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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
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: 2019-11-04Bibliographically 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
Åsberg, D. (2017). Fundamental and Regulatory Aspects of UHPLC in Pharmaceutical Analysis. (Doctoral dissertation). Karlstad: Karlstads universitet
Open this publication in new window or tab >>Fundamental and Regulatory Aspects of UHPLC in Pharmaceutical Analysis
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Ultra-high performance liquid chromatography (UHPLC) provides a considerable increase in throughput compared to HPLC and a reduced solvent consumption. The implementation of UHPLC in pharmaceutical analysis, e.g. quality control, has accelerated in recent years and there is currently a mix of HPLC and UHPLC instrumentation within pharmaceutical companies. There are, however, technical and regulatory challenges converting a HPLC method to UHPLC making it difficult to take full advantage of UHPLC in regulatory-focused applications like quality control in pharmaceutical production.

Using chromatographic modelling and fundamental theory, this thesis investigated method conversion between HPLC and UHPLC. It reports on the influence of temperature gradients due to viscous heating, pressure effects and stationary phase properties on the separation performance. It also presents a regulatory concept for less regulatory interaction for minor changes to approved methods to support efficient life cycle management.

The higher pressure in UHPLC gave a retention increase of up to 40% as compared to conventional HPLC while viscous heating, instead, reduced retention and the net result was very solute dependent. Selectivity shifts were observed even between solutes with similar structure when switching between HPLC and UHPLC and an experimental method to predict such selectivity shifts was therefore developed. The peak shape was negatively affected by the increase in pressure for some solutes since secondary interactions between the solute and the stationary phase increased with pressure.

With the upcoming ICH Q12 guideline, it will be possible for the industry to convert existing methods to UHPLC in a more flexible way using the deeper understanding and the regulatory concept presented here as a case example.

Abstract [en]

Ultra-high performance liquid chromatography (UHPLC) provides a considerable increase in throughput compared to conventional HPLC and a reduced solvent consumption. The implementation of UHPLC in pharmaceutical analysis has accelerated in recent years and currently both instruments are used. There are, however, technical and regulatory challenges converting a HPLC method to UHPLC making it difficult to take full advantage of UHPLC in regulatory-focused applications like quality control in pharmaceutical production. In UHPLC, the column is packed with smaller particles than in HPLC resulting in higher pressure and viscous heating. Both the higher pressure and the higher temperature may cause changes in retention and selectivity making method conversion unpredictable.

Using chromatographic modelling and fundamental theory, this thesis investigates method conversion between HPLC and UHPLC. It reports on the influence of temperature gradients due to viscous heating, pressure effects and stationary phase properties on the separation performance. It also presents a regulatory concept for less regulatory interaction for minor changes to approved quality control methods and how predicable method conversion is achieved by improved understanding.

Place, publisher, year, edition, pages
Karlstad: Karlstads universitet, 2017. p. 75
Series
Karlstad University Studies, ISSN 1403-8099 ; 2017:9
Keywords
Liquid chromatography, UHPLC, Pharmaceutical analysis, Adsorption isotherm, Design of experiments, Quality control
National Category
Analytical Chemistry
Research subject
Chemistry
Identifiers
urn:nbn:se:kau:diva-47852 (URN)978-91-7063-756-8 (ISBN)978-91-7063-757-5 (ISBN)
Public defence
2017-04-06, 9C204, Rejmersalen, Karlstads universitet, Universitetsgatan 2, Karlstad, 10:00 (English)
Opponent
Supervisors
Funder
Swedish Research Council, 2015-04627ÅForsk (Ångpanneföreningen's Foundation for Research and Development), 15/497
Available from: 2017-03-08 Created: 2017-02-10 Last updated: 2019-06-10Bibliographically approved
Åsberg, D., Samuelsson, J. & Fornstedt, T. (2016). A fundamental study of the impact of pressure on the adsorption mechanism in reversed-phase liquid chromatography. Journal of Chromatography A, 1457, 97-106
Open this publication in new window or tab >>A fundamental study of the impact of pressure on the adsorption mechanism in reversed-phase liquid chromatography
2016 (English)In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1457, p. 97-106Article in journal (Refereed) Published
Abstract [en]

A fundamental investigation of the pressure effect on individual adsorption sites was undertaken based on adsorption energy distribution and adsorption isotherm measurements. For this purpose, we measured adsorption equilibrium data at pressures ranging from 100 to 1000 bar at constant flow and over a wide concentration range for three low-molecular-weight solutes, antipyrine, sodium 2-naphthalenesulfonate, and benzyltriethylammonium chloride, on an Eternity C18 stationary phase. The adsorption energy distribution was bimodal for all solutes, remaining clearly so at all pressures. The bi-Langmuir model best described the adsorption in these systems and two types of adsorption sites were identified, one with a low and another with a high energy of interaction. Evidence exists that the low-energy interactions occur at the interface between the mobile and stationary phases and that the high-energy interactions occur nearer the silica surface, deeper in the C18 layer. The contribution of each type of adsorption site to the retention factor was calculated and the change in solute molar volume from the mobile to stationary phase during the adsorption process was estimated for each type of site. The change in solute molar volume was 2-4 times larger at the high-energy site, likely because of the greater loss of solute solvation layer when penetrating deeper into the C18 layer. The association equilibrium constant increased with increasing pressure while the saturation capacity of the low-energy site remained almost unchanged. The observed increase in saturation capacity for the high-energy site did not affect the column loading capacity, which was almost identical at 50- and 950-bar pressure drops over the column. (C) 2016 Elsevier B.V. All rights reserved.

