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  • 1.
    Asberg, Dennis
    et al.
    Karlstad Univ, Dept Engn & Chem Sci, SE-65188 Karlstad, Sweden..
    Weinmann, Annika Langborg
    AstraZeneca, Resp Inflammat & Autoimmun, Innovat Med & Early Dev Biotech Unit, SE-43183 Molndal, Sweden..
    Leek, Tomas
    AstraZeneca, Resp Inflammat & Autoimmun, Innovat Med & Early Dev Biotech Unit, SE-43183 Molndal, Sweden..
    Lewis, Richard J.
    AstraZeneca, Resp Inflammat & Autoimmun, Innovat Med & Early Dev Biotech Unit, SE-43183 Molndal, Sweden..
    Klarqvist, Magnus
    AstraZeneca, Resp Inflammat & Autoimmun, Innovat Med & Early Dev Biotech Unit, SE-43183 Molndal, Sweden..
    Lesko, Marek
    Rzeszow Univ Technol, Dept Chem & Proc Engn, PL-35959 Rzeszow, Poland..
    Kaczmarski, Krzysztof
    Rzeszow Univ Technol, Dept Chem & Proc Engn, PL-35959 Rzeszow, Poland..
    Samuelsson, Jörgen
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences (from 2013). Karlstad Univ, Dept Engn & Chem Sci, SE-65188 Karlstad, Sweden..
    Fornstedt, Torgny
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences (from 2013). Karlstad Univ, Dept Engn & Chem Sci, SE-65188 Karlstad, Sweden..
    The importance of ion-pairing in peptide purification by reversed-phase liquid chromatography2017In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1496, p. 80-91Article in journal (Refereed)
    Abstract [en]

    The adsorption mechanism for three peptides was studied under overloaded conditions through adsorption isotherm measurements in the presence of an ion-pairing reagent, trifluoroacetic acid (TFA), on an end-capped C18-bonded stationary phase. The overall aim of the study was to obtain a better understanding of how the acetonitrile and the TFA fractions in the eluent affected the overloaded elution profiles and the selectivity between peptides using mechanistic modelling and multivariate design of experiments. When studying the effect of TFA, direct evidence for ion pair formation between a peptide and TFA in acetonitrile-water solutions was provided by fluorine-proton nuclear Overhauser NMR enhancement experiments and the adsorption of TFA on the stationary phase was measured by frontal analysis. The adsorption isotherms for each peptide were then determined by the inverse method at eight TFA concentrations ranging from 2.6 mM to 37.3 mM (0.02–0.29 vol-%) in isocratic elution. The equilibrium between the peptide ion and the peptide-TFA complex was modelled by coupling the mass-balance to reaction kinetics and determining separate adsorption isotherms for the two species. We found that a Langmuir isotherm described the elution profile of peptide-TFA complex well while the peptide ion was described by a bi-Langmuir adsorption isotherm since it exhibited strong secondary interactions. The elution profiles had an unfavorable shape at low TFA concentrations consisting of a spike in their front and a long tailing rear due to the secondary interactions for the peptide ion having very low saturation capacity. The acetonitrile dependence on the adsorption isotherms was studied by determination of adsorption isotherms directly from elution profiles obtained in gradient elution which enabled a broad acetonitrile interval to be studied. Here, it was found that the column saturation capacity was quickly reached at very low acetonitrile fractions and that there were significant variations in adsorption with the molecular weight. Finally, practical implications for method development are discussed based on an experimental design where gradient slope and TFA concentrations are used as factors. (c) 2017 Published by Elsevier B.V.

  • 2.
    Cilpa-Karhu, Geraldine
    et al.
    Laboratory of Analytical Chemistry, Department of Chemistry, University of Helsinki.
    Lipponen, Katriina
    Laboratory of Analytical Chemistry, Department of Chemistry, University of Helsinki.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Ööri, Katariina
    Wihuri Research Institute, FIN-00290 Helsinki, Finland.
    Fornstedt, Torgny
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Riekkola, Marja-Liisa
    Chemistry, Department of Chemistry, University of Helsinki.
    Three complementary techniques for the clarification of temperature effect on low-density lipoprotein–chondroitin-6-sulfate interaction2013In: Analytical Biochemistry, ISSN 0003-2697, E-ISSN 1096-0309, Vol. 443, no 2, p. 139-147Article in journal (Refereed)
    Abstract [en]

    Abstract A rigorous processing of adsorption data from quartz crystal microbalance technology was successfully combined with the data obtained by partial filling affinity capillary electrophoresis and molecular dynamics for the clarification of the temperature effect on the interaction of a major glycosaminoglycan chain chondroitin-6-sulfate (C6S) of proteoglycans with low-density lipoprotein (LDL) and with a peptide fragment of apolipoprotein B-100 (residues 3359–3377 of LDL, PPBS). Two experimental techniques and computational atomistic methods demonstrated a nonlinear pattern of the affinity of C6S at temperatures above 38.0 °C to both LDL and PPBS. The temperature affects the interaction of C6S with LDL and PPBS by influencing the structural behavior of glycosaminoglycan C6S and/or that of LDL.

  • 3.
    Encarnacao, Joao Crispim
    et al.
    Ridgeview Instruments AB Uppsala.
    Barta, Pavel
    Charles Univ. Prague Czech Republic.
    Fornstedt, Torgny
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences (from 2013).
    Andersson, Karl
    Ridgeview Instruments AB Uppsala; Uppsala universitet.
    Impact of assay temperature on antibody binding characteristics in living cells: A case study2017In: BIiomedical reports, ISSN 2049-9434, Vol. 7, no 5, p. 400-406Article in journal (Refereed)
    Abstract [en]

    Kinetic and thermodynamic studies of ligand-receptor interactions are essential for increasing the understanding of receptor activation mechanisms and drug behavior. The characterization of molecular interactions on living cells in real-time goes beyond most current binding assays, and provides valuable information about the dynamics and underlying mechanism of the molecules in a living system. The effect of temperature on interactions in cell-based assays is, however, rarely discussed. In the present study, the effect of temperature on binding of monoclonal antibodies, cetuximab and pertuzumab to specific receptors on living cancer cells was evaluated, and the affinity and kinetics of the interactions were estimated at selected key temperatures. Changes in the behavior of the interactions, particularly in the on- and off-rates were observed, leading to greatly extended time to reach the equilibrium at 21 degrees C compared with at 37 degrees C. However, the observed changes in kinetic characteristics were less than a factor of 10. It was concluded that it is possible to conduct real-time measurements with living cells at different temperatures, and demonstrated that influences of the ambient temperature on the interaction behavior are likely to be less than one order of magnitude.

  • 4.
    Enmark, Martin
    et al.
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences. Karlstad Univ, INTERACT, Dept Engn & Chem Sci, SE-65188 Karlstad, Sweden..
    Asberg, Dennis
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences. Karlstad Univ, INTERACT, Dept Engn & Chem Sci, SE-65188 Karlstad, Sweden..
    Leek, Hanna
    AstraZeneca R&D, Resp Inflammat & Autoimmun, Innovat Med, S-43183 Molndal, Sweden..
    Ohlen, Kristina
    AstraZeneca R&D, Resp Inflammat & Autoimmun, Innovat Med, S-43183 Molndal, Sweden..
    Klarqvist, Magnus
    AstraZeneca R&D, Resp Inflammat & Autoimmun, Innovat Med, S-43183 Molndal, Sweden..
    Samuelsson, Jorgen
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences. Karlstad Univ, INTERACT, Dept Engn & Chem Sci, SE-65188 Karlstad, Sweden..
    Fornstedt, Torgny
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences. Karlstad Univ, INTERACT, Dept Engn & Chem Sci, SE-65188 Karlstad, Sweden..
    Evaluation of scale-up from analytical to preparative supercritical fluid chromatography2015In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1425, p. 280-286Article in journal (Refereed)
    Abstract [en]

    An approach for reliable transfer from analytical to preparative scale supercritical fluid chromatography was evaluated. Here, we accounted for the conditions inside the columns as well as to the fact that most analytical instruments are volume-controlled while most preparative scale units are mass-controlled. The latter is a particular problem when performing pilot scale experiments and optimizations prior to scaling up to production scale. This was solved by measuring the mass flow, the pressure and the temperature on the analytical unit using external sensors. Thereafter, it was revealed with a design of experiments approach that the methanol fraction and the pressure are the two most important parameters to control for preserved retention throughout the scale-up; for preserved selectivity the temperature was most important in this particular system. Using this approach, the resulting chromatograms from the preparative unit agreed well with those from the analytical unit while keeping the same column length and particles size. A brief investigation on how the solute elution volume varies with the volumetric flow rate revealed a complex dependency on pressure, density and apparent methanol content. Since the methanol content is a parameter of great importance to control during the scale up, we must be careful when changing operational and column design conditions which generates deviations in pressure, density and methanol content between different columns. (C) 2015 Elsevier B.V. All rights reserved.

