The LCGC Blog: New On-Line Sample Preparation and Analysis Combinations Challenge Routine Workflows

If you want to improve analytical methods to make them better, the sample preparation step is probably one of the best steps to target.

When I was growing up, I heard that a tell-tale sign someone was destined to be an engineer was if they were constantly of the mindset that there has to be a better way to do something. I am not technically an engineer, but that thought goes through my head constantly-I am always interested in finding a better way to do something. However, the concept of “better” can be defined in many ways. Usually, we think of things being better, if they are easier, cheaper, faster, more robust, higher performance, or any combination of these together. The field of analytical chemistry includes constant efforts toward improved analysis capabilities, broadly defined. To improve these capabilities, analysts must either design and build their own systems or make use of available technology in interesting ways. While I have colleagues who clearly approach innovation through the former, my research group is more attuned to making advances through the latter. 

We have been privileged to have developed an exceptional partnership with Shimadzu Scientific Instruments, Inc. (Columbia, Maryland) and Shimadzu Corporation (Kyoto, Japan). The UT Arlington–Shimadzu partnership currently stands at somewhere around $27 million in instrumentation and support services. As part of this arrangement, we are privy to some of the more recent advances made in instrument manufacturing. We often get the first opportunity to demonstrate the effectiveness of new technology and apply it to various analytical problems. The Shimadzu Institute for Research Technologies at UT Arlington ( manages several instruments of which we have the only one in the country, and more where we have one of only a few.

Shimadzu has made significant movement of late toward introduction of analytical systems that incorporate sample preparation on line. I realize that other manufacturers are also making novel advances in instrumentation, but I am writing here about what I know the most. For the past 6 or 7 years, we have been working to apply and refine on-line trap-and-elute liquid chromatography–mass spectrometry (LC–MS) for biological fluid analysis. On-line sample preparation in our hands has been facilitated by the combination of in situ derivatization (1) and restricted access media (2). Coupled with high efficiency separations and high sensitivity and specificity detection using triple-quadrupole MS, we have been successful in developing methods that can achieve single-digit parts-per-trillion detection limits for estrogens in matrices such as serum and cerebrospinal fluid (3,4). I am still surprised that this type of work flow has not been used more extensively. The low level of interest may be due in part to the need for a little additional hardware (a valve and a pump), or some challenges in method development (5). However, when all is said and done, very robust and high performance methods, which require essentially no human manipulation, can be developed. In clinical labs or core facilities, this level of automation can greatly reduce the burden on personnel and maximize the usage of instrumentation time.

Recently, I traveled to China to participate in the 2015 Sino American Pharmaceutical Association conferences held in Shanghai and Beijing. I had the opportunity to meet with representatives from Shimadzu China and learn about some of their developments. I was particularly interested in one system they had been quite successful with in China. It is a combined gel permeation chromatography–gas chromatography (GPC–GC) instrument designed primarily for pesticide analysis. Again, in the spirit of placing the majority of sample preparation on line, food extracts could be loaded into the instrument, separated based on size to remove large-molecule interferences, and then the fraction containing pesticides is directly injected into the gas chromatograph. Over 100 such systems have been sold in China, but as of yet, none have been sold outside of the country. We tried to reason why this might be so, but found few reasons besides the reason that the instrument was conceived and developed in China. I foresee that this could be quite a nice new product to bring into the United States, and other parts of the world, for that matter. Food safety and analysis needs will only continue to grow as the world population grows.

On the subject of new instrumentation featuring coupled solutions, we are excited to have recently installed in our laboratory an on-line supercritical fluid extraction–supercritical fluid chromatography–mass spectrometry (SFE–SFC–MS) instrument. If you look in the literature, there are many applications of SFE. There are also growing applications of SFC, but you will rarely see the two techniques coupled. If you do, they would be more likely coupled off line. Even more common is that SFE extracts are analyzed by GC, or other extraction techniques are used to prepare extracts for SFC analysis. Coupling SFC on line with MS detection has also been fraught with problems; flow-splitting has often been necessary and has been difficult to do highly reproducibly. We will get a chance to evaluate whether Shimadzu has solved these issues and found a unique solution by on-line coupling of SFE–SFC–MS. It seems an excellent opportunity for novel methods to extract analytes from solid samples. The instrument includes an autosampler rack to change SFE cartridges. By transferring extracts directly to the SFC–MS system, oxidation of highly labile compounds can be reduced; obvious improvements in recovery can also be expected.

If you want to improve analytical methods to make them better, the sample preparation step is probably one of the best steps to target. The overall variance of a method is the sum of the variance of the different steps, and the variance associated with the sample preparation step (or steps) is usually the largest. By automating these steps, and especially the transfer of extracts to the analytical system, sample losses can be reduced and reproducibility improved. The analytical scientist will still be needed to optimize and validate these on-line workflows, but once set, I believe that they can quickly become routine. Perhaps we should be using some concepts like “quality by design,” which is prominent in the pharmaceutical realm, in other areas, to ensure that we can develop highly reliable methods that provide superior information with little attention and high throughput. I believe that more and more we will see analytical methods reported in the literature reducing manual steps to increase their potential for broader applicability and higher throughput.



(1) Y. Baghdady and K.A. Schug, J. Sep. Sci. (in press).

(2) S.H. Yang, H. Fan, R.J. Classon, and K.A. Schug, J. Sep. Sci.36, 2922–2938 (2013).

(3) H. Fan, B. Papouskova, K. Lemr, J.G. Wigginton, and K.A. Schug, J. Sep. Sci.37, 2010–2017 (2014).

(4) J. Beinhauer, B. Liangqiao, H. Fan, M. Sebela, M. Kukula, J.A. Barrera, and K.A. Schug, Anal. Chim. Acta.858, 74–81 (2015).

(5) B. Papouskova, H. Fan, K. Lemr, and K.A. Schug, J. Sep. Sci.37, 2192–2199 (2014).

Kevin A. Schug is a Full Professor and Shimadzu Distinguished Professor of Analytical Chemistry in the Department of Chemistry & Biochemistry at The University of Texas (UT) at Arlington. He joined the faculty at UT Arlington in 2005 after completing a Ph.D. in Chemistry at Virginia Tech under the direction of Prof. Harold M. McNair and a post-doctoral fellowship at the University of Vienna under Prof. Wolfgang Lindner. Research in the Schug group spans fundamental and applied areas of separation science and mass spectrometry. Schug was named the LCGCEmerging Leader in Chromatography in 2009 and the 2012 American Chemical Society Division of Analytical Chemistry Young Investigator in Separation Science. He is a fellow of both the U.T. Arlington and U.T. System-Wide Academies of Distinguished Teachers.


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