Keywords
UHPLC, Pressure, Adsorption isotherm, Retention factor, Loading capacity
National Category
Chemical Sciences
Research subject
Chemistry
Identifiers
urn:nbn:se:kau:diva-44663 (URN)10.1016/j.chroma.2016.06.036 (DOI)000380080000012 ()27357740 (PubMedID)
Available from: 2016-08-12 Created: 2016-08-12 Last updated: 2017-12-06Bibliographically approved
Åsberg, D., Nilsson, M., Olsson, S., Samuelsson, J., Svensson, O., Klick, S., . . . Fornstedt, T. (2016). A quality control method enhancement concept: Continual improvement of regulatory approved QC methods. Journal of Pharmaceutical and Biomedical Analysis, 129, 273-281
Open this publication in new window or tab >>A quality control method enhancement concept: Continual improvement of regulatory approved QC methods
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2016 (English)In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 129, p. 273-281Article in journal (Refereed) Published
Abstract [en]

Quality Control methods (QC-methods) play an important role in the overall control strategy for drug manufacturing. However, efficient life-cycle management and continual improvement are hindered due to a variety of post-approval variation legislations across territories and a lack of harmonization of the requirements. As a result, many QC-methods fall behind the technical development. Developing the QC-method in accordance with the Quality by Design guidelines gives the possibility to do continual improvements inside the original Method Operable Design Region (MODR). However, often it is necessary to do changes outside the MODR, e.g. to incorporate new technology that was not available at the time the original method was development. Here, we present a method enhancement concept which allows minor adjustments, within the same measuring principle, outside the original MODR without interaction with regulatory agencies. The feasibility of the concept is illustrated by a case study of a QC-method based on HPLC, assumed to be developed before the introduction of UHPLC, where the switch from HPLC to UHPLC is necessary as a continual improvement strategy. The concept relies on the assumption that the System Suitability Test (SST) and failure modes are relevant for other conditions outside the MODR as well when the same measuring principle is used. It follows that it should be possible to move outside the MODR as long as the SST has passed. All minor modifications of the original, approved QC-method must be re-validated according to a template given in the original submission and a statistical equivalence should be shown between the original and modified QC-methods. To summarize, revalidation is handled within the pharmaceutical quality control system according to internal change control procedures, but without interaction with regulating agencies.

Place, publisher, year, edition, pages
Elsevier, 2016
Keywords
Continual improvement, HPLC, Method enhancement concept, Method transfer, Quality by design
National Category
Analytical Chemistry
Research subject
Chemistry
Identifiers
urn:nbn:se:kau:diva-47560 (URN)10.1016/j.jpba.2016.06.018 (DOI)000393847600035 ()
Funder
Knowledge Foundation, 20140179ÅForsk (Ångpanneföreningen's Foundation for Research and Development), 15/497Swedish Research Council, 2015-04627
Available from: 2016-12-30 Created: 2016-12-30 Last updated: 2019-11-04Bibliographically approved
Åsberg, D., Leśko, M., Samuelsson, J., Karlsson, A., Kaczmarski, K. & Fornstedt, T. (2016). Combining Chemometric Models with Adsorption Isotherm Measurements to Study Omeprazole in RP-LC. Chromatographia, 79(19), 1283-1291
Open this publication in new window or tab >>Combining Chemometric Models with Adsorption Isotherm Measurements to Study Omeprazole in RP-LC
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2016 (English)In: Chromatographia, ISSN 0009-5893, E-ISSN 1612-1112, Vol. 79, no 19, p. 1283-1291Article in journal (Refereed) Published
Abstract [en]

The adsorption of the proton-pump inhibitor omeprazole was investigated using RP-LC with chemometric models combined with adsorption isotherm modelling to study the effect of pH and type of organic modifier (i.e., acetonitrile or methanol). The chemometric approach revealed that omeprazole was tailing with methanol and fronting with acetonitrile along with increased fronting at higher pH. The increased fronting with higher pH for acetonitrile was explored using a pH-dependent adsorption isotherm model that was determined using the inverse method and it agreed well with the experimental data. The model indicated that the peaks exhibit more fronting at high pH due to a larger fraction of charged omeprazole molecules. This model could accurately predict the shape of elution profiles at arbitrary pH levels in the studied interval. Using a two-layer adsorption isotherm model, the difference between acetonitrile and methanol was studied at the lowest pH at which almost all omeprazole molecules are neutral. Omeprazole had adsorbate–adsorbate interactions that were similar in strength for the acetonitrile and methanol mobile phases, while the solute–adsorbent interactions were almost twice as strong with methanol. The difference in the relative strengths of these two interactions likely explains the different peak asymmetries (i.e., tailing/fronting) in methanol and acetonitrile. In conclusion, thermodynamic modelling can complement chemometric modeling in HPLC method development and increase the understanding of the separation.

