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  • 1.
    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).

  • 2.
    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

  • 3.
    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

  • 4.
    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.

  • 5.
    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.

  • 6.
    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.

  • 7.
    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.

  • 8.
    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.

  • 9.
    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.

  • 10.
    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

  • 11.
    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)
  • 12.
    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.

  • 13.
    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.

  • 14.
    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

  • 15.
    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

  • 16.
    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

  • 17.
    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

  • 18.
    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.

  • 19.
    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.

  • 20.
    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.

  • 21.
    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.

  • 22.
    Forssén, Patrik
    et al.
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences (from 2013).
    Multia, Evgen
    University of Helsinki, Finland.
    Samuelsson, Jörgen
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences (from 2013).
    Andersson, Marie
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences (from 2013).
    Aastrup, Teodor
    Attana AB, Sweden.
    Altun, Samuel
    Attana AB, Sweden.
    Wallinder, Daniel
    Attana AB, Sweden.
    Wallbing, Linus
    Attana AB, Sweden.
    Liangsupree, Thanaporn
    University of Helsinki, Finland.
    Riekkola, Marja-Liisa
    University of Helsinki, Finland.
    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.

  • 23.
    Forssén, Patrik
    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.
    Relative importance of column and adsorption parameters on the productivity in preparative liquid chromatography. I: Investigation of a chiral separation system2013In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1299, p. 58-63Article in journal (Refereed)
    Abstract [en]

    Starting out from an experimental chiral separation system we have used computer simulations for a systematic investigation on how the maximum productivity depends on changes in column length, packing particle size, column efficiency, back pressure, sample concentration/solubility, selectivity, retention factor of the first eluting component and monolayer saturation capacity. The study was performed by changing these parameters, one at a time, and then calculating the corresponding change in maximum productivity. The three most important parameters for maximum production rate was found to be (i) the selectivity (ii) the retention factor of the first eluting component and (iii) the column length. Surprisingly, the column efficiency and sample concentration/solubility were of minor importance. These findings can be used as rough guidelines for column selection, e.g. a low-efficiency column are more likely perform better, in terms of productivity, than a high-efficiency column that have higher retention factor for the first eluting component.

  • 24.
    Forssén, Patrik
    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.
    Relative importance of column and adsorption parameters on the productivity in preparative liquid chromatography II: Investigation of separation systems with competitive Langmuir adsorption isotherms2014In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1347, p. 72-79Article in journal (Refereed)
    Abstract [en]

    In this study we investigated how the maximum productivity for commonly used, realistic separation system with a competitive Langmuir adsorption isotherm is affected by changes in column length, packing particle size, mobile phase viscosity, maximum allowed column pressure, column efficiency, sample concentration/solubility, selectivity, monolayer saturation capacity and retention factor of the first eluting compound. The study was performed by generating 1000 random separation systems whose optimal injection volume was determined, i.e., the injection volume that gives the largest achievable productivity. The relative changes in largest achievable productivity when one of the parameters above changes was then studied for each system and the productivity changes for all systems were presented as distributions. We found that it is almost always beneficial to use shorter columns with high pressure drops over the column and that the selectivity should be greater than 2. However, the sample concentration and column efficiency have very limited effect on the maximum productivity. The effect of packing particle size depends on the flow rate limiting factor. If the pumps maximum flow rate is the limiting factor use smaller packing, but if the pressure of the system is the limiting factor use larger packing up to about 40μm.

  • 25.
    Hernandez, Victor Agmo
    et al.
    Uppsala University, Sweden.
    Samuelsson, Jorgen
    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.
    Fornstedt, Torgny
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences. Uppsala University, Sweden.
    Enhanced interpretation of adsorption data generated by liquid chromatography and by modern biosensors2013In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1317, p. 22-31Article in journal (Refereed)
    Abstract [en]

    In this study we demonstrate the importance of proper data processing in adsorption isotherm estimations. This was done by investigating and reprocessing data from five cases on two closely related platforms: liquid chromatography (LC) and biosensors. The previously acquired adsorption data were reevaluated and reprocessed using a three-step numerical procedure: (i) preprocessing of adsorption data, (ii) adsorption data analysis and (iii) final rival model fit. For each case, we will discuss what we really measure and what additional information can be obtained by numerical processing of the data. These cases clearly demonstrate that numerical processing of LC and biosensor data can be used to gain deeper understanding of molecular interactions with adsorption media. This is important because adsorption data, especially from biosensors, is often processed using old and simplified methods. (C) 2013 Elsevier B.V. All rights reserved.