  • 5.
    Enmark, Martin
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Fornstedt, Torgny
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Forssén, Patrik
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Gyllenhaal, Olle
    Computer-assisted optimization in preparative SFC, Challenges, Pitfalls and Solutions2010Conference paper (Refereed)
    Abstract [en]

    Preparative packed column SFC (pSFC) is an environmentally favorable alternative to normal phase HPLC. We are participating in a larger research project where the overreaching goal is to make an impact in the recovery of high-value compounds from agricultural byproducts and waste materials using environmentally sustainable techniques. Our specific task is to isolate large amounts of valuable compounds from discarded biomaterials using pSFC. It is still not possible to accurately model, simulate and optimize a preparative SFC proess, although SFC has been in use for almost fifty years. This is mainly because of the compressibility of the mobile phase and how this influences the physical parameters of the system. More particular, if pSFC is operated under combinations of back pressures and flow rates that give negligible pressure drop, it has been demonstrated and implied, that the tools developed and used within HPLC, can be transferred and used successfully [1, 2]. However, when the pressure drop becomes noticeable, the induced density gradient significantly increases the complexity. An earlier study has clearly described the effect of this pressure gradient on the retention factor, and also the column efficiency [3]. However, it remains to be investigated how the entire adsorption isotherm depends on the density.In this study we will investigate the use of the inverse and the perturbation peak methods, originally developed within LC, to determine the nonlinear adsorption isotherm for i) negligible, and ii) non-negligible pressure drop conditions respectively. To do this, we will use a simple racemic substance and a cellulose based CSP with a column equipped with pressure sensors at the inlet and outlet. Using obtained parameters we will validate the methods by simulating the separation using a variable coefficient version of the Equilibrium-Dispersive model for cases i and ii. [1] S. Ottiger, J. Kluge, A. Rajendran , M. Mazzotti, J. Chromatogr., A 1162 (2007) 74-82[2] C. Wenda, A. Rajendran, J. Chromatogr., A 1216 (2009) 8750-8758[3]A. Rajendran, O. Kräuchi, M. Mazzotti, M. Morbidelli, J Chromatogr., A, 1092 (2005) 149-160[4] G. Guiochon, A. Felinger, D. G. Shirazi, A. M. Katti, Fundamentals of Preparative and Nonlinear Chromatography 2nd Ed, Elsevier Academic Press (2006).

  • 6.
    Enmark, Martin
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Fornstedt, Torgny
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Arnell, Robert
    Forssén, Patrik
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Kaczmarski, Krzysztof
    A systematic investigation of algorithm impact in preparative chromatography with experimental verifications2011In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1218, no 5, p. 662-672Article in journal (Refereed)
    Abstract [en]

    Computer-assisted optimization of chromatographic separations requires finding the numerical solution of the Equilibrium-Dispersive (ED) mass balance equation. Furthermore, the competitive adsorption isotherms needed for optimization are often estimated numerically using the inverse method that also solves the ED equations. This means that the accuracy of the estimated adsorption isotherm parameters explicitly depends on the numerical accuracy of the algorithm that is used to solve the ED equations. The fast and commonly used algorithm for this purpose, the Rouchon Finite Difference (RFD) algorithm, has often been reported not to be able to accurately solve the ED equations for all practical preparative experimental conditions, but its limitations has never been completely and systematically investigated. In this study, we thoroughly investigate three different algorithms used to solve the ED equations: the RFD algorithm, the Orthogonal Collocation on Finite Elements (OCFE) method and a Central Difference Method (CDM) algorithm, both for increased theoretical understanding and for real cases of industrial interest. We identified discrepancies between the conventional RFD algorithm and the more accurate OCFE and CDM algorithms for several conditions, such as low efficiency, increasing number of simulated components and components present at different concentrations. Given high enough efficiency, we experimentally demonstrate good prediction of experimental data of a quaternary separation problem using either algorithm, but better prediction using OCFE/CDM for a binary low efficiency separation problem or separations when the compounds have different efficiency. Our conclusion is to use the RFD algorithm with caution when such conditions are present and that the rule of thumb that the number of theoretical plates should be greater than 1000 for application of the RFD algorithm is underestimated in many cases

  • 7.
    Enmark, Martin
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Fornstedt, Torgny
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Arnell, Robert
    Forssén, Patrik
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Kaczmarski, Krzysztof
    Computer Assisted Optimization of Pharmaceutical Purification - The Impact of Algorithms and Experimental Approach2010Conference paper (Refereed)
    Abstract [en]

    Computer assisted process optimization of chromatographic separations requires the selection of computer algorithms and measurement of relevant parameters. In this study, we will investigate how the choice of algorithms and the number of performed initial experiments affect the estimated optimal separations conditions. We will focus on conditions typically encountered for slurry packing coated 20 µm CSP in large-scale columns used for pharmaceutical intermediate purification.Probably the most essential for parameters in this context are the adsorption isotherm parameters for the components. The rapid "inverse method" is commonly used and this method requires that one numerically solve the mass balance equations describing the chromatographic process. Here we thoroughly investigate how different algorithms that solve the Equilibrium-Dispersive (ED) mass balance equations will affect the estimated adsorption isotherm parameters.Furthermore, we will investigate and compare how different strategies affect the prediction of the optimal separation conditions. First, we will use a more rapid approach that requires a minimum of experiments and uses standard algorithms to estimate optimal conditions. Secondly, we will use a more exact approach that requires more experiments and uses more advanced simulation- and optimization algorithms

  • 8.
    Enmark, Martin
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Fornstedt, Torgny
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Forssén, Patrik
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Kaczmarski, Krzysztof
    A systematic investigation on the accuracy of computer simulations for optical isomers in industrial settings2010Conference paper (Refereed)
    Abstract [en]

    Predicting the band profiles of typical chromatographic separations using the approach of the inverse method (IM) [2] requires finding the numerical solution of the Equilibrium-Dispersive (ED) mass balance equation [1]. The accuracy of the determination of the competitive adsorption isotherms is therefore explicitly dependent on the choice of algorithm to solve the ED model. Earlier studies have shown that the well known RFD algorithm [3] has limitations in its accuracy for certain simulated conditions such as column efficiency and adsorption isotherm type [5]. In this study, we thoroughly investigate three different algorithms, the rapid and well known Rouchon Finite Difference (RFD) algorithm [3], the Orthogonal Collocation on Finite Elements (OCFE) method [4] and the Central Difference Method (CDM) algorithm developed by us. Firstly, a systematic investigation is made, comparing the different algorithms under a broad range of different synthetic conditions. Secondly, we apply all three algorithms using the IM on real experimental systems; (I) one high efficiency quaternary separation and (II) one pharmaceutical industry application with a chiral intermediate separation. We have found discrepancies between the conventional (RFD) and the more accurate (OCFE and CDM) algorithms for several synthetic conditions such as low efficiency, increasing number of simulated components and components present at different concentrations. Given high enough efficiency, we experimentally demonstrate good prediction of experimental data of a quaternary separation problem using either algorithm but better prediction of OCFE/CDM for a binary low efficiency separation problem. Our conclusion is to use the RFD algorithm with caution when any of the particular conditions we have investigated is valid. When the highest accuracy is sought, there is no doubt that OCFE or CDM should be the algorithms of choice. However, given the computational speed of RFD, we also recommend it for preliminary parameter fitting. For conditions where we have shown the algorithms to produce practically identical solutions, RFD can be applied with greater certainty. It remains to be thoroughly investigated the effect on the particular shape of the adsorption isotherm on the obtained solution, for example type III having inflection points.