Place, publisher, year, edition, pages
Springer Berlin/Heidelberg, 2016
Keywords
HPLC, pH, Adsorption, Omeprazole
National Category
Analytical Chemistry
Research subject
Chemistry
Identifiers
urn:nbn:se:kau:diva-47561 (URN)10.1007/s10337-016-3151-8 (DOI)000387326400007 ()
Funder
Knowledge Foundation, 20140179ÅForsk (Ångpanneföreningen's Foundation for Research and Development), 15/497Swedish Research Council, 2015-04627
Available from: 2016-12-30 Created: 2016-12-30 Last updated: 2018-11-22Bibliographically approved
Enmark, M., Åsberg, D., Shalliker, A., Samuelsson, J. & Fornstedt, T. (2015). A closer study of peak distortions in supercritical fluid chromatography as generated by the injection. Journal of Chromatography A, 1400, 131-139
Open this publication in new window or tab >>A closer study of peak distortions in supercritical fluid chromatography as generated by the injection
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2015 (English)In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1400, p. 131-139Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
Elsevier, 2015
Keywords
Supercritical fluid chromatography, Viscous fingering, Peak distortion, Solvent strength, Modeling, Tracer peak
National Category
Analytical Chemistry
Identifiers
urn:nbn:se:kau:diva-37860 (URN)10.1016/j.chroma.2015.04.059 (DOI)000356742500016 ()26002105 (PubMedID)
Available from: 2015-09-07 Created: 2015-09-07 Last updated: 2019-10-14Bibliographically approved
Lesko, M., Åsberg, D., Enmark, M., Samuelsson, J., Fornstedt, T. & Kaczmarski, K. (2015). Choice of Model for Estimation of Adsorption Isotherm Parameters in Gradient Elution Preparative Liquid Chromatography. Chromatographia, 78(19-20), 1293-1297
Open this publication in new window or tab >>Choice of Model for Estimation of Adsorption Isotherm Parameters in Gradient Elution Preparative Liquid Chromatography
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2015 (English)In: Chromatographia, ISSN 0009-5893, E-ISSN 1612-1112, Vol. 78, no 19-20, p. 1293-1297Article in journal (Refereed) Published
Abstract [en]

The inverse method is a numerical method for fast estimation of adsorption isotherm parameters directly from a few overloaded elution profiles and it was recently extended to adsorption isotherm acquisition in gradient elution conditions. However, the inverse method in gradient elution is cumbersome due to the complex adsorption isotherm models found in gradient elution. In this case, physicochemically correct adsorption models have very long calculation times. The aim of this study is to investigate the possibility of using a less complex adsorption isotherm model, with fewer adjustable parameters, but with preserved/acceptable predictive abilities. We found that equal or better agreement between experimental and predicted elution profiles could be achieved with less complex models. By being able to select a model with fewer adjustable parameters, the calculation times can be reduced by at least a factor of 10. 

Place, publisher, year, edition, pages
Springer Berlin/Heidelberg, 2015
Keywords
cycloheptanone; cyclohexanone; ketone; unclassified drug, adsorption; adsorption isotherm; Article; calculation; controlled study; elution; isotherm; liquid chromatography; model; physical chemistry; predictive value; priority journal; simulation; theory
National Category
Analytical Chemistry
Research subject
Chemistry; Chemical Engineering
Identifiers
urn:nbn:se:kau:diva-42370 (URN)10.1007/s10337-015-2949-0 (DOI)000361798500007 ()2-s2.0-84942368375 (Scopus ID)
Funder
Swedish Research Council, 621-2012-3978
Available from: 2016-06-07 Created: 2016-05-23 Last updated: 2018-11-22Bibliographically approved
Enmark, M., Asberg, D., Leek, H., Ohlen, K., Klarqvist, M., Samuelsson, J. & Fornstedt, T. (2015). Evaluation of scale-up from analytical to preparative supercritical fluid chromatography. Journal of Chromatography A, 1425, 280-286
Open this publication in new window or tab >>Evaluation of scale-up from analytical to preparative supercritical fluid chromatography
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2015 (English)In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1425, p. 280-286Article in journal (Refereed) Published
Abstract [en]

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

Keywords
SFC, Chiral separation, Transfer of method, Scale-up, Operational parameters, Design of experiments
National Category
Chemical Engineering
Research subject
Chemical Engineering
Identifiers
urn:nbn:se:kau:diva-40985 (URN)10.1016/j.chroma.2015.11.001 (DOI)000366770400032 ()
Available from: 2016-03-08 Created: 2016-03-08 Last updated: 2019-07-12Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-8561-6872

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