  • 26.
    Liangsupree, Thanaporn
    et al.
    University Helsinki, Finland.
    Multia, Evgen
    University Helsinki, Finland.
    Metso, Jari
    Biomedicum 2U, Finland.
    Jauhiainen, Matti
    Biomedicum 2U, Finland.
    Forssén, Patrik
    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).
    Oorni, Katariina
    Wihuri Research Institute, Finland.
    Podgornik, Ales
    University Ljubljana, Slovenia.
    Riekkola, Marja-Liisa
    University Helsinki, Finland.
    Rapid affinity chromatographic isolation method for LDL in human plasma by immobilized chondroitin-6-sulfate and anti-apoB-100 antibody monolithic disks in tandem2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 11235Article in journal (Refereed)
    Abstract [en]

    Low-density lipoprotein (LDL) is considered the major risk factor for the development of atherosclerotic cardiovascular diseases (ASCVDs). A novel and rapid method for the isolation of LDL from human plasma was developed utilising affinity chromatography with monolithic stationary supports. The isolation method consisted of two polymeric monolithic disk columns, one immobilized with chondroitin-6-sulfate (C6S) and the other with apolipoprotein B-100 monoclonal antibody (anti-apoB-100 mAb). The first disk with C6S was targeted to remove chylomicrons, very-low-density lipoprotein (VLDL) particles, and their remnants including intermediate-density lipoprotein (IDL) particles, thus allowing the remaining major lipoprotein species, i.e. LDL, lipoprotein(a) (Lp(a)), and high-density lipoprotein (HDL) to flow to the anti-apoB-100 disk. The second disk captured LDL particles via the anti-apoB-100 mAb attached on the disk surface in a highly specific manner, permitting the selective LDL isolation. The success of LDL isolation was confirmed by different techniques including quartz crystal microbalance. In addition, the method developed gave comparable results with ultracentrifugation, conventionally used as a standard method. The reliable results achieved together with a short isolation time (less than 30 min) suggest the method to be suitable for clinically relevant LDL functional assays.

  • 27.
    Lin, G.
    et al.
    Zhejiang Univ, China.
    Zhang, Y.
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences (from 2013). Örebro universitet.
    Cheng, X.
    Zhejiang Univ, China.
    Gulliksson, M.
    Örebro universitet.
    Forssén, Patrik
    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).
    A regularizing Kohn-Vogelius formulation for the model-free adsorption isotherm estimation problem in chromatography2018In: Applicable Analysis, ISSN 0003-6811, E-ISSN 1563-504X, Vol. 97, no 1, p. 13-40Article in journal (Refereed)
    Abstract [en]

    Competitive adsorption isotherms must be estimated in order to simulate and optimize modern continuous modes of chromatography in situations where experimental trial-and-error approaches are too complex and expensive. The inverse method is a numeric approach for the fast estimation of adsorption isotherms directly from overloaded elution profiles. However, this identification process is usually ill-posed. Moreover, traditional model-based inverse methods are restricted by the need to choose an appropriate adsorption isotherm model prior to estimate, which might be very hard for complicated adsorption behavior. In this study, we develop a Kohn-Vogelius formulation for the model-free adsorption isotherm estimation problem. The solvability and convergence for the proposed inverse method are studied. In particular, using a problem-adapted adjoint, we obtain a convergence rate under substantially weaker and more realistic conditions than are required by the general theory. Based on the adjoint technique, a numerical algorithm for solving the proposed optimization problem is developed. Numerical tests for both synthetic and real-world problems are given to show the efficiency of the proposed regularization method.

  • 28.
    Petersson, Patrik
    et al.
    AstraZeneca R&D Lund, SE-221 87 Lund, Sweden.
    Forssén, Patrik
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Edström, Lena
    Department of Physical and Analytical Chemistry, BMC Box 577, SE-751 23 Uppsala, Sweden.
    Samie, Farzad
    AstraZeneca Nordic Headquarters (ISMO), Södertälje.
    Tatterton, Stephen
    AstraZeneca R&D Charnwood, Loughborough, Leicestershire LE11 5RH, UK.
    Clarke, Adrian
    AstraZeneca R&D Charnwood, Loughborough, Leicestershire LE11 5RH, UK.
    Fornstedt, Torgny
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Why ultra high performance liquid chromatography produces more tailing peaks than high performance liquid chromatography, why it does not matter and how it can be addressed2011In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 1218, no 39, p. 6914-6921Article in journal (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 &lt; 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 μm porous and 2.7 μm superficially porous particles (UHPLC) produce significantly higher Tf-values than the corresponding separation based on 3 μm 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.

