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Fundamental Investigations of Supercritical Fluid Chromatography
Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Engineering and Chemical Sciences.ORCID iD: 0000-0002-8943-6286
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis aims at a deeper understanding of Supercritical Fluid

Chromatography (SFC). Although preparative SFC has started to replace Liquid Chromatography (LC) in the pharmaceutical industry - because of its advantages in speed and its less environmental impact - fundamental understanding is still lacking. Therefore there is no rigid framework to characterize adsorption or to understand the impact of changes in operational conditions.

 

In Paper I we demonstrated, after careful system verification, that most methods applied to determine adsorption isotherms in LC could not be applied directly in SFC. This was mainly due to operational differences and to the fact that the fluid is compressible which means that everything considered constant in LC varies in SFC.

 

In Paper II we showed that the most accurate methods for adsorption isotherm determination in LC, the so called plateau methods, do not work properly for SFC. Instead, methods based on overloaded profiles should be preferred.

 

In Paper III a Design of Experiments approach was successfully used to quantitatively describe the retention behavior of several solutes and the productivity of a two component separation system. This approach can be used to optimize SFC separations or to provide information about the separation system.

 

In Paper IV severe peak distortion effects, suspected to arise from injection solvent and mobile phase fluid mismatches, were carefully investigated using experiments and simulations. By this approach it was possible to examine the underlying reasons for the distortions, which is vital for method development.

 

Finally, in Paper V, the acquired knowledge from Paper I-IV was used to perform reliable scale-up in an industrial setting for the first time. This was done by carefully matching the conditions inside the analytical and preparative column with each other. The results could therefore provide the industry with key knowledge for further implementation of SFC.

Abstract [en]

This thesis aims at a deeper understanding of Supercritical Fluid

Chromatography (SFC). Although preparative SFC has started to replace Liquid Chromatography (LC) in the pharmaceutical industry - because of its advantages in speed and its less environmental impact - fundamental understanding is still lacking. Therefore there is no rigid framework to characterize adsorption or to understand the impact of changes in operational conditions.

 

In Paper I-II it was demonstrated why most methods applied to determine adsorption isotherms in LC could not be applied directly for SFC. Methods based on extracting data from overloaded profiles should be preferred.

 

In Paper III a Design of Experiments approach was successfully used to quantitatively describe the behavior of several solutes in a

separation system. This approach can be used to optimize SFC separations or to provide information about the separation system.

 

In Paper IV severe peak distortion effects often observed in SFC were carefully investigated and explained using experiments and simulations.

 

Finally, in Paper V, the prerequisites for performing reliable and predictable scale-up of SFC were investigated by small and large scale experiments.

Place, publisher, year, edition, pages
Karlstad: Karlstads universitet, 2015. , 63 p.
Series
Karlstad University Studies, ISSN 1403-8099 ; 2015:45
Keyword [en]
Supercritical Fluid Chromatography, SFC, Modeling, Adsorption Isotherms, Scale-up, Peak Distortion, Injection, Design of Experiments, Perturbation Peak Method, Elution by Characteristic Points Method, Method transfer
National Category
Analytical Chemistry Chemical Engineering
Research subject
Chemistry
Identifiers
URN: urn:nbn:se:kau:diva-37913ISBN: 978-91-7063-663-9 (print)OAI: oai:DiVA.org:kau-37913DiVA: diva2:853088
Public defence
2015-10-16, Nyquistsalen 9C 203, Karlstads universitet, Karlstad, 10:15 (English)
Opponent
Supervisors
Note

Paper 4 ("Evaluation of scale-up from analytical to preparative...") ingick som manuskript med samma titel i avhandlingen. Nu publicerad. 

Available from: 2015-09-25 Created: 2015-09-11 Last updated: 2016-03-08Bibliographically approved
List of papers
1. Determination of adsorption isotherms in supercritical fluid chromatography
Open this publication in new window or tab >>Determination of adsorption isotherms in supercritical fluid chromatography
2013 (English)In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1312, 124-133 p.Article in journal (Refereed) Published
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.

Keyword
Adsorption isotherms, Elution by Characteristic Points, Inverse method, Perturbation Peak method, Retention Time Method, Supercritical fluid chromatography
National Category
Physical Chemistry
Research subject
Chemistry
Identifiers
urn:nbn:se:kau:diva-34380 (URN)10.1016/j.chroma.2013.09.007 (DOI)000325123200016 ()24041510 (PubMedID)
Available from: 2014-10-15 Created: 2014-10-15 Last updated: 2017-12-06Bibliographically approved
2. Investigation of plateau methods for adsorption isotherm determination in supercritical fluid chromatography
Open this publication in new window or tab >>Investigation of plateau methods for adsorption isotherm determination in supercritical fluid chromatography
Show others...
2014 (English)In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1354, 129-138 p.Article in journal (Refereed) Published
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.

Keyword
Adsorption isotherms, Antipyrine, Elution by Characteristic Points, Perturbation Peak method, Supercritical fluid chromatography
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kau:diva-34392 (URN)10.1016/j.chroma.2014.05.070 (DOI)000339144000015 ()24931444 (PubMedID)
Available from: 2014-10-15 Created: 2014-10-15 Last updated: 2017-12-06Bibliographically approved
3. Evaluation of co-solvent fraction, pressure and temperature effects in analytical and preparative supercritical fluid chromatography
Open this publication in new window or tab >>Evaluation of co-solvent fraction, pressure and temperature effects in analytical and preparative supercritical fluid chromatography
2014 (English)In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1374, 254-260 p.Article in journal (Refereed) Published
Abstract [en]

Abstract A chemometric approach is used for studying the combined effect of temperature, pressure and co-solvent fraction in analytical and preparative supercritical fluid chromatography (SFC). More specifically, by utilizing design of experiments coupled with careful measurements of the experimental conditions the interaction between pressure, temperature and co-solvent fraction was studied with respect to productivity, selectivity and retention in chiral SFC. A tris-(3,5-dimethylphenyl) carbamoyl cellulose stationary phase with carbon dioxide/methanol as mobile phase and the two racemic analytes trans-stilbene oxide (TSO) and 1,1′-bi-2-naphthol (BINOL) were investigated. It was found for the investigated model system that the co-solvent fraction and pressure were the parameters that most affected the retention factors and that the co-solvent fraction and column temperature were most important for controlling the selectivity. The productivity in the preparative mode of SFC was most influenced by the co-solvent fraction and temperature. Both high co-solvent fraction and temperature gave maximum productivity in the studied design space.

Place, publisher, year, edition, pages
Elsevier, 2014
Keyword
Supercritical fluid chromatography, Methanol, Temperature, Pressure, Design of experiments
National Category
Analytical Chemistry
Identifiers
urn:nbn:se:kau:diva-37861 (URN)10.1016/j.chroma.2014.11.045 (DOI)000347605000029 ()25499060 (PubMedID)
Available from: 2015-09-07 Created: 2015-09-07 Last updated: 2017-10-31Bibliographically approved
4. A closer study of peak distortions in supercritical fluid chromatography as generated by the injection
Open this publication in new window or tab >>A closer study of peak distortions in supercritical fluid chromatography as generated by the injection
Show others...
2015 (English)In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1400, 131-139 p.Article 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
Keyword
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: 2017-10-31Bibliographically approved
5. Evaluation of scale-up from analytical to preparative supercritical fluid chromatography
Open this publication in new window or tab >>Evaluation of scale-up from analytical to preparative supercritical fluid chromatography
Show others...
2015 (English)In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1425, 280-286 p.Article 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.

Keyword
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: 2017-12-06Bibliographically approved

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