coventry, UK CV4 7AL.
    Solid-state 17O, 13C and 15N NMR: from tackling structure of Alzheimer's Aβ fibrils to studies on anti-inflammatory drugs, Indomethacin-saccharin cocrystal2007Conference paper (Other academic)
  • 31.
    Ariane, Mostapha
    et al.
    School of Chemical Engineering, University of Birmingham.
    Kassinos, Stavros
    Department of Mechanical and Manufacturing Engineering, University of Cyprus.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Alexiadis, Alessio
    School of Chemical Engineering, University of Birmingham.
    Discrete multi-physics simulations of diffusive and convective mass transfer in boundary layers containing motile cilia in lungs2018In: Computers in Biology and Medicine, ISSN 0010-4825, E-ISSN 1879-0534, Vol. 95, p. 34-42Article in journal (Refereed)
    Abstract [en]

    In this paper, the mass transfer coefficient (permeability) of boundary layers containing motile cilia is investigated by means of discrete multi-physics. The idea is to understand the main mechanisms of mass transport occurring in a ciliated-layer; one specific application being inhaled drugs in the respiratory epithelium. The effect of drug diffusivity, cilia beat frequency and cilia flexibility is studied. Our results show the existence of three mass transfer regimes. A low frequency regime, which we called shielding regime, where the presence of the cilia hinders mass transport; an intermediate frequency regime, which we have called diffusive regime, where diffusion is the controlling mechanism; and a high frequency regime, which we have called convective regime, where the degree of bending of the cilia seems to be the most important factor controlling mass transfer in the ciliated-layer. Since the flexibility of the cilia and the frequency of the beat changes with age and health conditions, the knowledge of these three regimes allows prediction of how mass transfer varies with these factors.

  • 32.
    Basavoju, Srinivas
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Boström, Dan
    Umeå universitet.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Crystal Structures of Hydrates of Norfloxacin2006In: 2006 AAPS Annual Meeting and Exposition, American Association of Pharmaceutical Scientists , 2006Conference paper (Refereed)
    Abstract [en]

    Description: Purpose: The aim was to identify new phases of norfloxacin and to analyse their crystal structures. Methods: Norfloxacin was crystallized in methanol under various conditions using solvent-drop grinding method. The single crystal X-ray diffraction data sets were collected on a Bruker Nonius Kappa CCD, using Mo Kα radiation (λ = 0.71073 Å). Results: Norfloxacin mono-and trihydrates were identified. Mono and trihydrates crystallize in Pbca, P21/c space groups respectively. One of the water molecules in trihydrate is in disorder. In these structures, inversion related norfloxacin molecules form stacked layers with quinolone moieties and stabilized by ππ (3.449 to 4.016 Å) interactions. The norfloxacin molecules in stacked layers generate hydrophilic channels to include water molecules through O-HO, O-HO¯ and N-HO¯ interactions. A significant difference in the torsional angles of the piperazinyl ring of norfloxacin in mono-, di- (reported), and trihydrate was evident for conformational flexibility. Conclusion: We report crystal structures of mono and trihydrates of norfloxacin that are channel hydrates. Norfloxacin may exhibit conformational polymorphism

