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Samuelsson, J., Eiriksson, F. F., Åsberg, D., Thorsteinsdóttir, M. & Fornstedt, T. (2019). Determining gradient conditions for peptide purification in RPLC with machine-learning-based retention time predictions. Journal of Chromatography A, 1598, 92-100
Open this publication in new window or tab >>Determining gradient conditions for peptide purification in RPLC with machine-learning-based retention time predictions
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2019 (English)In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1598, p. 92-100Article in journal (Refereed) Published
Abstract [en]

A strategy for determining a suitable solvent gradient in silico in preparative peptide separations is presented. The strategy utilizes a machine-learning–based method, called ELUDE, for peptide retention time predictions based on the amino acid sequences of the peptides. A suitable gradient is calculated according to linear solvent strength theory by predicting the retention times of the peptides being purified at three different gradient slopes. The advantage of this strategy is that fewer experiments are needed to develop a purification method, making it useful for labs conducting many separations but with limited resources for method development. The preparative separation of met-enkephalin and leu-enkephalin was used as model solutes on two stationary phases: XBridge C18 and CSH C18. The ELUDE algorithm contains a support vector regression and is pre-trained, meaning that only 10–50 peptides are needed to calibrate a model for a certain stationary phase and gradient. The calibration is done once and the model can then be used for new peptides similar in size to those in the calibration set. We found that the accuracy of the retention time predictions is good enough to usefully estimate a suitable gradient and that it was possible to compare the selectivity on different stationary phases in silico. The absolute relative errors in retention time for the predicted gradients were 4.2% and 3.7% for met-enkephalin and leu-enkephalin, respectively, on the XBridge C18 column and 2.0% and 2.8% on the CSH C18 column. The predicted retention times were also used as initial values for adsorption isotherm parameter determination, facilitating the numerical calculation of overloaded elution profiles. Changing the trifluoroacetic acid (TFA) concentration from 0.05% to 0.15% in the eluent did not seriously affect the error in the retention time predictions for the XBridge C18 column, an increase of 1.0 min (in retention factor, 1.3). For the CSH C18 column the error was, on average, 2.6 times larger. This indicates that the model needs to be recalibrated when changing the TFA concentration for the CSH column. Studying possible scale-up complications from UHPLC to HPLC such as pressure, viscous heating (i.e., temperature gradients), and stationary-phase properties (e.g., packing heterogeneity and surface chemistry) revealed that all these factors were minor to negligible. The pressure effect had the largest effect on the retention, but increased retention by only 3%. In the presented case, method development can therefore proceed using UHPLC and then be robustly transferred to HPLC.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
In silico determination, Machine learning, Peptide, Preparative, Purification, Retention time prediction, Bioinformatics, Calibration, Errors, Forecasting, Learning systems, Pressure effects, Separation, Surface chemistry, In-silico, Linear solvent strengths, Numerical calculation, Preparative separation, Purification method, Support vector regression (SVR), Peptides
National Category
Materials Engineering Bioinformatics and Systems Biology Analytical Chemistry
Identifiers
urn:nbn:se:kau:diva-72137 (URN)10.1016/j.chroma.2019.03.043 (DOI)2-s2.0-85063889315 (Scopus ID)
Available from: 2019-05-28 Created: 2019-05-28 Last updated: 2019-07-04Bibliographically approved
Enmark, M., Rova, M., Samuelsson, J., Örnskov, E., Schweikart, F. & Fornstedt, T. (2019). Investigation of factors influencing the separation of diastereomers of phosphorothioated oligonucleotides. Analytical and Bioanalytical Chemistry, 411(15), 3383-3394
Open this publication in new window or tab >>Investigation of factors influencing the separation of diastereomers of phosphorothioated oligonucleotides
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2019 (English)In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 411, no 15, p. 3383-3394Article in journal (Refereed) Published
Abstract [en]