  • 9.
    Enmark, Martin
    et al.
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Forssén, Patrik
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Fornstedt, Torgny
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Determination of adsorption isotherms in supercritical fluid chromatography2013In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1312, p. 124-133Article in journal (Refereed)
    Abstract [en]

    Abstract In this study we will demonstrate the potential of modern integrated commercial analytical SFC-systems for rapid and reliable acquisition of thermodynamic data. This will be done by transferring the following adsorption isotherm determination methods from liquid chromatography (LC) to supercritical fluid chromatography (SFC): Elution by Characteristic Points (ECP), the Retention Time Method (RTM), the Inverse Method (IM) and the Perturbation Peak (PP) method. In order to transfer these methods to SFC in a reliable, reproducible way we will demonstrate that careful system verification using external sensors of mass flow, temperature and pressure are needed first. The adsorption isotherm data generated by the different methods were analyzed and compared and the adsorption isotherms ability to predict new experimental elution profiles was verified by comparing experiments with simulations. It was found that adsorption isotherm data determined based on elution profiles, i.e., ECP, IM and RTM, were able to accurately predict overloaded experimental elution profiles while the more tedious and time-consuming PP method, based on small injections on concentration plateaus, failed in doing so.

  • 10.
    Enmark, Martin
    et al.
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Physics (from 2013).
    Glenne, Emelie
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences (from 2013).
    Leśko, Marek
    Rzeszów University of Technology, Poland.
    Langborg Weinmann, Annika
    AstraZeneca.
    Leek, Tomas
    AstraZeneca.
    Kaczmarski, Krzysztof
    AstraZeneca.
    Klarqvist, Magnus
    AstraZeneca.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences (from 2013).
    Fornstedt, Torgny
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences (from 2013).
    Investigation of robustness for supercritical fluid chromatography separation of peptides: Isocratic vs gradient mode2018In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1568, p. 177-187Article in journal (Refereed)
    Abstract [en]

    We investigated and compared the robustness of supercritical fluid chromatography (SFC) separations of the peptide gramicidin, using either isocratic or gradient elution. This was done using design of experiments in a design space of co-solvent fraction, water mass fraction in co-solvent, pressure, and temperature. The density of the eluent (CO2-MeOH-H2O) was experimentally determined using a Coriolis mass flow meter to calculate the volumetric flow rate required by the design. For both retention models, the most important factor was the total co-solvent fraction and water mass fraction in co-solvent. Comparing the elution modes, we found that gradient elution was more than three times more robust than isocratic elution. We also observed a relationship between the sensitivity to changes and the gradient steepness and used this to draw general conclusions beyond the studied experimental system. To test the robustness in a practical context, both the isocratic and gradient separations were transferred to another laboratory. The gradient elution was highly reproducible between laboratories, whereas the isocratic system was not. Using measurements of the actual operational conditions (not the set system conditions), the isocratic deviation was quantitatively explained using the retention model. The findings indicate the benefits of using gradient elution in SFC as well as the importance of measuring the actual operational conditions to be able to explain observed differences between laboratories when conducting method transfer.

  • 11.
    Enmark, Martin
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Fornstedt, Torgny
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    A Deeper Understanding of a Complex Adsorption Behavior in a Common Chiral, Separation System2011Conference paper (Refereed)
    Abstract [en]

    The adsorption equilibria of racemic methyl mandelate on a tris-(3,5-dimethylphenyl)carbamoyl cellulose chiral stationary phase (CSP) was investigated. This separation has previously been performed and analyzed on a methylcellulose tribenzoate coated CSP. In that case, both enantiomers could be described with a bi-Langmuir adsorption isotherm, convex upwards (type I). In our case, two fundamentally different properties were observed. First, the elution order was reversed. Furthermore, only the less retained enantiomer shows type I adsorption behavior, while the adsorption isotherm of the more retained compound contained an inflection point at low concentration. To analyze these differences, adsorption isotherms were determined and further analyzed using Scatchard plots and adsorption energy distribution calculations. The less retained enantiomer was best described by Tóth adsorption isotherm while the second enantiomer was best described with a bi-Moreau adsorption isotherm. The Moreau model is an extension of the Langmuir model including non-ideal adsorbate-adsorbate interactions; here the unusual model provided an explanation to the non-ideal adsorption of the more retained enantiomer. Furthermore, the possibility of using the Moreau model as a local model for adsorption in AED calculations was evaluated by synthetically generated raw adsorption slope data. It was demonstrated that the AED accurately could predict the number of adsorption sites for the generated data. The adsorption behavior of both enantiomers was also studied at several different temperatures and it was found to be exothermic; in addition, the non-idealadsorbate-adsorbate interaction strength decreases with increasing temperature. Stochastic analysis of the adsorption process could identify a single kinetic site for each enantiomer. The average amount of adsorption/desorption events increases and the sojourn time decreases with increasing temperature.

  • 12.
    Enmark, Martin
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Fornstedt, Torgny
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    A thermodynamic and kinetic study of an unusual adsorption behavior-Methyl Mandelate on commercially available Tris-(3,5- dimethylphenyl)carbamoyl Cellulose Chiral Stationary Phase2012Conference paper (Other academic)
    Abstract [en]

    The adsorption equilibria of racemic methyl mandelate on a tris-(3,5- dimethylphenyl)carbamoyl cellulose chiral stationary phase (CSP) was investigated. The following were observed, the less retained enantiomer shows “Langmuirian” (type I) adsorption behavior, while the adsorption isotherm of the more retained compound contained an inflection point at low concentration. To analyze these differences, adsorption isotherms were determined and further analyzed using Scatchard plots and adsorption energy distribution (AED) calculations. The less retained enantiomer was best described by heterogeneous unimodal adsorption model (Tóth) while the second enantiomer was best described with a heterogeneous adsorption model with adsorbate-adsorbate interactions (bi-Moreau). The adsorption behavior of both enantiomers was also studied at several different temperatures and it was found to be exothermic; in addition, the non-idealadsorbate-adsorbate interaction strength decreases with increasing temperature. Stochastic analysis of the adsorption process could identify a single kinetic site for each enantiomer. The average amount of adsorption/desorption events increases and the sojourn time decreases with increasing temperature. This is an industrial – academic cooperation in the Fundamental Separation Science Group www.separationscience.se

  • 13.
    Enmark, Martin
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Fornstedt, Torgny
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Characterization of the Adsorption of Racemic Methyl Mandelate on Tris-(3,5-dimethylphenyl)carbamoyl Cellulose Chiral Stationary Phase2011Conference paper (Refereed)
    Abstract

    The adsorption equilibria of racemic methyl mandelate on a tris-(3,5-dimethylphenyl)carbamoyl cellulose chiral stationary phase (CSP) was investigated. This separation has previously been performed and analyzed on a methylcellulose tribenzoate coated CSP. In that case, both enantiomers could be described with a bi-Langmuir adsorption isotherm, convex upwards (type I). In our case, two fundamentally different properties were observed. First, the elution order was reversed. Furthermore, only the less retained enantiomer shows type I adsorption behavior, while the adsorption isotherm of the more retained compound contained an inflection point at low concentration.

    To analyze these differences, adsorption isotherms were determined and further analyzed using Scatchard plots and adsorption energy distribution calculations. The less retained enantiomer was best described by Tóth adsorption isotherm while the second enantiomer was best described with a bi-Moreau adsorption isotherm. The Moreau model is an extension of the Langmuir model including non-ideal adsorbate-adsorbate interactions; here the unusual model provided an explanation to the non-ideal adsorption of the more retained enantiomer. Furthermore, the possibility of using the Moreau model as a local model for adsorption in AED calculations was evaluated by synthetically generated raw adsorption slope data. It was demonstrated that the AED accurately could predict the number of adsorption sites for the generated data. The adsorption behavior of both enantiomers was also studied at several different temperatures and it was found to be exothermic; in addition, the non-idealadsorbate-adsorbate interaction strength decreases with increasing temperature.

    Stochastic analysis of the adsorption process could identify a single kinetic site for each enantiomer. The average amount of adsorption/desorption events increases and the sojourn time decreases with increasing temperature.