  • 33.
    Basavoju, Srinivas
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Boström, Dan
    Energy Technology and Thermal Process Chemistry, Umeå University.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Indomethacin-saccharin cocrystal: design, synthesis and preliminary pharmaceutical characterization2008In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 25, no 3, p. 530-41Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To design and prepare cocrystals of indomethacin using crystal engineering approaches, with the ultimate objective of improving the physical properties of indomethacin, especially solubility and dissolution rate. MATERIALS AND METHODS: Various cocrystal formers, including saccharin, were used in endeavours to obtain indomethacin cocrystals by slow evaporation from a series of solvents. The melting point of crystalline phases was determined. The potential cocrystalline phase was characterized by DSC, IR, Raman and PXRD techniques. The indomethacin-saccharin cocrystal (hereafter IND-SAC cocrystal) structure was determined from single crystal X-ray diffraction data. Pharmaceutically relevant properties such as the dissolution rate and dynamic vapour sorption (DVS) of the IND-SAC cocrystal were evaluated. Solid state and liquid-assisted (solvent-drop) cogrinding methods were also applied to indomethacin and saccharin. RESULTS: The IND-SAC cocrystals were obtained from ethyl acetate. Physical characterization showed that the IND-SAC cocrystal is unique vis-a-vis thermal, spectroscopic and X-ray diffraction properties. The cocrystals were obtained in a 1:1 ratio with a carboxylic acid and imide dimer synthons. The dissolution rate of IND-SAC cocrystal system was considerably faster than that of the stable indomethacin gamma-form. DVS studies indicated that the cocrystals gained less than 0.05% in weight at 98%RH. IND-SAC cocrystal was also obtained by solid state and liquid-assisted cogrinding methods. CONCLUSIONS: The IND-SAC cocrystal was formed with a unique and interesting carboxylic acid and imide dimer synthons interconnected by weak N-Hcdots, three dots, centeredO hydrogen bonds. The cocrystals were non-hygroscopic and were associated with a significantly faster dissolution rate than indomethacin (gamma-form).

  • 34.
    Basavoju, Srinivas
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Boström, Dan
    Energy Technology and Thermal Process Chemistry, Umeå University.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Pharmaceutical cocrystal and salts of norfloxacin2006In: Crystal Growth & Design, ISSN 1528-7483, E-ISSN 1528-7505, Vol. 6, no 12, p. 2699-2708Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate the structural and pharmaceutical properties of norfloxacin (a poorly soluble antibacterial drug), its cocrystal, and salts. Norfloxacin in the anhydrous form (form A, 1) was crystallized. It was cocrystallized with isonicotinamide (2), and organic salts were prepared with succinic acid, malonic acid, and maleic acid (3-5, respectively). These phases were characterized by differential scanning calorimetry (DSC), infrared (IR) and Raman spectroscopy, and powder X-ray diffraction (PXRD). Single-crystal X-ray diffraction data were obtained, and crystal structures were solved. The apparent solubility of these phases was determined. Robust O-H⋯O, O-H⋯O-, O-H⋯N, N-H⋯O, N+-H-O -, and N-H⋯N interactions were present in all these structures. Quinolone moieties in these structures stack with π⋯π interactions and form channels to include CHCl3 or H2O. Herein we report a new cocrystal and salts of norfloxacin with improved aqueous solubility

  • 35.
    Basavoju, Srinivas
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Boström, Dan
    Energy Technology and Thermal Process Chemistry, Umeå University.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Pharmaceutical salts of fluoroquinolone antibacterial drugs with acesulfame sweetener2012In: Molecular Crystals and Liquid Crystals, ISSN 1542-1406, E-ISSN 1563-5287, Vol. 562, no 1, p. 254-264Article in journal (Refereed)
    Abstract [en]

    Novel organic salts of norfloxacin and ciprofloxacin with artificial sweeteners such as saccharin and acesulfame were prepared. The two salts 1 and 2 were characterized by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). Finally, the crystal structures were solved by single crystal X-ray diffraction data and the structures were analyzed in terms of supramolecular synthons. In norfloxacin acesulfamate 1, two norfloxacin cations and two acesulfame anions form an eight membered cyclic tetramer supramolecular synthon. The salt, ciprofloxacin acesulfamate 2, has a similar structure as salt 1. This study contributes the importance of crystal engineering and supramolecular chemistry to the pharmaceutical applications in terms of interactions and structural correlations in the design of new solid phases. Supplemental materials are available for this article. Go to the publisher's online edition of Molecular Crystals and Liquid Crystals to view the free supplemental file

  • 36.
    Basavoju, Srinivas
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Khan, Wasim
    Biovitrum AB, Stockholm.
    Boström, Dan
    Umeå universitet.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Pharmaceutical Co-crystallization of Norfloxacin2006In: 2006 AAPS Annual Meeting and Exposition, American Association of Pharmaceutical Scientists , 2006Conference paper (Refereed)
    Abstract [en]