This study presents a systematic investigation of factors influencing the chromatographic separation of diastereomers of phosphorothioated pentameric oligonucleotides as model solutes. Separation was carried out under ion-pairing conditions using an XBridge C18 column. For oligonucleotides with a single sulfur substitution, the diastereomer selectivity was found to increase with decreasing carbon chain length of the tertiary alkylamine used as an ion-pair reagent. Using an ion-pair reagent with high selectivity for diastereomers, triethylammonium, it was found the selectivity increased with decreased ion-pair concentration and shallower gradient slope. Selectivity was also demonstrated to be dependent on the position of the modified linkage. Substitutions at the center of the pentamer resulted in higher diastereomer selectivity compared to substitutions at either end. For mono-substituted oligonucleotides, the retention order and stereo configuration were consistently found to be correlated, with Rp followed by Sp, regardless of which linkage was modified. The type of nucleobase greatly affects the observed selectivity. A pentamer of cytosine has about twice the diastereomer selectivity of that of thymine. When investigating the retention of various oligonucleotides eluted using tributylammonium as the ion-pairing reagent, no diastereomer selectivity could be observed. However, retention was found to be dependent on both the degree and position of sulfur substitution as well as on the nucleobase. When analyzing fractions collected in the front and tail of overloaded injections, a significant difference was found in the ratio between Rp and Sp diastereomers, indicating that the peak broadening observed when using tributylammonium could be explained by partial diastereomer separation.

Place, publisher, year, edition, pages
Springer, 2019
Keywords
IP-RPLC, Ion-pair, Oligonucleotide, Antisense, Phosphorothioate, Diastereomerr
National Category
Chemical Sciences
Research subject
Chemistry
Identifiers
urn:nbn:se:kau:diva-72453 (URN)10.1007/s00216-019-01813-2 (DOI)000469757300016 ()
Available from: 2019-06-12 Created: 2019-06-12 Last updated: 2019-07-01
Vera, C. M., Samuelsson, J., Fornstedt, T., Dennis, G. R. & Shalliker, R. A. (2019). Visualisation of axial temperature gradients and heat transfer process of different solvent compositions in ultra high performance liquid chromatography using thermography. Microchemical journal (Print), 145, 927-935
Open this publication in new window or tab >>Visualisation of axial temperature gradients and heat transfer process of different solvent compositions in ultra high performance liquid chromatography using thermography
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2019 (English)In: Microchemical journal (Print), ISSN 0026-265X, E-ISSN 1095-9149, Vol. 145, p. 927-935Article in journal (Refereed) Published
Abstract [en]

Thermal imaging was used to visualise axial temperature gradients in chromatography columns running solvents of water, methanol and acetonitrile at various compositions. The non-monotonic relationship between solvent composition and viscosity enabled the testing of solvent conditions with equivalent viscosities, but with different percentages of water. It was observed that at equivalent power the increase in water composition leads to an increase in the magnitude of the axial temperature gradients (Delta T-A). Observing the change in temperature at defined points (Delta T-p) with increasing power indicates that the relationship between Delta T-p and power is not linear but deviates at higher power. The degree of this deviation depends on what point along the column axis is observed as well what solvent composition is used. Being able to monitor the entire length of the column using thermography also allowed for the observation of different rates of heat transfer through to the bulky stainless steel end fittings from solvent to solvent. Revealing that water is able to transfer heat to the stainless steel surface in such a way that the temperature profile of transition point between columns to end fitting is more gradual compared to when methanol or acetonitrile is used. This evidence plus video data collected indicates that at constant flow rate an equilibrium between heat generated and heat dissipated through the stainless steel is formed, which differs from solvent to solvent. Moreover any disruption to this equilibrium, i.e. a change in flow rate will momentarily change the shape of the temperature profile.

Place, publisher, year, edition, pages
Elsevier, 2019
National Category
Physical Chemistry
Research subject
Physics
Identifiers
urn:nbn:se:kau:diva-71232 (URN)10.1016/j.microc.2018.11.037 (DOI)000457513000118 ()
Available from: 2019-02-21 Created: 2019-02-21 Last updated: 2019-03-06Bibliographically approved
Enmark, M., Glenne, E., Leśko, M., Langborg Weinmann, A., Leek, T., Kaczmarski, K., . . . Fornstedt, T. (2018). Investigation of robustness for supercritical fluid chromatography separation of peptides: Isocratic vs gradient mode. Journal of Chromatography A, 1568, 177-187
Open this publication in new window or tab >>Investigation of robustness for supercritical fluid chromatography separation of peptides: Isocratic vs gradient mode
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2018 (English)In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1568, p. 177-187Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Gramicidin, Method transfer, Peptide, Robustness, SFC, Water, Design of experiments, Effluent treatment, Gas chromatography, Oceanography, Peptides, Robustness (control systems), Supercritical fluids, Coriolis mass flow meter, Experimental system, Gradient separations, Method transfers, Operational conditions, Super critical fluid chromatography, Volumetric flow rate, Solvents
National Category
Chemical Engineering
Research subject
Chemical Engineering
Identifiers
urn:nbn:se:kau:diva-69063 (URN)10.1016/j.chroma.2018.07.029 (DOI)000443669600019 ()
Available from: 2018-09-06 Created: 2018-09-06 Last updated: 2018-11-22Bibliographically approved
Samuelsson, J., Leśko, M., Enmark, M., Högblom, J., Karlsson, A. & Kaczmarski, K. (2018). Optimizing Column Length and Particle Size in Preparative Batch Chromatography Using Enantiomeric Separations of Omeprazole and Etiracetam as Models: Feasibility of Taguchi Empirical Optimization. Chromatographia, 81(6), 851-860
Open this publication in new window or tab >>Optimizing Column Length and Particle Size in Preparative Batch Chromatography Using Enantiomeric Separations of Omeprazole and Etiracetam as Models: Feasibility of Taguchi Empirical Optimization
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2018 (English)In: Chromatographia, Vol. 81, no 6, p. 851-860Article in journal (Refereed) Published
Abstract [en]