  • 14.
    Enmark, Martin
    et al.
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Fornstedt, Torgny
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    On the Reproducibility between Different Modern Supercritcal Fluid Chromatographic Systems2013Conference paper (Other academic)
    Abstract [en]

    Three different, commercially available, Supercritical Fluid Chromatography (SFC) systems were investigated: Thar Super Pure Discovery Series SFC, Waters UPC2 and Agilent 1260 Infinity SFC. The reason for choosing the two analytical systems from Agilent and Waters is that they represent two of the latest commercial systems available while the semi-preparative instrument was added to widen the study to include instruments also used for preparative purposes. With identical operational conditions set these systems were used to acquire analytical retention data and adsorption isotherms from overloaded injections. The investigation was limited to the use of methanol as modifier and operational conditions, temperature and back pressure most typically observed when utilizing SFC to separate polar compounds. The results clearly show that both analytical retention times and elution profiles are system dependent. Since the overloaded elution profiles are system dependent the adsorption isotherm will also be different. However, this do not mean that the adsorption is different, instead this it is due to the fact that identical instrumental settings, especially pressure and modifier composition settings, does not necessarily mean that the conditions inside the column are identical. This means that it is not possible to transfer an established separation method from one system to another, even if one is using the same column and identical instrument settings. Understanding of SFC-systems will be of fundamental importance for successful transfer of methods between systems, reliable adsorption isotherm determination, and analytical quality work and scaling up from analytical to preparative mode. These issues can probably be solved by measuring mass flow, pressure and temperature along the column, together with a sound understanding of the density variations of the mobile phase. However, the work of finding acceptable applications or guidelines to remove the tedious need for these measurements is currently investigated in our lab. This is a contribution from the Fundamental Separation Science Group www.FSSG.se

  • 15.
    Enmark, Martin
    et al.
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Fornstedt, Torgny
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Using Modern SFC Systems for Adsorption Characterization2013Conference paper (Other academic)
    Abstract [en]

    Recently the pharmaceutical industry has started to replace preparative HPLC with preparative SFC to lower the environmental impact and to increase performance. Reliable characterization of the adsorption processes in SFC is therefore of utmost importance. The key thermodynamic phase system information is obtained by rigorous determination of adsorption isotherm data over a broad concentration range. If properly processed, this data gives not only correct information about the degree of heterogeneity but also the energy of interactions and mono layer capacities of each individual type of adsorption site in the phase system. Ultimately, this can result in identification of the types of interactions, i.e., dipole-dipole, van der Waals interactions etc. In this study we will present transfer of selected adsorption characterization methods, traditionally applied with success in LC, to SFC. We have here transferred all available knowledge from LC – from model selection to validation. We will also, using recent findings, explain the effects of pressure and temperature variations as well as how to accurately measure the volumetric flow rate on a modern analytical SFC system. We will demonstrate how the latest SFC instruments, with some critical modifications; have the potential for rapid and reliable acquisition of thermodynamic data using the ECP method. Finally we will elaborate on how the adsorption depends on density, temperature and modifier content in the mobile phase. This is a contribution from the Fundamental Separation Science Group www.FSSG.se

  • 16.
    Enmark, Martin
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Fornstedt, Torgny
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Forssén, Patrik
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Preparative Separation of Chiral Pharmaceutical Compounds - The Effects of Packing Particle Size, Pressure Limit and Column Geometry on Productivity and Solvent Consumption2011Conference paper (Refereed)
    Abstract [en]

    In this study, omeprazole was used as a model compound. Omeprazole and other related sulfoxidebenzimidazolesare used against gastric ulcersand have been extensively studied regarding chromatographic resolution techniques using several different chiral stationary phases.First, AstraZeneca launched Losec, a racemic mixture of RS-omeprazole. Facing loss of patent, the more potent S-enantiomer was developed and marketed as Nexium. Now the patent of Nexium is close expiration why methods for isolation of the pure S-enantiomer will be of importance for the generic pharmaceutical companies.The experimental model separation system represents a system with good selectivity and high solubility of the solute in the eluent. In this investigation the productivity optima for three different particle sizes (5, 10 and 25 µm) at maximum system pressure ranging from 50 to 400 bars are studied. Two different optimizations cases were studied in depth. First,a process optimization with fixed column geometry is studied. The results clearly show that larger packing materials have higher productivity at low pressure drops on the analytical size column.With increasing allowed pressure drops, over 200 bar, the smaller packing materials have substantially higher productivity. The results also show that smaller packing material will always have much lower solvent consumption compared to larger particles.The second process optimization was performed with a fixed column volume, but the column geometry was variable. The results shows that the productivity obtained for the smaller packing particles materials was higher compared to the large for all allowed pressure drops. The productivity obtained for the small particle compared to the large increased by 25-300 % while maintaining 50-300 % less solvent consumption for the purification of the first enantiomer.The addition of TEA seems to be unfavorable for all tested conditions.In conclusion, the optimization of the enantioseparation of omeprazole has been shown to be dependent on column packing particle size as well as column geometry. It has been demonstrated that all parameters need to be simultaneously optimized to reach a global productivity optima.

  • 17.
    Enmark, Martin
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Fornstedt, Torgny
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Forssén, Patrik
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Preparative Separation of Omeprazole: Predictions of the Optimal Experimental Conditions by Computer Simulations2011Conference paper (Refereed)
    Abstract [en]

    In this study, omeprazole was used as a model compound. Omeprazole and other related sulfoxide benzimidazoles are used against gastric ulcers and have been extensively studied regarding chromatographic resolution techniques using several different chiral stationary phases.First, AstraZeneca launched Losec, a racemic mixture of RS-omeprazole. Facing loss of patent, the more potent S-enantiomer was developed and marketed as Nexium. Now the patent of Nexium is close expiration why methods for isolation of the pure S-enantiomer will be of importance for the generic pharmaceutical companies.The experimental model separation system represents a system with good selectivity and high solubility of the solute in the eluent. In this investigation the productivity optima for three different particle sizes (5, 10 and 25 µm) at maximum system pressure ranging from 50 to 400 bars are studied. Two different optimizations cases were studied in depth. First,a process optimization with fixed column geometry is studied. The results clearly show that larger packing materials have higher productivity at low pressure drops on the analytical size column.With increasing allowed pressure drops, over 200 bar, the smaller packing materials have substantially higher productivity.The results also show that smaller packing material will always have much lower solvent consumption compared to larger particles.The second process optimization was performed with a fixed column volume, but the column geometry was variable. The results shows that the productivity obtained for the smaller packing particles materials was higher compared to the large for all allowed pressure drops. The productivity obtained for the small particle compared to the large increased by 25-300 % while maintaining 50-300 % less solvent consumption for the purification of the first enantiomer.The addition of TEA seems to be unfavorable for all tested conditions.In conclusion, the optimization of the enantioseparation of omeprazole has been shown to be dependent on column packing particle size as well as column geometry. It has been demonstrated that all parameters need to be simultaneously optimized to reach a global productivity optima.

  • 18.
    Enmark, Martin
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Fornstedt, Torgny
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Undin, Torgny
    A Deeper Investigation of Strange Preparative Band Shapes of a Simple Racemic Solute on tris-(3, 5- dimethylphenyl)carbamoyl Cellulose as Chiral Stationary Phase2011Conference paper (Refereed)
    Abstract

    The adsorption equilibria of racemic methyl mandelate on a tris-(3, 5-dimethylphenyl)carbamoyl cellulose chiral stationary phase (CSP) has a peculiar behavior. The preparative band shape of the more retained enantiomer was very unusual with an inflection point at low concentrations whereas the less retained enantiomer shows normal type I adsorption behavior. For a deeper understanding of this separation adsorption isotherms were determined and further analyzed with Scatchard plots combined with adsorption energy distribution calculations. The less retained enantiomer was best described by Tóth adsorption isotherm while the second enantiomer was best described with a bi-Moreau adsorption isotherm. The Moreau model is an extension of the Langmuir model including non-ideal adsorbate-adsorbate interactions; here the unusual model provided an explanation to the non-ideal adsorption of the more retained enantiomer. Furthermore, the possibility of using the Moreau model as a local model for adsorption in AED calculations was evaluated by synthetically generated raw adsorption slope data. It was demonstrated that the AED accurately could predict the number of adsorption sites for the generated data. The adsorption behavior of both enantiomers was also studied at several different temperatures and it was found to be exothermic; in addition, the non-ideal adsorbate-adsorbate interaction strength decreases with increasing temperature. Stochastic analysis of the adsorption process could identify a single kinetic site for each enantiomer. The average amount of adsorption/desorption events increases and the sojourn time decreases with increasing temperature

  • 19.
    Enmark, Martin
    et al.
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Forss, Erik
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Forssén, Patrik
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Fornstedt, Torgny
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Investigation of plateau methods for adsorption isotherm determination in supercritical fluid chromatography2014In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1354, p. 129-138Article in journal (Refereed)
    Abstract [en]

    The Perturbation Peak (PP) method and Frontal analysis (FA) are considered as the most accurate methods for adsorption isotherms determination in liquid chromatography. In this study we investigate and explain why this is not the case in Supercritical Fluid Chromatography (SFC), where the PP method does not work at all, using a modern analytical system. The main reason was found to be that the solute to be studied must be dissolved in the MeOH reservoir before it is mixed with CO2. Since the solute occupies a certain partial volume in the reservoir, the larger the solute content the larger this fractional volume will be, and the final MeOH fraction in the mobile phase will then be smaller compared to the bulk mobile phase without solute in the modifier. If the retention of small injections on the concentration plateaus, i.e., “analytical-size” perturbation peaks, is sensitive to small variations of MeOH in the eluent, this will seriously decrease the accuracy of the PP method. This effect was verified and compensated for and we also demonstrated that the same problem will occur in frontal analysis, another concentration plateau method.