    Description: Aim: The objective of the study was to prepare co-crystal and salts of norfloxacin and to investigate their structural and pharmaceutical properties. Methods: Norfloxacin was crystallized in a series of solvents in an effort to investigate the polymorphism. Norfloxacin was also co-crystallized with isonicotinamide and succinic acid in different solvents. We have characterised these materials using DSC, IR, Raman and PXRD. The single crystal X-ray diffraction data was obtained and crystal structures were solved. The solubility and moisture sorption behaviour (0-90%RH) of these materials were determined. Results: Norfloxacin Anhydrate, 1 crystallizes in the triclinic P-1 space group with one neutral molecule in the asymmetric unit. The carboxylic acid group participates in the intramolecular O­­-HO (D=2.525 Å) hydrogen bonding with carbonyl group of the quinolone moiety. NorfloxacinIsonicotinamideCHCl3, 2 crystallizes in the centrosymmetric C2/c space group with one molecule of norfloxacin, one molecule of isonicotinamide and one molecule of CHCl3.in the asymmetric unit. Four molecules of norfloxacin generate a rectangular host type network with N-HO (D=2.668 Å) and N-HO (D=2.657 Å) interactions. Two isonicotinamide molecules form robust amideamide (N-HO, D=2.889 Å) homodimer synthon and fits into the rectangular grid (N-HO, D=2.929 Å). The CHCl3 molecules lie in the channels of the host frame work. Norfloxacin (Succinate)0.5 Hydrate, 3 crystallizes in the triclinic P-1 space group with one norfloxacin cation, half molecule of succinate dianion and one H2O molecule in the asymmetric unit. The two succinate anions and two norfloxacin cations form a cyclic tetramer synthon (N-HO, D=2.726 Å) and extends with H2O molecules through the hydrophilic channel generated by quinolone stacked layers (ππ, 4.041 Å) along the a-axis via O-HO (D=2.928 Å) interactions. The rank order of the solubility of these materials was 1<2

  • 37.
    Bejarano, J.
    et al.
    Advanced Center for Chronic Diseases (ACCDiS), Facultad Ciencias Químicas y Farmaceuticas, Universidad de Chile, Santiago, Chile.
    Navarro-Marquez, M.
    Advanced Center for Chronic Diseases (ACCDiS), Facultad Ciencias Químicas y Farmaceuticas, Universidad de Chile, Santiago, Chile.
    Morales-Zavala, F.
    Advanced Center for Chronic Diseases (ACCDiS), Facultad Ciencias Químicas y Farmaceuticas, Universidad de Chile, Santiago, Chile.
    Morales, Javier O.
    Luleå University of Technology, Department of Health Sciences, Medical Science. Advanced Center for Chronic Diseases (ACCDiS), Facultad Ciencias Químicas y Farmaceuticas, Universidad de Chile, Santiago, Chile; Departamento de Ciencias y Tecnología Farmacéuticas, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.
    Garcia-Carvajal, I.
    Advanced Center for Chronic Diseases (ACCDiS), Facultad Ciencias Químicas y Farmaceuticas, Universidad de Chile, Santiago, Chile.
    Araya-Fuentes, E.
    Advanced Center for Chronic Diseases (ACCDiS), Facultad Ciencias Químicas y Farmaceuticas, Universidad de Chile, Santiago, Chile; Departamento de Ciencias Quimicas, Facultad de Ciencias Exactas, Universidad Andres Bello, Santiago, Chile.
    Flores, Y.
    Advanced Center for Chronic Diseases (ACCDiS), Facultad Ciencias Químicas y Farmaceuticas, Universidad de Chile, Santiago, Chile.
    Verdejo, H.E.
    Advanced Center for Chronic Diseases (ACCDiS), División de Enfermedades Cardiovasculares, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
    Castro, P.F.
    Advanced Center for Chronic Diseases (ACCDiS), División de Enfermedades Cardiovasculares, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
    Lavandero, S.
    Advanced Center for Chronic Diseases (ACCDiS), Facultad Ciencias Químicas y Farmaceuticas, Universidad de Chile, Santiago, Chile; Advanced Center for Chronic Diseases (ACCDiS), Centro de Estudios en Ejercicio, Metabolismo y Cáncer (CEMC), Instituto de Ciencias Biomedicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile; Department of Internal Medicine (Cardiology Division), University of Texas Southwestern Medical Center, Dallas, TX, United States.
    Kogan, M.J.
    Advanced Center for Chronic Diseases (ACCDiS), Facultad Ciencias Químicas y Farmaceuticas, Universidad de Chile, Santiago, Chile; Departamento de Química Farmacológica y Toxicológica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Chile.
    Nanoparticles for diagnosis and therapy of atherosclerosis and myocardial infarction: evolution toward prospective theranostic approaches2018In: Theranostics, ISSN 1838-7640, E-ISSN 1838-7640, no 17, p. 4710-4732Article in journal (Refereed)
    Abstract [en]