The overreaching purpose of this study is to evaluate new approaches for determining the optimal operational and column conditions in chromatography laboratories, i.e., how best to select a packing material of proper particle size and how to determine the proper length of the column bed after selecting particle size. As model compounds, we chose two chiral drugs for preparative separation: omeprazole and etiracetam. In each case, two maximum allowed pressure drops were assumed: 80 and 200 bar. The processes were numerically optimized (mechanistic modeling) with a general rate model using a global optimization method. The numerical predictions were experimentally verified at both analytical and pilot scales. The lower allowed pressure drop represents the use of standard equipment, while the higher allowed drop represents more modern equipment. For both compounds, maximum productivity was achieved using short columns packed with small-particle size packing materials. Increasing the allowed backpressure in the separation leads to an increased productivity and reduced solvent consumption. As advanced numerical calculations might not be available in the laboratory, we also investigated a statistically based approach, i.e., the Taguchi method (empirical modeling), for finding the optimal decision variables and compared it with advanced mechanistic modeling. The Taguchi method predicted that shorter columns packed with smaller particles would be preferred over longer columns packed with larger particles. We conclude that the simpler optimization tool, i.e., the Taguchi method, can be used to obtain “good enough” preparative separations, though for accurate processes, optimization, and to determine optimal operational conditions, classical numerical optimization is still necessary

Place, publisher, year, edition, pages
Springer, 2018
Keywords
Preparative chromatography, Omeprazole, Etiracetam, Optimization of productivity, Taguchi optimization, Equilibrium–dispersive model
National Category
Biochemistry and Molecular Biology Analytical Chemistry
Identifiers
urn:nbn:se:kau:diva-67311 (URN)10.1007/s10337-018-3519-z (DOI)2-s2.0-85046036669 (Scopus ID)
Available from: 2018-05-11 Created: 2018-05-11 Last updated: 2019-06-12Bibliographically approved
Vera, C. M., Samuelsson, J., Fornstedt, T., Dennis, G. R. & Shalliker, R. A. (2018). Protocol for the visualisation of axial temperature gradients in ultra high performance liquid chromatography using infrared cameras. Microchemical journal (Print), 141, 141-147
Open this publication in new window or tab >>Protocol for the visualisation of axial temperature gradients in ultra high performance liquid chromatography using infrared cameras
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2018 (English)In: Microchemical journal (Print), ISSN 0026-265X, E-ISSN 1095-9149, Vol. 141, p. 141-147Article in journal (Refereed) Published
Abstract [en]