  • 20.
    Enmark, Martin
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Forssén, Patrik
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Fornstedt, Torgny
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Enantioseparation of omeprazole effect of different packing particle size on productivity2012In: Journal of Chromatography A, ISSN 0021-9673, Vol. 1240, no 1, p. 123-131Article in journal (Refereed)
    Abstract [en]

    Enantiomeric separation of omeprazole has been extensively studied regarding both product analysis and preparation using several different chiral stationary phases. In this study, the preparative chiral separation of omeprazole is optimized for productivity using three different columns packed with amylose tris (3,5-dimethyl phenyl carbamate) coated macroporous silica (5, 10 and 25 Όm) with a maximum allowed pressure drop ranging from 50 to 400 bar. This pressure range both covers low pressure process systems (50–100 bar) and investigates the potential for allowing higher pressure limits in preparative applications in a future. The process optimization clearly show that the larger 25 Όm packing material show higher productivity at low pressure drops whereas with increasing pressure drops the smaller packing materials have substantially higher productivity. Interestingly, at all pressure drops, the smaller packing material result in lower solvent consumption (L solvent/kg product); the higher the accepted pressure drop, the larger the gain in reduced solvent consumption. The experimental adsorption isotherms were not identical for the different packing material sizes; therefore all calculations were recalculated and reevaluated assuming identical adsorption isotherms (with the 10 Όm isotherm as reference) which confirmed the trends regarding productivity and solvent consumption.

  • 21.
    Enmark, Martin
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Högblom, Joakim
    Eka Chemicals.
    Forssén, Patrik
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Fornstedt, Torgny
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Adsorption Isotherm Determination for Reliable Phase System Characterization in SFC: Challenges and Pitfalls2012Conference paper (Refereed)
    Abstract [en]

    Recently the pharmaceutical industry has started to replace HPLC with SFC because of incentives to lower the environmental impact and as well as increasing performance. Reliable characterization of the adsorption processes in SFC, is therefore of utmost importance. The key thermodynamic phase system information is obtained by rigorous determination of adsorption isotherms over a broad concentration range. If properly processed, this data gives not only correct information about the degree of heterogeneity but also the values of the energy of interactions and monolayer capacities of each individual type of adsorption site in the phase system; ultimately, this can result in identification of the types of interactions (dipole-dipole, van der Waals interactions etc.). In this study, we will present the transfer of LC adsorption characterization methods to SFC conditions using several model compounds with several different methods for adsorption isotherm determination traditionally applied with success in LC, and now modified for SFC. We have limited our investigation to methanol as modifier and used the operational conditions, temperature and backpressure most typically observed in industrial settings; in addition, we have used commercial standard SFC-equipment. The results clearly shows that adsorption isotherm determinations in SFC are considerably more complicated than in LC; we will go through the most important pitfalls and give guidelines for more rigorous determinations of adsorption data in SFC. This is an industrial – academic cooperation in the Fundamental Separation Science Group www.separationscience.se

  • 22.
    Enmark, Martin
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Undin, Torgny
    Uppsala University Analytisk Kemi.
    Fornstedt, Torgny
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Characterization of an unusual adsorption behavior of racemic methyl-mandelate on a tris-(3,5-dimethylphenyl) carbamoyl cellulose chiral stationary phase2011In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1218, no 38, p. 6688-6696Article in journal (Refereed)
    Abstract [en]

    An interesting adsorption behavior of racemic methyl mandelate on a tris-(3,5-dimethylphenyl)carbamoyl cellulose chiral stationary phase was theoretically and experimentally investigated. The overloaded band of the more retained enantiomer had a peculiar shape indicating a type V adsorption isotherm whereas the overloaded band of the less retained enantiomer had a normal shape indicating a type I adsorption behavior. For a closer characterization of this separation, adsorption isotherms were determined and analyzed using an approach were Scatchard plots and adsorption energy distribution (AED) calculations are combined for a deeper analysis. It was found that the less retained enantiomer was best described by a Tóth adsorption isotherm while the second one was best described with a bi-Moreau adsorption isotherm. The latter model comprises non-ideal adsorbate–adsorbate interactions, providing an explanation to the non-ideal adsorption of the more retained enantiomer. Furthermore, the possibility of using the Moreau model as a local model for adsorption in AED calculations was evaluated using synthetically generated raw adsorption slope data. It was found that the AED accurately could predict the number of adsorption sites for the generated data. The adsorption behavior of both enantiomers was also studied at several different temperatures and found to be exothermic; i.e. the adsorbate–adsorbate interaction strength decreases with increasing temperature. Stochastic analysis of the adsorption process revealed that the average amount of adsorption/desorption events increases and the sojourn time decreases with increasing temperature.

  • 23.
    Enmark, Martin
    et al.
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Åsberg, Dennis
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Fornstedt, Torgny
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    The Effect of Temperature, Pressure and Co-Solvent on a Chiral Supercritical Fluid Chromatography Separation2014In: Chromatography Today, ISSN 1752-8070, Vol. 7, no 3, p. 14-17Article in journal (Refereed)
  • 24.
    Enmark, Martin
    et al.
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Åsberg, Dennis
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Shalliker, Andrew
    Samuelsson, Jörgen
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Fornstedt, Torgny
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    A closer study of peak distortions in supercritical fluid chromatography as generated by the injection2015In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1400, p. 131-139Article in journal (Refereed)
    Abstract [en]

    Abstract In SFC the sample cannot be dissolved in the mobile phase, so it is often dissolved in pure modifier, or another liquid, sometimes resulting in serious distortions of the eluted peak profiles already at moderately high injection volumes. It is suspected the reasons for these effects are solvent strength mismatch and/or viscosity mismatch. This study presents a systematic and fundamental investigation of the origin of these peak deformations due to the injection solvent effects in SFC, using both systematic experiments and numerical modeling. The first set of experiments proved that the injection volume and the elution strength of the sample solution had a major impact of the shapes of the eluted peaks. Secondly, the sample band elution profile was numerically modeled on a theoretical basis assuming both un-retained and retained co-solvent injection plugs, respectively. These calculations quantitatively confirmed our first set of experiments but also pointed out that there is also an additional significant effect. Third, viscous fingering experiments were performed using viscosity contrast conditions imitating those encountered in SFC. These experiments clearly proved that viscous fingering effects play a significant role. A new method for determination of adsorption isotherms of solvents was also developed, called the “Retention Time Peak Method” (RTPM). The RTPM was used for fast estimation of the adsorption isotherms of the modifier and required using only two experiments.

  • 25.
    Fornstedt, Torgny
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Introduction to "Fundamental challenges and opportunities for preparative supercritical fluid chromatography by G. Guiochon, A. Tarafder [J. Chromatogr. A 1218 (2011) 1037-1114]"2016In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1446, p. 19-20Article in journal (Other academic)
  • 26.
    Fornstedt, Torgny
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Modern supercritical fluid chromatography: Possibilities and pitfalls2015In: LC GC Europe, ISSN 1471-6577, Vol. 33, no 3, p. 166-174Article in journal (Refereed)
    Abstract [en]

    There has been a revival of supercritical fluid chromatography (SFC) in recent years, especially in the chiral preparative field, but also more recently in the analytical area. However, SFC is considerably more complex than liquid chromatography (LC), mainly because of the compressibility of the mobile phase. One can say that SFC is a "€rubber variant of LC where everything considered constant in LC varies in SFC. In this review, we go through advances in theory, instrumentation, and novel applications.