    Cardiovascular diseases are the leading cause of death worldwide. Despite preventive efforts, early detection of atherosclerosis, the common pathophysiological mechanism underlying cardiovascular diseases remains elusive, and overt coronary artery disease or myocardial infarction is often the first clinical manifestation. Nanoparticles represent a novel strategy for prevention, diagnosis, and treatment of atherosclerosis, and new multifunctional nanoparticles with combined diagnostic and therapeutic capacities hold the promise for theranostic approaches to this disease. This review focuses on the development of nanosystems for therapy and diagnosis of subclinical atherosclerosis, coronary artery disease, and myocardial infarction and the evolution of nanosystems as theranostic tools. We also discuss the use of nanoparticles in noninvasive imaging, targeted drug delivery, photothermal therapies together with the challenges faced by nanosystems during clinical translation.

  • 38.
    Berg, Christer
    et al.
    School of Pure and Applied Natural Sciences, University of Kalmar.
    Haupt, Dan
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Ekedahl, Anders
    School of Pure and Applied Natural Sciences, University of Kalmar.
    Prescriptions on split tablets: a common drug related problem - but unnecessary?2007In: Tackling inequalities in the delivery of of pharmaceutical care: 7th ESCP Spring conference on clinical pharmacy : Edinburgh, 16-19 May 2007, ESCP , 2007, p. 16-Conference paper (Refereed)
  • 39.
    Berggren, Ida
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Stange, Josefina
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Magnetresonanstomografi vid diagnostisering av misstänkt scaphoideumfraktur: - fördelar med den tidiga undersökningen2018Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Inledning: Det är omkring 30 % av alla scaphoideumfrakturer som i dag inte går att identifiera med den första konventionella radiologiska undersökningen. Vid misstänkt fraktur på scaphoideum börjar man med en klinisk undersökning av patienten, och går sen vidare med en konventionell röntgenundersökning för att kunna utesluta eller bekräfta eventuell fraktur.Dock är det klargjort att alla skadorna inte syns initialt på röntgenbilderna, vilket leder till att det blir svårt att ställa en säker diagnos av dessa patienter. MR-undersökningar kan vid behov användas för att kunna fastställa en diagnos. Syfte: Syftet med studien var att sammanställa kunskap kring vilka fördelar en tidig magnetresonanstomografiundersökning har vid en misstänkt scaphoideumfraktur. Metod: Studien genomfördes som en allmän litteraturstudie. Tio artiklarkvalitetsgranskades, analyserades och resultatet presenterades i kategorier. Resultat: Resultatet visade att de scaphoideumfrakturer som de konventionella röntgenbilderna inte kunde identifiera gick att identifiera med en tidig MR-undersökning. Det gick även att identifiera mjukdelsskador vilket medverkade till att patienten fick behandling utifrån diagnos. Dessutom visade resultatet att totalkostnaderna inte skiljer sig åt mellan konventionellt röntgenundersökta patienter gentemot MR-undersökta patienter. Det anses vara viktigt att radiologen har goda erfarenheter av att bedöma MR-bilder.Konklusion:Tidig MR-undersökning av en misstänkt scaphoideumfraktur påverkar hur patientens behandling utformas. Med en tidig undersökning kan patienter få en definitiv diagnos och därmed inte behöva vänta tills det är dags för en efterkontroll. Vidare forskning anses nödvändigt inom området där det undersöks hur patienter i Sverige påverkas av undersökningsförändringen med en tidig MR-undersökning, vid misstänkt scaphoideumfraktur.