A protocol was developed for the visualisation of axial temperature gradients on a Kinetex column (1.3 μm C18 100 Å 50 × 2.1 mm) operated at near maximum pressure of the system (Pmax) using an infrared camera. Real time viscous frictional heating effects across the entire column length was observed, and showed that with increasing flow rate there was an increase in the maximum temperature of the column, and the difference between the inlet and outlet temperatures. Temperature profile data over the entire length of the column revealed the dynamics of heat exchange processes along different parts of the column, and raises the question on potential heating effects on eluents. The axial temperature gradients of eluents such as pure methanol, isopropyl alcohol and acetonitrile near Pmax were compared; finding that acetonitrile which had the highest flow velocity at Pmax gave the highest overall temperature increase for these eluents.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Frictional heating, High pressure, Thermal effects, Thermal imagining, UHPLC
National Category
Biochemistry and Molecular Biology Chemical Sciences
Identifiers
urn:nbn:se:kau:diva-67492 (URN)10.1016/j.microc.2018.05.004 (DOI)2-s2.0-85047094080 (Scopus ID)
Available from: 2018-06-07 Created: 2018-06-07 Last updated: 2018-07-11Bibliographically approved
Forssén, P., Multia, E., Samuelsson, J., Andersson, M., Aastrup, T., Altun, S., . . . Fornstedt, T. (2018). Reliable Strategy for Analysis of Complex Biosensor Data. Analytical Chemistry, 90(8), 5366-5374
Open this publication in new window or tab >>Reliable Strategy for Analysis of Complex Biosensor Data
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2018 (English)In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 90, no 8, p. 5366-5374Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
Keywords
Biosensors, Dissociation, Kinetics, Molecular biology, Analyte concentration, Complex concentration, Complex formation reactions, Dissociation kinetics, Experimental system, Global fitting procedures, Heterogeneous interactions, Numerical algorithms, Rate constants
National Category
Chemical Sciences Organic Chemistry Biochemistry and Molecular Biology
Research subject
Chemistry
Identifiers
urn:nbn:se:kau:diva-67280 (URN)10.1021/acs.analchem.8b00504 (DOI)000430512200059 ()2-s2.0-85045627010 (Scopus ID)
Available from: 2018-05-04 Created: 2018-05-04 Last updated: 2018-11-22Bibliographically approved
Åsberg, D., Chutkowski, M., Leśko, M., Samuelsson, J., Kaczmarski, K. & Fornstedt, T. (2017). A practical approach for predicting retention time shifts due to pressure and temperature gradients in ultra-high-pressure liquid chromatography. Journal of Chromatography A, 1479, 107-120
Open this publication in new window or tab >>A practical approach for predicting retention time shifts due to pressure and temperature gradients in ultra-high-pressure liquid chromatography
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2017 (English)In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1479, p. 107-120Article in journal (Refereed) Published
Abstract [en]

Large pressure gradients are generated in ultra-high-pressure liquid chromatography (UHPLC) using sub–2 μm particles causing significant temperature gradients over the column due to viscous heating. These pressure and temperature gradients affect retention and ultimately result in important selectivity shifts. In this study, we developed an approach for predicting the retention time shifts due to these gradients. The approach is presented as a step-by-step procedure and it is based on empirical linear relationships describing how retention varies as a function of temperature and pressure and how the average column temperature increases with the flow rate. It requires only four experiments on standard equipment, is based on straightforward calculations, and is therefore easy to use in method development. The approach was rigorously validated against experimental data obtained with a quality control method for the active pharmaceutical ingredient omeprazole. The accuracy of retention time predictions was very good with relative errors always less than 1% and in many cases around 0.5% (n = 32). Selectivity shifts observed between omeprazole and the related impurities when changing the flow rate could also be accurately predicted resulting in good estimates of the resolution between critical peak pairs. The approximations which the presented approach are based on were all justified. The retention factor as a function of pressure and temperature was studied in an experimental design while the temperature distribution in the column was obtained by solving the fundamental heat and mass balance equations for the different experimental conditions. We strongly believe that this approach is sufficiently accurate and experimentally feasible for this separation to be a valuable tool when developing a UHPLC method. After further validation with other separation systems, it could become a useful approach in UHPLC method development, especially in the pharmaceutical industry where demands are high for robustness and regulatory oversight.

Place, publisher, year, edition, pages
Elsevier, 2017
Keywords
Gradient effects, Method development, Pressure effects, Retention time, Temperature, UHPLC
National Category
Analytical Chemistry
Research subject
Chemistry
Identifiers
urn:nbn:se:kau:diva-47559 (URN)10.1016/j.chroma.2016.11.050 (DOI)000392681300012 ()27986288 (PubMedID)
Funder
Knowledge Foundation, 20150233ÅForsk (Ångpanneföreningen's Foundation for Research and Development), 15/497Swedish Research Council, 2015-04627
Available from: 2016-12-30 Created: 2016-12-30 Last updated: 2019-06-17Bibliographically approved
Forss, E., Haupt, D., Stalberg, O., Enmark, M., Samuelsson, J. & Fornstedt, T. (2017). Chemometric evaluation of the combined effect of temperature, pressure, and co-solvent fractions on the chiral separation of basic pharmaceuticals using actual vs set operational conditions. Journal of Chromatography A, 1499, 165-173
Open this publication in new window or tab >>Chemometric evaluation of the combined effect of temperature, pressure, and co-solvent fractions on the chiral separation of basic pharmaceuticals using actual vs set operational conditions
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2017 (English)In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1499, p. 165-173Article in journal (Refereed) Published
Abstract [en]