  • 27.
    Fornstedt, Torgny
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Edström, Lena
    Department of Physical and Analytical Chemistry, Uppsala University.
    Lämmerhofer, Michael
    Lindner, Wolfgang
    Forssén, Patrik
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    A Novel Optimization Strategy for Incorporating of Additives in the Modelling Aimed at Improved Process Optimization2010Conference paper (Refereed)
  • 28.
    Fornstedt, Torgny
    et al.
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Forssen, Patrik
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Westerlund, Douglas
    Dept Med Chem, Analyt Pharmaceut Chem, POB 574, SE-75123 Uppsala, Sweden..
    System peaks and their impact in liquid chromatography2016In: TrAC. Trends in analytical chemistry, ISSN 0165-9936, E-ISSN 1879-3142, Vol. 81, p. 42-50Article, review/survey (Refereed)
    Abstract [en]

    A sample injected into a chromatographic system can generate extra peaks, called "system peaks", which in general are undetectable. However, for small analytical injections, solute zones eluting with a system zone will often give strongly deformed solute peaks. But, if a solute zone is eluted in a particular region of the system zone it will instead be strongly compressed and well-shaped. For overloaded solute injections, another type of complex band deformation may take place due to large system peaks. This review will present results related to system peak distortions of both small analytical peaks and large preparative ones. Guidelines will be given on how to avoid unwanted distortions and how to utilize the distortions for increased detectability in analytical chromatography, or enhanced production rate in preparative chromatography. The works reviewed here were mainly made by Georges Guiochon, and some of his close colleagues, and is dedicated to his memory. 

  • 29.
    Fornstedt, Torgny
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Forssén, Patrik
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Peterson, Patrik
    Astrazeneca.
    Edström, Lena
    Uppsala Universitet.
    Samie, Farzad
    Astrazeneca.
    Tatterton, Stephen
    Clarke, Adrian
    Astrazeneca.
    Why UHPLC Produces More Tailing Peaks Than HPLC, Why it Does Not Matter and How it Can be Addressed2012Conference paper (Refereed)
    Abstract [en]

    The purpose of this study is to demonstrate, with experiments and with computer simulations based on a firm chromatographic theory, that the wide spread perception of that the United States Pharmacopeia tailing factor must be lower than 2 (Tf < 2) is questionable when using the latest generation of LC equipment. It is shown that highly efficient LC separations like those obtained with sub-2 ÎŒm porous and 2.7 ÎŒm superficially porous particles (UHPLC) produce significantly higher Tf -values than the corresponding separation based on 3 ÎŒm porous particles (HPLC) when the same amount of sample is injected. Still UHPLC separations provide a better resolution to adjacent peaks. Expressions have been derived that describe how the Tf-value changes with particle size or number of theoretical plates. Expressions have also been derived that can be used to scale the injection volume based on particle size or number of theoretical plates to maintain the Tf-value when translating a HPLC separation to the corresponding UHPLC separation. An aspect that has been ignored in previous publications. Finally, data obtained from columns with different age/condition indicate that Tf-values should be complemented by a peak width measure to provide a more objective quality measure.

  • 30.
    Fornstedt, Torgny
    et al.
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Forssén, Patrik
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Modeling of Preparative Liquid Chromatography2013In: Liquid Chromatography: Fundamentals and Instrumentation / [ed] Salvatore Fanali, Paul R. Haddad; Poole, Colin; Schoenmakers, Peter; Lloyd, David K., Elsevier, 2013, p. 407-425Chapter in book (Refereed)
    Abstract [en]

    Abstract Preparative chromatography is today the best generic method for the purification of small drugs and valuable chemical components at the &lt;10 kg-level. Recent progress in computer technology and the development of new nonchiral and chiral stationary phases, as well as numerous improvements in reliability and economic performance, have considerably increased the interest in modeling in academic and industrial communities. This chapter serves as an introduction to the field of modeling preparative liquid chromatography in the classical batch mode, aiming at improved process purification of valuable chemical components, drugs, and chiral components. We go through the most important column and adsorption models and methods for determination of the essential thermodynamic adsorption data for both column characterization and process improvement. But, we also cover important operational conditions sometimes neglected in the modeling procedure, such as the impact of injection profiles and accounting for the additive in the modeling procedure.

  • 31.
    Fornstedt, Torgny
    et al.
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Forssén, Patrik
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Westerlund, Douglas
    Uppsala University.
    Basic HPLC Theory and Definitions: Retention, Thermodynamics, Selectivity, Zone Spreading, Kinetics, and Resolution2015In: Analytical Separation Science / [ed] AvJared Anderson, Alain Berthod, Veronica Pino, Apryll M. Stalcup, John Wiley & Sons, 2015, 1, p. 1-24Chapter in book (Refereed)
  • 32.
    Fornstedt, Torgny
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Peterson, Patrik
    Forssén, Patrik
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Karlsson, Anders
    Astrazeneca.
    HPLC vs UHPLC - a comparison of peak asymmetry and plan to step forward using Quality by Design (QbD) related to analytical methods2012Conference paper (Refereed)
    Abstract [en]

    The purpose of this study is to demonstrate, with experiments and with computer simulations based on a firm chromatographic theory, that the wide spread perception of that the United States Pharmacopeia tailing factor must be lower than 2 (Tf < 2) is questionable when using the latest generation of LC equipment. It is shown that highly efficient LC separations like those obtained with sub-2 m porous and 2.7 m superficially porous particles (UHPLC) produce significantly higher Tf-values than the corresponding separation based on 3 m porous particles (HPLC) when the same amount of sample is injected. Still UHPLC separations provide a better resolution to adjacent peaks. Expressions have been derived that describe how the Tf-value changes with particle size or number of theoretical plates. Expressions have also been derived that can be used to scale the injection volume based on particle size or number of theoretical plates to maintain the Tf-value when translating a HPLC separation to the corresponding UHPLC separation. This aspect has been ignored in previous publications. Finally, data obtained from columns with different age/condition indicate that Tf-values should be complemented by a peak width measure to provide a more objective quality measure. A plan to take a further step for using Quality by Design (QbD) related to analytical methods will also be presented [Ref 1]. Continuous improvement of an original HPLC method to an UHPLC method will be the used as a case study. The capability of the two methods will be deeply studied using mechanistic comparisons. Method criteria that must be fulfilled for the two chromatographic methods will be stated. [1] 2012 PDA Europe Workshop Quality by Design The Role of Analytical Science in Implementing QbD − Technical and Regulatory Aspects, Liverpool UK 6-7 March. This is an industrial – academic cooperation in the Fundamental Separation S

  • 33.
    Fornstedt, Torgny
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    A more reliable procedure for estimating interactions between drugs and biomolecules using biosensors: a comparison with chromatography2012Conference paper (Other academic)
    Abstract [en]

    This poster serves as background information to the corresponding lecture. Adsorption isotherms are essential in order to understand the interaction between small molecules such as pharmaceutical compounds and larger biomolecules. An adsorption isotherm describes the relationship of free substance in a solution with adsorbed substance to a surface, at a specific and constant temperature. Adsorption isotherms could be determined using several different method, all method have their pros and cons. In this study we are using two modern but principally different biosensors to determine interactions: quarts micro-balance (QCM) and Surface plasmon resonance (SPR) to determine interactions. For a long time adsorption isotherms has been determined solely by the chromatographic community. In this study we will present transformation of adsorption analysis tools from chromatography to biosensors, especially calculation of adsorption energy distribution prior adsorption model fit. We will also discuss how the experiments should be conducted. Guidelines will be given for the experimental setup and for when the chromatographic or a biosensor technique is to be preferred. This is a contribution from the Fundamental Separation Science Group in Karlstad www.separationscience.se

  • 34.
    Fornstedt, Torgny
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Determination of adsorption processes in modern chromatographic systems - Characterization, illustrations and guidlines how to avoid common pitfalls2010Conference paper (Refereed)
  • 35.
    Fornstedt, Torgny
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Insights into retention mechanisms and bio-molecular interactions gained from rigorous evaluation of adsorption data derived from HPLC and modern biosensors2012Conference paper (Refereed)
    Abstract [en]

    The estimation of reliable adsorption / equilibrium data are crucial for researchers in a wide range of fields such as analytical chemistry, biochemistry, chemical engineering, pharmacology and pharmacokinetics. Traditionally, equilibrium data are simply estimated from the statistically best-fitted model to adsorption data; but there are many dangerous pitfalls on this road. We have therefore recently improved several methods for adsorption isotherm determinations. As example, the accuracy of generating adsorption data by the elution by characteristic points (ECP) method was increased considerably by a new experimental approach that eliminated the post-loop dispersion; the method was also expanded to cover more different general types of adsorption isotherms than before. We have also made important improvements on the processing and evaluation of the data based on a firm theoretical basis. In this context, a new numerical tool was developed, calculation of the adsorption energy distribution (AED) allowing the estimation of the degree of heterogeneity of the interaction prior to the rival model fit. This concept has also been transposed to modern biosensors such as surface plasmon resonance (SPR) technology and continuous flow quartz crystal microbalance (QCM). We have utilized the improvements of generating and evaluation adsorption data to reveal more detailed information about molecular interactions in systems aimed at analytical and preparative separations and to understand better bio-molecular interactions derived from modern biosensors. This is a contribution from the Fundamental Separation Science Group in Karlstad www.separationscience.se