  • 29.
    Samuelsson, Jörgen
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Enmark, Martin
    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.
    Highlighting Important Parameters Often Neglected in Numerical Optimization of Preparative Chromatography2012In: Chemical Engineering & Technology, ISSN 0930-7516, E-ISSN 1521-4125, Vol. 35, no 1, p. 149-156Article in journal (Refereed)
    Abstract [en]

    When a chromatographic separation process is numerically optimized, a number of input parameters to the column model need to be accurately determined, and the accuracy will affect the reliability of the predicted optimal operational conditions. Furthermore, the numerical accuracy of the solution to the column model will have similar impact. The input parameters holdup volume, injection profiles, and the selection of an algorithm for solving the column model were investigated. Errors in parameters or a numerical error in the solution of the column model were found to lead to a prediction of a product fraction where the set purity and/or yield requirements are not met.

  • 30.
    Samuelsson, Jörgen
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Enmark, Martin
    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.
    Characterization of adsorption in SFC: An evaluation of methods used in LC2012Conference 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

  • 31.
    Samuelsson, Jörgen
    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.
    Högblom, Joakim
    Eka Chemicals.
    A Holistic View on Optimization of Preparative Liquid Chromatography – Importance of Column Properties and Design.2012Conference paper (Refereed)
    Abstract [en]

    Several important studies based on firm theory ground - have been made on the different parameters of importance in chromatographic process optimizations during the recent years. In this presentation we take an holistic view by investigating i) the relative importance of the operational parameters and column properties and ii) how these effect the optimal column design. For optimization we used an advanced global response surface method combined with local gradient methods. As a model system we used the practical problem of purification of one or both optical isomers of a racemate. In the first part, we investigated the relative importance of stationary phase characteristics such as: (i) the retention factor, (ii) the selectivity, (iii) the saturation capacity (iv), the efficiency and (v) the maximum allowed operational pressure. In the second part we investigated how the optimal column design for a preparative separation problem is affected by column properties, such as particle size, and optimization constraints, such as required yield. The investigation showed – in contrast to what is generally believed – that the saturation capacity of the stationary phase is of minor importance, instead the maximum allowed operational pressure is one of the most important parameter. Moreover, smaller size packing materials always shows much lower solvent consumption. This is a great environmental and economical advantage of using smaller packing materials. Rules of thumbs, derived from the holistic optimizations, will be given for industrial preparative settings in the batch mode.

  • 32.
    Samuelsson, Jörgen
    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.
    Fornstedt, Torgny
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Sample conditions to avoid pH distortion in RP-LC2013In: Journal of Separation Science, ISSN 1615-9306, E-ISSN 1615-9314, Vol. 36, no 23, p. 3769-3775Article in journal (Refereed)
    Abstract [en]

    Band deformations might take place for acids and bases in preparative applications and adsorption studies where it is necessary to use overloaded injections. In this study, we focus on how deformations can be prevented without using highly concentrated buffers that may precipitate in the eluent. We have systematically investigated how the elution zones depend on which protolytic form the analyte has when it is dissolved. Basic and acidic model compounds are investigated using eluents with different pH values and the resulting elution profiles are compared when the analytes are dissolved in their protonated and deprotonated form, i.e., in uncharged form or as different kinds of salts. Depending on the analyte's protolytic form, a sample zone is created at the column inlet whose pH deviates, more or less, from the bulk eluent's. If the local adsorption strength in this sample zone is greater than the bulk eluent's, the elution profiles are compressed. Under opposite conditions, the eluted bands are more or less deformed and may even be split; completely different deformations can even take place for different kinds of salt combinations. Explanations of these, and other, effects, together with detailed guidelines for proper sample preparation to avoid peak deformations, are given.

  • 33.
    Samuelsson, Jörgen
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Ņsberg, Dennis
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Enmark, Martin
    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.
    Modeling Competitive Adsorption Isotherms in Gradient Elution Nonlinear Reversed Phase Liquid Chromatography.2012Conference paper (Refereed)
    Abstract [en]

    Several important studies – based on firm theory ground - have been made on the different parameters of importance in chromatographic process optimizations during the recent years. In this presentation we take an holistic view by investigating i) the relative importance of the operational parameters and column properties and ii) how these effect the optimal column design. For optimization we used an advanced global response surface method combined with local gradient methods. As a model system we used the practical problem of purification of one or both optical isomers of a racemate. In the first part, we investigated the relative importance of stationary phase characteristics such as: (i) the retention factor, (ii) the selectivity, (iii) the saturation capacity (iv), the efficiency and (v) the maximum allowed operational pressure. In the second part we investigated how the optimal column design for a preparative separation problem is affected by column properties, such as particle size, and optimization constraints, such as required yield. The investigation showed – in contrast to what is generally believed – that the saturation capacity of the stationary phase is of minor importance, instead the maximum allowed operational pressure is one of the most important parameter. Moreover, smaller size packing materials always shows much lower solvent consumption. This is a great environmental and economical advantage of using smaller packing materials. Rules of thumbs, derived from the holistic optimizations, will be given for industrial preparative settings in the batch mode.