The need to determine the actual operational conditions, instead of merely using the set operational conditions, was investigated for in packed supercritical fluid chromatography (SFC) by design of experiments (DoE) using a most important type of compounds, pharmaceutical basics, as models. The actual values of temperature, pressure, and methanol levels were recorded and calculated from external sensors, while the responses in the DoE were the retention factors and selectivity. A Kromasil CelluCoat columh was used as the stationary phase, carbon dioxide containing varying methanol contents as the mobile phase, and the six racemates of alprenolol, atenolol, metoprolol, propranolol, clenbuterol, and mianserin were selected as model solutes. For the retention modeling, the most important term was the methanol fraction followed by the temperature and pressure. Significant differences (p<0.05) between most of the coefficients in the retention models were observed when comparing models from set and actual conditions. The selectivity was much less affected by operational changes, and therefore was not severely affected by difference between set and actual conditions. The temperature differences were usually small, maximum +/- 1.4 degrees C, whereas the pressure differences were larger, typically approximately +10.5 bar. The set and actual fractions of methanol also differed, usually by +/- 0.4 percentage points. A cautious conclusion is that the primary reason for the discrepancy between the models is a mismatch between the set and actual methanol fractions. This mismatch is more serious in retention models at low methanol fractions. The study demonstrates that the actual conditions should almost always be preferred. (C) 2017 Elsevier B.V. All rights reserved.

Place, publisher, year, edition, pages
Elsevier, 2017
Keywords
Supercritical fluid chromatography, Basic pharmaceuticals, Chiral separations, Design of experiments, Actual conditions, Set conditions
National Category
Chemical Sciences
Research subject
Chemistry
Identifiers
urn:nbn:se:kau:diva-71672 (URN)10.1016/j.chroma.2017.03.077 (DOI)000401394200017 ()28389095 (PubMedID)
Note

Dan Haupt och Olle Stålberg har affiliering KAU på artikeln men hittar dem inte via personalkatalogen./BHJ

Available from: 2019-03-29 Created: 2019-03-29 Last updated: 2019-04-04Bibliographically approved
Åsberg, D., Lesko, M., Leek, T., Samuelsson, J., Kaczmarski, K. & Fornstedt, T. (2017). Estimation of Nonlinear Adsorption Isotherms in Gradient Elution RP-LC of Peptides in the Presence of an Adsorbing Additive. Chromatographia, 80(6), 961-966
Open this publication in new window or tab >>Estimation of Nonlinear Adsorption Isotherms in Gradient Elution RP-LC of Peptides in the Presence of an Adsorbing Additive
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2017 (English)In: Chromatographia, ISSN 0009-5893, E-ISSN 1612-1112, Vol. 80, no 6, p. 961-966Article in journal (Refereed) Published
Abstract [en]

In electrostatic repulsive interaction chromatography, using a charged surface hybrid sorbent carrying positive charges can improve the peak shape of peptides in reversed-phase liquid chromatography (RP-LC), especially in overloaded conditions, compared with standard C-18 sorbents. However, the positive surface charges can interact with anionic additives commonly used in peptide separations, e.g., trifluoroacetic acid (TFA), complicating adsorption isotherm estimation. We investigated how the competition for available adsorption sites between TFA and two peptides influenced the adsorption isotherm in gradient elution. A model accounting for the competition with TFA was compared with a model neglecting TFA adsorption. We found that the two models predicted elution profiles with the same accuracy. We also found that the adsorption isotherms were extremely similar in shape, leading to the conclusion that neglecting the competition with TFA is a valid approximation enabling faster and more robust adsorption isotherm estimation for the studied type of sorbent.

Place, publisher, year, edition, pages
Springer, 2017
Keywords
Liquid chromatography · Peptide separation, Charged surface hybrid, Adsorption isotherm, Gradient elution
National Category
Chemical Sciences
Research subject
Chemistry
Identifiers
urn:nbn:se:kau:diva-65567 (URN)10.1007/s10337-017-3298-y (DOI)000402824400014 ()28725083 (PubMedID)
Available from: 2018-01-11 Created: 2018-01-11 Last updated: 2018-11-22Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-1819-1709

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