Debby Mangelings, LCGC’s 2016 Emerging Leader Award Winner, Focuses on Chiral Separations

Debby Mangelings, the winner of the 2016 LCGC Emerging Leader in Chromatography award, is an associate professor in the Department of Analytical Chemistry and Pharmaceutical Technology at the Vrije Universiteit Brussel, in Brussels, Belgium. Mangelings’s work has focused primarily on chiral separations. She has focused on the definition and updating of chiral separation strategies for various modes of high performance liquid chromatography (HPLC)-including normal-phase, reversed-phase, and polar organic solvent chromatography (POSC)-as well as for capillary electrophoresis (CE) and capillary electrochromatography (CEC). She has more recently developed supercritical fluid chromatography (SFC) methods for chiral analyses and non-chiral analysis for drug impurity profiling. The synthesis of in-capillary stationary phases, such as monoliths for both chiral and achiral separations in CEC, is another one of her interests. More recently, Mangelings has become involved in the chemometric data analysis of chiral separation data to study systems with similar or dissimilar enantioselectivity. In CEC, she is working on the evaluation of new stationary phases, such as those with smaller particle diameters or with core–shell particles. Finally, she recently was involved in the successful chiral separation of uncommon compounds as the boron cluster species. Mangelings recently spoke to LCGC about her scientific background, interests, and recent work.

Where or how did your interest in analytical chemistry and chemistry begin?

When I was studying pharmacy, the theoretical courses and the practical exercises of analytical chemistry were always appealing to me. Though these techniques seemed complicated for a student, I enjoyed learning what one can do with them. The same applies for chirality: as a first year student, I became fascinated by the fact that mirror images of molecules exist, and that they display different activities in the human body. Later, I had the opportunity to do my master’s degree thesis on chiral separations with reversed-phase liquid chromatography. This was the perfect subject!

You have done some significant research in chiral separations. How did the project on defining and updating chiral separation strategies for several separation techniques such as high performance liquid chromatography (HPLC), CE, CEC, and SFC get started? What were the biggest challenges in that project? What benefits does it bring to the field?

The chiral project in our department already started a few years before I began my PhD work. It originated from a cooperation with Sanofi, who wanted us to develop software (a knowledge-based system) that guided the analyst through chiral method development without prior knowledge of compound structures. This was the basis of developing strategies: They had to be generic, so applicable to any new drug compound, regardless of its structure. To develop such software, the strategies were constructed as decision trees, providing information on what to do next based on the outcome of the previous experiment. In all of our strategies some method optimization steps are also included, while most others just stop after the screening step. We always used polysaccharide-based chiral phases in our strategies. In the initial studies, the selection of the chiral phases for the screening step was quite straightforward. However, after the cooperation with Sanofi was finished, new chiral stationary phases (CSPs) were marketed with chlorinated polysaccharide selectors, which provided possibly better separation rates than those with non-chlorinated selectors. Therefore, in the next project we initiated the update of existing strategies in the HPLC modes and also in CEC. At the same time, we also started research in SFC (earlier work was done at Sanofi), and defined a strategy for that technique too.

The benefits of the strategies are quite obvious: Anyone can use them for chiral method development for their compounds of interest, as they are applicable to any small molecule, independent of its structure.

The biggest challenge for me personally in the chiral project was the introduction of CEC in the lab, and the definition of a chiral separation strategy with this technique, which was the subject of my PhD thesis. CEC is a combination technique of capillary electrophoresis and capillary liquid chromatography, which is still mostly used at the academic level because it has too many disadvantages at this moment to be used in an industrial environment. One also needs some skills to pack CEC columns, but once you have the knowledge, you can easily work with the technique.

In addition, the introduction of SFC in our lab for chiral separations was also a very exciting period: I was really impressed by how fast this technique is and how easy it is to tune the separations.

What prompted your research into the chemometric data analysis of chiral separation data to study systems with similar or dissimilar enantioselectivity? What have your results shown so far?

When selecting the best chiral phases to be included in a screening step, we always counted the number of separations obtained from a test set manually and then we selected a number of complementary phases to be included in the screening. This work tends to be very time consuming, which is the reason why we tried to use chemometric algorithms to do this selection automatically. It would facilitate the work of updating existing strategies with new phases. If there is a new phase, one just needs to analyze it at the screening conditions of the strategies using a fixed test set of compounds, and then this phase would be characterized by the obtained resolutions or selectivities. Chemometric techniques then allow us to see whether the phase adds something new to the earlier tested ones and then select the most dissimilar (most complementary) phases. Our research indicated the usefulness of chemometrics in the comparison of phases, but also revealed that visualization of the selected results is always needed, because a phase that does not separate any compound is also very dissimilar to a phase that is able to separate many compounds. Of course, it is obvious that the former phase is not useful in a screening step.