  • 40.
    Biasca, Nicola
    et al.
    Spital Oberengadin, Orthopaedic Clinic.
    Agosti, Reto
    Headache Center Hirslanden, Zurich.
    Tegner, Yelverton
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Battaglia, Hugo
    SUVA, Luzern.
    Gerber, Christian
    University of Zürich, Department of Orthopedics.
    Procedure after minor traumatic brain injury (mTBI) in ice hockey to prevent neurological sequele2004In: Safety in ice hockey, fourth volume: [papers presented at the Fourth Symposium on Ice Hockey held 5 - 6 May 2002 in Pittsburgh, Pennsylvania] / [ed] David J. Pearsall; Alan B. Ashare, West Conshohocken, Pa: ASTM International, 2004Conference paper (Other academic)
  • 41.
    Biasca, Nicola
    et al.
    Spital Oberengadin, Orthopaedic Clinic.
    Agosti, Reto
    Headache Center Hirslanden, Zurich.
    Tegner, Yelverton
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Battaglia, Hugo
    SUVA, Luzern.
    Gerber, Christian
    University of Zürich, Department of Orthopedics.
    Procedures after minor traumatic brain injury (mTBI) in ice hockey to prevent neurological sequelae2001In: British Journal of Sports Medicine, ISSN 0306-3674, E-ISSN 1473-0480, Vol. 35, no 5, p. 367-Article in journal (Other academic)
  • 42.
    Biasca, Nicola
    et al.
    Spital Oberengadin, Orthopaedic Surgery and Trauma Surgery.
    Lorentzon, Ronny
    Umeå University, Department of Musculoskeletal Research.
    Tegner, Yelverton
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Montag, Wolf-Dieter
    Injury report system2000In: Safety in ice hockey: third volume / [ed] Alan B. Ashare, West Conshohocken, Pa: ASTM International, 2000, p. 44-62Conference paper (Refereed)
  • 43.
    Biasca, Nicola
    et al.
    Spital Oberengadin, Orthopaedic Surgery and Trauma Surgery.
    Tegner, Yelverton
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    International sports injury system: ISIS2001In: Sports medicine & hockey: a summit for the NHL and beyond, AOSSM , 2001, p. 15-36Conference paper (Refereed)
  • 44.
    Biasca, Nicola
    et al.
    Spital Oberengadin, Clinic of Orthopedic Surgery, Trauma Surgery, and Sports Medicine, Department of Surgery.
    Wirth, Stephan
    Spital Oberengadin, Orthopaedic Clinic.
    Tegner, Yelverton
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Head injuries and facial injuries in ice hockey: role of the protective equipment2005In: European Journal of Trauma, ISSN 1439-0590, E-ISSN 1615-3146, Vol. 31, no 4, p. 369-75Article in journal (Refereed)
    Abstract [en]

    Background and Purpose: Despite a decreasing tendency of head and facial injuries in ice hockey the number of these injuries still seems to be too high. The purpose of this prospective investigation was to study the mechanism of facial and eye injuries as well as the role of protective equipment and revised rules. Methods: A prospective epidemiologic analysis of ice hockey-related injuries in the two highest-ranking Swiss Ice Hockey Leagues-League A (NLA) and B (NLB)-was performed by the Swiss Medical Committee during the two seasons 1996 and 1997. Results: A total of 392 injuries occurred during games or practice. Head injuries and facial injuries made up 26% of these injuries. Most of these injuries were classified as minor injuries. All eye injuries occurred in players either not wearing visors at all or wearing the visor incorrectly. Most injuries were caused by the illegal use of sticks. Conclusion: Most head injuries and facial injuries could be prevented by wearing helmet and visor correctly and by playing the game according to the rules