  • 34.
    Zhang, Y.
    et al.
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences (from 2013).
    Forssén, Patrik
    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).
    Gulliksson, M.
    Orebrov Univ, Sch Sci & Technol, Dept Math, Orebro, Sweden.
    Dai, X.
    Zhejiang Univ, City Coll, Sch Comp Sci, Hangzhou, Zhejiang, Peoples R China.
    An adaptive regularization algorithm for recovering the rate constant distribution from biosensor data2018In: Inverse Problems in Science and Engineering, ISSN 1741-5977, E-ISSN 1741-5985, Vol. 26, no 10, p. 1464-1489Article in journal (Refereed)
    Abstract [en]

    We present here the theoretical results and numerical analysis of a regularization method for the inverse problem of determining the rate constant distribution from biosensor data. The rate constant distribution method is a modern technique to study binding equilibrium and kinetics for chemical reactions. Finding a rate constant distribution from biosensor data can be described as a multidimensional Fredholm integral equation of the first kind, which is a typical ill-posed problem in the sense of J. Hadamard. By combining regularization theory and the goal-oriented adaptive discretization technique, we develop an Adaptive Interaction Distribution Algorithm (AIDA) for the reconstruction of rate constant distributions. The mesh refinement criteria are proposed based on the a posteriori error estimation of the finite element approximation. The stability of the obtained approximate solution with respect to data noise is proven. Finally, numerical tests for both synthetic and real data are given to show the robustness of the AIDA.

  • 35.
    Zhang, Y.
    et al.
    Orebro Univ, Sch Sci & Technol, Dept Math, Orebro, Sweden.;Karlstad Univ, Dept Engn & Chem Sci, Karlstad, Sweden..
    Lin, G.
    Zhejiang Univ, Dept Math, Hangzhou, Zhejiang, Peoples R China..
    Gulliksson, M.
    Orebro Univ, Sch Sci & Technol, Dept Math, Orebro, Sweden..
    Forssén, Patrik
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences (from 2013). Karlstad Univ, Dept Engn & Chem Sci, 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, Karlstad, Sweden..
    Cheng, X.
    Zhejiang Univ, Dept Math, Hangzhou, Zhejiang, Peoples R China..
    An adjoint method in inverse problems of chromatography2017In: Inverse Problems in Science and Engineering, ISSN 1741-5977, E-ISSN 1741-5985, Vol. 25, no 8, p. 1112-1137Article in journal (Refereed)
    Abstract [en]

    How to determine adsorption isotherms is an issue of significant importance in chromatography. A modern technique of obtaining adsorption isotherms is to solve an inverse problem so that the simulated batch separation coincides with actual experimental results. In this work, as well as the natural least-square approach, we consider a Kohn-Vogelius type formulation for the reconstruction of adsorption isotherms in chromatography, which converts the original boundary fitting problem into a domain fitting problem. Moreover, using the first momentum regularizing strategy, a new regularization algorithm for both the Equilibrium-Dispersive model and the Transport-Dispersive model is developed. The mass transfer resistance coefficients in the Transport-Dispersive model are also estimated by the proposed inverse method. The computation of the gradients of objective functions for both of the two models is derived by the adjoint method. Finally, numerical simulations for both a synthetic problem and a real-world problem are given to show the robustness of the proposed algorithm.

  • 36.
    Åsberg, Dennis
    et al.
    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 Chemical Sciences.
    Samuelsson, Jörgen
    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.
    Kaczmarski, Krzysztof
    Rzeszow University of Technology.
    Fornstedt, Torgny
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.
    Prediction of Overloaded Profiles in Gradient Elution Chromatography2013Conference paper (Other academic)
    Abstract [en]

    This poster is a compliment to the oral presentation “A new procedure for improved predictions of overloaded profiles in gradient elution”. In order 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 that covers 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. We 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 the calculated and the experimental elution profiles. This is an extension of the inverse 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 makes it possible 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. A similar situation occurs in SFC and the proposed approach could with modifications probably be used also there. This is a contribution from the Fundamental Separation Science Group www.FSSG.se

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