Can you tell us about your research in the evaluation of new stationary phases for CEC, such as those with smaller particle diameters or with core–shell particles?

The research on core–shell particles in CEC is challenging, especially at the level of column packing. We are still in the beginning of this research so conclusive results still need to be generated. We also have not yet begun to use very small particles for chiral separations.

You were also recently involved in the successful chiral separation of uncommon compounds as the boron cluster species. Can you tell us about that work and what it entailed?

Boron cluster species composed a completely new set of test compounds to me, so it was a challenge to know whether the screening conditions of our chiral strategies in normal-phase LC and POSC were applicable for them.  Two types of boron clusters were considered, that is, zwitterions and anions. For the first class, our normal-phase LC and POSC screenings were applicable. However, the anions usually could not be eluted in normal-phase LC, probably because of precipitation, and in POSC they were not separated in the majority of the tested conditions. This study showed that the chiral discrimination potential of polysaccharide selectors is meaningful to analyze structurally chiral boron cluster species, but needs further systematic research, in which recognition mechanisms should be explored.

What research are you the most proud of thus far?

I believe that the PhD research one performs always remains special. Given the challenge to introduce capillary electrochromatography  in the lab and the results I was able to generate with this technique, I am proud on the work I performed with CEC.

Also, our work in SFC was impressive to me: We introduced the technique in our lab and defined a complete chiral separation strategy in a rather short time.

What kind of research is your group currently involved in?

For chiral separations, we currently have two research projects: The first one investigates new types of chiral stationary phases in CEC mode, such as core–shell phases, and the second focuses on developing a methodology for the enantioseparation of peptides. In all of our research, we try to implement the use of experimental designs in method optimization to gain knowledge about the entire experimental domain.

Besides these projects, we are working on precision improvement and transferability of capillary electrophoresis methods between different instruments and laboratories. Also here, we are using chiral separations as test cases.

In SFC, we have a project on the development of drug impurity profiles. We finished the characterization of an extended set of stationary phases and the selection of the most dissimilar stationary phases. Now we are investigating the parameters that can be used for optimization of the obtained separations, which will be followed by the definition and validation of the complete methodology.

A final topic is the analysis of herbal extracts, on which we have several ongoing projects. Herein we try to characterize given plants with medicinal properties through the development of fingerprint chromatograms, occasionally followed by liquid chromatography–mass spectrometry (LC–MS) to identify important peaks. The resulting fingerprint chromatograms are analyzed by means of chemometric techniques and allow us to identify samples and perform similarity analysis, classify samples, predict activities (for example, anti-oxidant, toxicity) of the samples from the obtained fingerprints, and indicate peaks in the chromatogram that may be responsible for a given activity.

You have previously supervised six PhD students and currently supervise six more. How do you guide your students to select important or relevant theses and research projects?

The topics our PhD students work on are usually defined by me and my colleague (Yvan Vander Heyden) based on what is provided to us as interesting research subjects from pharmaceutical companies, what we see as a next stage in ongoing research, or what we consider interesting for a new PhD project. We define the initial project, but of course the student develops and executes the experiments and occasionally it is to be modified as a consequence of the obtained results.

Your work has been published extensively (about 70 articles and 11 book chapters) and you have given or coauthored 61 oral and 83 poster presentations at national and international congresses and symposia. How do you balance working on new or cutting-edge research and the demands of teaching, supervising PhD students, as well as giving lectures and writing papers to share with your peers?

I consider the supervision of PhD students, giving lectures, and writing papers all as part of research. As a professor at a university, one is supposed to both teach and do research. Finding the balance between teaching and research is not evident: Often, lots of administrative tasks come along with teaching, and they take more time than one may expect. For the moment, I am teaching all my courses in the first semester of the academic year, which only leaves me limited time for research in that semester. On the other hand, I, in principle, have a whole second semester to spend on research! However, reality is in some periods different because of other university obligations. Searching for a good balance between research, teaching, and other university-related tasks is therefore a continuous challenge!

Have you faced any difficulties as a young, female scientist? What advice would you offer to other female scientists just starting out?

I have never experienced any difficulties as female scientist, or not that I know of. The main reason is that we are a pharmaceutical department and the majority of pharmacists are women.

My advice to other female scientists is that finding a good balance between family life and an academic career is not an easy task, but it is possible and worthwhile to try.

What do you plan to focus on next? Is there one big problem in separation science that you really want to tackle?

Further investigating of the possibilities of CEC as a separation technique will be something I will always try to continue. I hope that the technique will be able to deliver what is expected one day. The project on the chiral separation of peptides is also something I am really looking forward to. We will also use chiral phases with other selectors than those we have been studying until now, so it will definitely be an instructive period!