  • 45.
    Biasca, Nicola
    et al.
    Spital Oberengadin, Orthopaedic Surgery and Trauma Surgery.
    Wirth, Stephan
    Spital Oberengadin, Orthopaedic Clinic.
    Tegner, Yelverton
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    The avoidability of head and neck injuries in ice hockey: an historical review2002In: British Journal of Sports Medicine, ISSN 0306-3674, E-ISSN 1473-0480, Vol. 36, no 6, p. 410-27Article in journal (Refereed)
    Abstract [en]

    The number of minor traumatic brain injury (mTBI), cerebral concussions, is increasing and cannot be eliminated by any kind of equipment. Prevention strategies, such as the introduction of "checking from behind" rules have become effective in decreasing the number of severe spinal injuries. A new "head checking" rule should reduce mTBI in the same way in the following years. Mouthguards should be mandatory as an effective device for the prevention of dental and orofacial injuries, as well as reducing the incidence and severity of mTBI. A new internet database system, the International Sports Injury System (ISIS) should improve epidemiological analysis of head, face, and spinal injuries worldwide.ISIS should provide an internationally compatible system for continuous monitoring of risk factors, protective effects of equipment, and protective effects of equipment and effects of changes in rules through the years.

  • 46.
    Bradley, Jonathan P.
    et al.
    Department of Physics, Warwick University, Coventry.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Antzutkin, Oleg
    Luleå University of Technology, Department of Civil, Environmental and Natural Resources Engineering, Sustainable Process Engineering.
    Brown, Steven P.
    Department of Physics, Warwick University, Coventry.
    Probing intermolecular crystal packing in gamma-indomethacin by high-resolution 1H solid-state NMR spectroscopy2011In: Crystal Growth & Design, ISSN 1528-7483, E-ISSN 1528-7505, Vol. 11, no 8, p. 3463-3471Article in journal (Refereed)
    Abstract [en]

    An NMR crystallography approach that combines experimental solid-state magic-angle-spinning (MAS) NMR with calculation is applied to the gamma polymorph of the pharmaceutical molecule, indomethacin. First-principles calculations (GIPAW) for the full crystal structure and an isolated molecule show changes in the (1)H chemical shift for specific aliphatic and aromatic protons of over -1 ppm that are due to intermolecular CH-pi interactions. For the OH proton, (1)H double-quantum (DQ) CRAMPS (combined rotation and multiple-pulse spectroscopy) spectra reveal intermolecular H-H proximities to the OH proton of the carboxylic acid dimer as well as to specific aromatic CH protons. The enhanced resolution in (1)H DQ-(13)C spectra, recorded at 850 MHz, enables separate (1)H DQ build-up curves (as a function of the DQ recoupling time) to be extracted for the aromatic CH protons. Supported by eight-spin density-matrix simulations, it is shown how the relative maximum intensities and rates of build-up provide quantitative insight into intramolecular and intermolecular H-H proximities that characterize the crystal packing

  • 47.
    Briggs, Karen K.
    et al.
    Steadman Hawkins research foundation, Basic science research, Vail.
    Lysholm, Jack
    Winternet.
    Tegner, Yelverton
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Rodkey, William G.
    Steadman Hawkins research foundation, Basic science research, Vail.
    Steadman, J. Richard
    Steadman Hawkins research foundation, Basic science research, Vail.
    25 years later: the reliability, validity and responsiveness of the Lysholm score and Tegner activity scale for anterior cruciate ligament injury of tne knee2008In: Knee Surgery, Sports Traumatology, Arthroscopy, ISSN 0942-2056, E-ISSN 1433-7347, Vol. 16, no Suppl. 1, p. S34-Article in journal (Other academic)
  • 48.
    Brogårdh, Christina
    et al.
    Skåne University Hospital, Lund.
    Flansbjer, Ulla-Britt
    Lund University.
    Lexell, Jan
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    No effects of whole-body vibration training on muscle strength and gait performance in persons with late effects of polio: a pilot study2010In: Archives of Physical Medicine and Rehabilitation, ISSN 0003-9993, E-ISSN 1532-821X, Vol. 91, no 9, p. 1474-1477Article in journal (Refereed)
    Abstract [en]