  • 36.
    Fornstedt, Torgny
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    The Tracer-pulse Experience €œ"reveiling the invisible iceberg"2010Conference paper (Refereed)
    Abstract [en]

    This Poster gives complementary material to the Lecture “Visualization of Chromatographic Surprises – The Helfferich Paradox Revisited. Here we will give more information on the remarkable deformations of invisible zones in the most simple and chromatographic system, unknown for most chromatographer. It is like reviling the part of the iceberg that is invisible, under the water.We recently described that “the injected sample molecules are not always found in the peak”. This happens if a small excess of molecules is injected into a column equilibrated with the same kind of molecules. Only one single peak will appear on the chromatogram (the system peak) while the injected molecules elute later in an invisible zone. The latter zones can be visualized by smart, but tedious, experimental procedures using either tracers or enantiomers. The phenomenon which was predicted by Helfferich in Science around 40 years ago was recently experimentally proven by us for the first time.As we continued to investigate the phenomena we could see that invisible zones containing the injected molecules take on the most strange and deformed shapes at higher sample loads. We will further show that a similar type of phenomenon appears in frontal analysis which results in invisible break-through and desorption curves. Depending on the conditions, the invisible breakthrough curves become more or less deformed. We explain the effects with the help of computer simulations which show an excellent agreement with experimental profiles of peaks and fronts.

    Single component, small perturbation

    Experimental Proof of a Chromatographic Paradox: Are the Injected Molecules in the Peak? Jörgen Samuelsson, Patrik Forsén, Morgan Stefansson and Torgny Fornstedt. Analytical Chemistry 2004, 76(4). 953-958.

    Single component, large perturbation

    Invisible Analyte Peak Deformations in Single-Component Liquid Chromatography” by Jörgen Samuelsson, Robert Arnell and Torgny Fornstedt. Analytical Chemistry (2006) 78 2765-2771.

    Single component, frontal analysis

    Discovery of invisible extra fronts in single-component frontal analysis in liquid chromatography by Jörgen Samuelsson and Torgny Fornstedt. Journal of Chromatography A (2006) 1114, 53-61.

    Multi-component, small perturbation

    Validation of the Tracer Pulse Method for Multi Component Liquid Chromatography- a Classical Paradox Revisited. Robert Arnell and Torgny Fornstedt. Analytical Chemistry (2006) 78, 4615-4623.

  • 37.
    Fornstedt, Torgny
    et al.
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Visualization of Chromatographic Surprises - The Helfferich Paradox Revisited2011Other (Other academic)
  • 38.
    Fornstedt, Torgny
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Edström, Lena
    A systematic investigation of deformations of overloaded peak shapes of basic compounds in reversed phase chromatography2010Conference paper (Refereed)
  • 39.
    Fornstedt, Torgny
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Edström, Lena
    Deformations of overloaded bands under pH-stable conditions in reversed phase chromatography2011In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1218, no 15, p. 1966-1973Article in journal (Refereed)
    Abstract

    It has recently been demonstrated, using mathematical models, how peculiar overloaded band profiles of basic compounds are due to the local pH in the column when using low capacity buffers. In this study, overloaded peak shapes resulting after injection of carefully pH matched samples close to the pKa of the chosen solute are investigated primarily on two columns; one hybrid silica C18 column (Kromasil Eternity) and one purely polymeric column (PLRP-S), the latter lacking C18 ligands. It was found that distorted peaks of the basic test compound appear even though there is no difference in pH between the injected sample solution and the eluent; the previous explanation to why these effects occur is based on a pH mismatch. Thus, the unusual band shapes are not due to an initial pH difference. Furthermore, it was observed that the effect does not appear on polymeric columns without C18 ligands, but only on columns with C18 ligands, independently of the base matrix (silica, hybrid silica, polymeric)

  • 40.
    Fornstedt, Torgny
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Edström, Lena
    Peak Deformations of Basic Compounds in Reversed Phase Chromatography Under pH-stable conditions2010Conference paper (Refereed)
  • 41.
    Fornstedt, Torgny
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Edström, Lena
    Department of Physical and Analytical Chemistry, Uppsala University.
    Forssén, Patrik
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Injection profiles in liquid chromatography. I. A fundamental investigation2010In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1217, no 26, p. 4306-4312Article in journal (Refereed)
    Abstract [en]

    This is a fundamental experimental and theoretical investigation on how the injection profile depends on important experimental parameters. The experiments revealed that the injection profile becomes more eroded with increased (i) flow rate, (ii) viscosity of the eluent, (iii) size of the solute, (iv) injection volume and (v) inner diameter of the injection loop capillary. These observations cannot be explained by a 1D-convection-diffusion equation, since it does not account for the effect of the parabolic flow and the radial diffusion on the elution profile. Therefore, the 1D model was expanded into a 2D-convection-diffusion equation with cylindrical coordinates, a model that showed a good agreement with the experimental injection profiles dependence on the experimental parameters. For a deeper understanding of the appearance of the injection profile the 2D model is excellent, but to account for injection profiles of various injection volumes and flow rates in preparative and process-chromatography using computer-optimizations, a more pragmatic approach must be developed. The result will give guidelines about how to reduce the extra-column variance caused by the injection profile. This is important both for preparative and analytical chromatography; in particular for modern analytical systems using short and narrow columns

  • 42.
    Fornstedt, Torgny
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Forssén, Patrik
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Transposing Advanced LC Theory to Modern Biosensors - Estimation of Bio-Molecular Interactions and Drug-Protein Interactions by Transposing LC-Theory to Biosensors2012Conference paper (Other academic)
    Abstract [en]

    This poster will also serves as background information to the lecture “Deeper insights in retention mechanisms and molecular interactions through improved methods for generating and evaluation adsorption data”. Adsorption isotherms are essential in order to understand the interaction between small molecules such as pharmaceutical compounds and larger biomolecules. An adsorption isotherm describes the relationship of free substance in a solution with adsorbed substance to a surface, at a specific and constant temperature. Adsorption isotherms could be determined using several different method, all method have their pros and cons. In this study we are using two modern but principally different biosensors to determine interactions: quarts micro-balance (QCM) and Surface plasmon resonance (SPR) to determine interactions. For a long time adsorption isotherms has been determined solely by the chromatographic community. In this study we will present transformation of adsorption analysis tools from chromatography to biosensors, especially calculation of adsorption energy distribution prior adsorption model fit. We will also discuss how the experiments should be conducted. Guidelines will be given for the experimental setup and for when the chromatographic or a biosensor technique is to be preferred. This is a contribution from the Fundamental Separation Science Group in Karlstad www.separationscience.se

  • 43.
    Fornstedt, Torgny
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Undin, Torgny
    Petersson, Patrik
    Törncrona, Anders
    Ekeroth,, Johan
    A New Approach for Characterization of Adsorption Processes in Analytical Chromatographic Systems by Combining Linear and Nonlinear Methods2010Conference paper (Refereed)
  • 44.
    Fornstedt, Torgny
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Undin, Torgny
    Törncrona,, Anders
    Deeper characterization of new hybrid silica phases - A combined experimental and theoretical approach2010Conference paper (Refereed)
  • 45.
    Fornstedt, Torgny
    et al.
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Åsberg, Dennis
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Lesko, Marek
    Rzeszow University of Technology.
    Enmark, Martin
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Physics.
    Forssén, Patrik
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Kaczmarski, Krzysztof
    Rzeszow University of Technology.
    New Procedure for Predictions of Overloaded Profiles in Gradient Elution2013Conference paper (Other academic)
    Abstract [en]