    ObjectiveTo evaluate the feasibility and possible effects of whole-body vibration (WBV) training on muscle strength and gait performance in people with late effects of polio.DesignA case-controlled pilot study with assessments before and after training.SettingA university hospital rehabilitation department.ParticipantsPeople (N=5; 3 men, 2 women; mean age, 64±6.7y; range, 55-71y) with clinically and electrophysiologically verified late effects of polio.InterventionsAll participants underwent 10 sessions of supervised WBV training (standing with knees flexed 40°-55° up to 60 seconds per repetition and 10 repetitions per session twice weekly for 5 weeks).Main Outcome MeasuresIsokinetic and isometric knee muscle strength (dynamometer), and gait performance (Timed Up & Go, Comfortable Gait Speed, Fast Gait Speed, and six-minute walk tests).ResultsAll participants completed the 5 weeks of WBV training, with no discernible discomfort. No significant changes in knee muscle strength or gait performance were found after the WBV training period.ConclusionsThis pilot study did not show any significant improvements in knee muscle strength and gait performance following a standard protocol of WBV training. Thus, the results do not lend support to WBV training for people with late effects of polio.

  • 49.
    Brogårdh, Christina
    et al.
    Umeå University, Rehabilitation Medicine, Department of Community Medicine and Rehabilitation.
    Flansbjer, Ulla-Britt
    Department of Rehabilitation, Lund University Hospital, Sweden.
    Lexell, Jan
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    What is the long term benefit of constraint induced movement therapy?: a 4-year follow-up2009In: Clinical Rehabilitation, ISSN 0269-2155, E-ISSN 1477-0873, Vol. 23, no 5, p. 418-423Article in journal (Refereed)
    Abstract [en]

    Objective: To evaluate the long-term benefits of constraint-induced movement therapy in chronic stroke.Design: A four-year follow-up after constraint-induced group therapy assessing arm and hand function and self-reported daily hand use.Subjects: Fourteen post-stroke individuals (six women and eight men; mean age 59.6 ± 12.7 years, range 23-75 years) with mild to moderate impairments of hand function.Outcome measures: The Sollerman hand function test and the Motor Activity Log test.Results: Four years after constraint-induced group therapy the participants had maintained their hand function, as measured by the Sollerman hand function test. The self-reported use and quality of movements of the more affected hand, as measured by the Motor Activity Log test, had decreased compared to post-treatment and three months follow-up (P < 0.01), but was still significantly higher than pre-treatment (P < 0.05).Conclusion: There seems to be a long-term benefit of constraint-induced group therapy. Hand function was maintained over time and daily hand use had increased compared to pre-treatment. To provide guidelines about the clinical use of constraint-induced movement therapy further, larger and controlled studies are needed.

  • 50.
    Brogårdh, Christina
    et al.
    Lund University Hospital.
    Lexell, Jan
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    A 1-year follow-up after shortened constraint-induced movement therapy with and without mitt poststroke2010In: Archives of Physical Medicine and Rehabilitation, ISSN 0003-9993, E-ISSN 1532-821X, Vol. 91, no 3, p. 460-464Article in journal (Refereed)
    Abstract [en]

    ObjectiveTo explore the long-term benefits of shortened constraint-induced movement therapy (CIMT) in the subacute phase poststroke.DesignA 1-year follow-up after shortened CIMT (3h training/d for 2wk) where the participants had been randomized to a mitt group or a nonmitt group.SettingA university hospital rehabilitation department.ParticipantsPoststroke patients (N=20, 15 men, 5 women; mean age 58.8y; on average 14.8mo poststroke) with mild to moderate impairments of hand function.InterventionsNot applicable.Main Outcome MeasuresThe Sollerman hand function test, the modified Motor Assessment Scale, and the Motor Activity Log test. Assessments were made by blinded observers.ResultsOne year after shortened CIMT, participants within both the mitt group and the nonmitt group showed statistically significant improvements in arm and hand motor performance and on self-reported motor ability compared with before and after treatment. No significant differences between the groups were found in any measure at any time.ConclusionsShortened CIMT seems to be beneficial up to 1 year after training, but the restraint may not enhance upper motor function. To determine which components of CIMT are most effective, larger randomized studies are needed.

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