    To simulate the separation process in liquid chromatography, the competitive adsorption isotherms need to be known. In gradient elution, the adsorption isotherms are determined with isocratic experiments on different mobile-phase plateaus, levels covering the range used in the gradient program. This can lead to extreme retention times for some mobile-phase compositions and therefore it might even be impossible to determine all necessary adsorption data using the traditional isocratic approach. In this talk, we will present a method where single and competitive nonlinear adsorption isotherms are determined directly from overloaded elution profiles in gradient elution. The numerical coefficients in the adsorption isotherms are determined by the inverse method that minimizes the difference between calculated and experimental elution profiles. This is a new method where the need for tedious/impossible isocratic experiments is eliminated. The method is systematically verified using both synthetic and experimental data. Finally the new method is used to successfully predict elution profiles for a two-component mixture in gradient elution. The new method open up the opportunity to study the adsorption of substances whose retention factor vary strongly with the mobile-phase composition, like peptides and proteins, where the classic methods will fail. We also intend to transfer the metholology for SFC in near future; but there are some problems to be solved first (see our SFC posters). This is a contribution from the Fundamental Separation Science Group www.FSSG.se

  • 46.
    Forssen, Patrik
    et al.
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Fornstedt, Torgny
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    A model free method for estimation of complicated adsorption isotherms in liquid chromatography2015In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1409, p. 108-115Article in journal (Refereed)
    Abstract [en]

    Here we show that even extremely small variations in the adsorption isotherm can have a tremendous effect on the shape of the overloaded elution profiles and that the earlier in the adsorption isotherms the variation take place, the larger its impact on the shape of the elution profile. These variations are so small that they can be "hidden" by the discretization and in the general experimental noise when using traditional experimental methods, such as frontal analysis, to measure adsorption isotherms. But as the effects of these variations are more clearly visible in the elution profiles, the Inverse Method (IM) of adsorption isotherm estimation is an option. However, IM usually requires that one selects an adsorption isotherm model prior to the estimation process. Here we show that even complicated models might not be able to estimate the adsorption isotherms with multiple inflection points that small variations might give rise to. We therefore developed a modified IM that, instead of fixed adsorption isotherm models, uses monotone piecewise interpolation. We first validated the method with synthetic data and showed that it can be used to estimate an adsorption isotherm, which accurately predicts an extremely "strange" elution profile. For this case it was impossible to estimate the adsorption isotherm using IM with a fixed adsorption model. Finally, we will give an example of a real chromatographic system where adsorption isotherm with inflection points is estimated by the modified IM.

  • 47. Forssén, P.
    et al.
    Multia, E.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences (from 2013).
    Andersson, M.
    Aastrup, T.
    Altun, S.
    Wallinder, D.
    Wallbing, L.
    Liangsupree, T.
    Riekkola, M. -L
    Fornstedt, Torgny
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences (from 2013).
    Reliable Strategy for Analysis of Complex Biosensor Data2018In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 90, no 8, p. 5366-5374Article in journal (Refereed)
    Abstract [en]

    When using biosensors, analyte biomolecules of several different concentrations are percolated over a chip with immobilized ligand molecules that form complexes with analytes. However, in many cases of biological interest, e.g., in antibody interactions, complex formation steady-state is not reached. The data measured are so-called sensorgram, one for each analyte concentration, with total complex concentration vs time. Here we present a new four-step strategy for more reliable processing of this complex kinetic binding data and compare it with the standard global fitting procedure. In our strategy, we first calculate a dissociation graph to reveal if there are any heterogeneous interactions. Thereafter, a new numerical algorithm, AIDA, is used to get the number of different complex formation reactions for each analyte concentration level. This information is then used to estimate the corresponding complex formation rate constants by fitting to the measured sensorgram one by one. Finally, all estimated rate constants are plotted and clustered, where each cluster represents a complex formation. Synthetic and experimental data obtained from three different QCM biosensor experimental systems having fast (close to steady-state), moderate, and slow kinetics (far from steady-state) were evaluated using the four-step strategy and standard global fitting. The new strategy allowed us to more reliably estimate the number of different complex formations, especially for cases of complex and slow dissociation kinetics. Moreover, the new strategy proved to be more robust as it enables one to handle system drift, i.e., data from biosensor chips that deteriorate over time.

  • 48.
    Forssén, Patrik
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Edström, Lena
    Uppsala University.
    Lämmerhofer, Michael
    Institute of Pharmaceutical Sciences, University of Tübingen, Germany.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Karlsson, Anders
    Department of Molecular Biology, Göteborg University .
    Lindner, Wolfgang
    Department of Analytical Chemistry, University of Vienna, Austria.
    Fornstedt, Torgny
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences. Uppsalas universitet.
    Optimization strategies accounting for the additive in preparative chiral liquid chromatography2012In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1269, p. 279-286, article id SIArticle in journal (Refereed)
    Abstract [en]

    This study is an in-depth investigation on how numerical optimization strategies that also account forthe additive type and concentration, in preparative batch chromatography, should be performed. As amodel system, the separation of Z-(R,S)-2-aminobutyric acid enantiomers on a quinidine carbamate-based chiral stationary phase in polar organic mode was used, with different additive strengths of aceticacid or hexanoic acid in methanol. The inverse method was used to determine the competitive adsorp-tion isotherm parameters for the enantiomers and the additives. Three different optimization strategieswere examined: (1) injection volume optimization, (2) optimization of injection volume and additiveconcentration, and (3) full optimization including injection volume, additive concentration, sample con-centration and flow rate. It was concluded that (i) it is important to incorporate the additive concentrationin the optimization procedure to achieve the highest production rates, (ii) the full optimization strategyhad the overall best results, and (iii) the selection of additive is very important (here acetic acid additivewas superior to the hexanoic acid additive). By including the additive in the adsorption model and inthe numerical optimization it is not only possible to achieve higher production rates but also to properlyselect the additive that is most advantageous for the specific separation problem.

  • 49.
    Forssén, Patrik
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Edström, Lena
    Uppsala University.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Fornstedt, Torgny
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Injection profiles in liquid chromatography II: Predicting accurate injection-profiles for computer-assisted preparative optimizations2011In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1218, no 34, p. 5794-5800Article in journal (Refereed)
    Abstract [en]

    In computer assisted optimization of liquid chromatography it has been known for some years that it is important to use experimental injection profiles, instead of rectangular ones, in order to calculate accurate elution bands. However, the incorrectly assumed rectangular profiles are still mostly used especially in numerical optimizations. The reason is that the acquisition of injection profiles, for each injection volume and each flow rate considered in a computer-assisted optimization requires a too large number of experiments. In this article a new function is proposed, which enables highly accurate predictions of the injection profiles and thus more accurate computer optimizations, with a minimum experimental effort. To model the injection profiles for any injection volume at a constant flow rate, as few as two experimental injection profiles are required. If it is desirable to also take the effect of flow rate on the injection profiles into account, then just two additional experiments are required. The overlap between fitted and experimental injection profiles at different flow rates and different injection volumes were excellent, more than 90%, using experimental injection profiles from just four different injection volumes at two different flow rates. Moreover, it was demonstrated that the flow rate has a minor influence on the injection profiles and that the injection volume is the main parameter that needs to be accounted for.

  • 50.
    Forssén, Patrik
    et al.
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences (from 2013).
    Fornstedt, Torgny
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences (from 2013).
    Impact of column and stationary phase properties on the productivity in chiral preparative LC2018In: Journal of Separation Science, ISSN 1615-9306, E-ISSN 1615-9314, Vol. 41, no 6, p. 1346-1354Article in journal (Refereed)
    Abstract [en]

    By generating 1500 random chiral separation systems, assuming two-site Langmuir interactions, we investigated numerically how the maximal productivity (P-R,P-max) was affected by changes in stationary phase adsorption properties. The relative change in P-R,P-max, when one adsorption property changed 10%, was determined for each system and for each studied parameter the corresponding productivity change distribution of the systems was analyzed. We could conclude that there is no reason to have columns with more than 500 theoretical plates and larger selectivity than 3. More specifically, we found that changes in selectivity have a major impact on P-R,P-max if it is below similar to 2 and, interestingly, increasing selectivity when it is above similar to 3 decreases P-R,P-max. Increase in relative saturation capacity will have a major impact on P-R,P-max if it is below similar to 40%, but only modest above this percent. Increasing total monolayer saturation capacity, or decreasing the first eluting enantiomer's retention factor, will have a modest effect on P-R,P-max and increased efficiency will have almost no effect at all on P-R,P-max unless it is below similar to 500 theoretical plates. Finally, we showed that chiral columns with superior analytic performance might have inferior preparative performance, or vice versa. It is, therefore, not possible to assess columns based on their analytical performance alone.

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