Skip to main content
Log in

The capillary gap sampler, a new microfluidic platform for direct coupling of automated solid-phase microextraction with ESI-MS

  • Research Paper
  • Published:
Analytical and Bioanalytical Chemistry Aims and scope Submit manuscript

Abstract

A new technology for rapid, automated coupling of solid-phase microextraction and mass spectrometry is introduced. Use of a so-called capillary gap sampler for automated solid-phase microextraction and direct delivery of the extracted analytes to a mass spectrometer provides certain advantages over existing technologies: coupling of the capillary gap sampler to a mass spectrometer offers quick, automated, and site-specific extraction from very low volume samples. High stability, reusability, and repeatability were achieved through systematic optimization. Diazepam, oxazepam, and nordiazepam were used as test compounds in all experiments. The ability of the sampler to extract benzodiazepines from human plasma (limit of detection 0.3 μg/mL) in the therapeutic range was confirmed. A linear dynamic range from 1 to 1000 ng/mL for all three analytes was found. The relative standard deviation of 20 extractions was between 11% and 17%, for oxazepam, nordiazepam, and diazepam, indicating acceptable repeatability of the method.

Schematic of the desorption step inside the liquid bridge formed between two capillaries in thecapillary gap sampler

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Arthur CL, Pawliszyn J. Solid phase microextraction with thermal desorption using fused silica optical fibers. Anal Chem. 1990;62:2145–8. https://doi.org/10.1021/ac00218a019.

    Article  CAS  Google Scholar 

  2. Zhang Z, Yang MJ, Pawliszyn J. Solid-phase microextraction. A solvent-free alternative for sample preparation. Anal Chem. 1994;66:844A–53A. https://doi.org/10.1021/ac00089a001.

    Article  CAS  Google Scholar 

  3. Theodoridis G, Koster EH, de Jong GJ. Solid-phase microextraction for the analysis of biological samples. J Chromatogr B. 2000;745:49–82.

    Article  CAS  Google Scholar 

  4. Ulrich S. Solid-phase microextraction in biomedical analysis. J Chromatogr A. 2000;902:167–94. https://doi.org/10.1016/S0021-9673(00)00934-1.

    Article  CAS  Google Scholar 

  5. Snow NH. Solid-phase micro-extraction of drugs from biological matrices. J Chromatogr A. 2000;885:445–55.

    Article  CAS  Google Scholar 

  6. Sides SL, Polowy KB, Thornquest AD Jr, Burinsky DJ. Identification of a pharmaceutical packaging off-odor using solid phase microextraction gas chromatography/mass spectrometry. J Pharm Biomed Anal. 2001;25:379–86. https://doi.org/10.1016/S0731-7085(00)00517-3.

    Article  CAS  Google Scholar 

  7. Teitz DS, Khan S, Powell ML, Jemal M. An automated method of sample preparation of biofluids using pierceable caps to eliminate the uncapping of the sample tubes during sample transfer. J Biochem Biophys Methods. 2000;45:193–204.

    Article  CAS  Google Scholar 

  8. Jemal M, Teitz D, Ouyang Z, Khan S. Comparison of plasma sample purification by manual liquid-liquid extraction, automated 96-well liquid-liquid extraction and automated 96-well solid-phase extraction for analysis by high-performance liquid chromatography with tandem mass spectrometry. J Chromatogr B. 1999;732:501–8.

    Article  CAS  Google Scholar 

  9. Mitani K, Fujioka M, Kataoka H. Fully automated analysis of estrogens in environmental waters by in-tube solid-phase microextraction coupled with liquid chromatography–tandem mass spectrometry. J Chromatogr A. 2005;1081:218–24. https://doi.org/10.1016/j.chroma.2005.05.058.

    Article  CAS  Google Scholar 

  10. Tong XS, Wang J, Zheng S, Pivnichny JV. High-throughput pharmacokinetics screen of VLA-4 antagonists by LC/MS/MS coupled with automated solid-phase extraction sample preparation. J Pharm Biomed Anal. 2004;35:867–77. https://doi.org/10.1016/j.jpba.2004.02.017.

    Article  CAS  Google Scholar 

  11. Lord HL, Grant RP, Walles M, Incledon B, Fahie B, Pawliszyn JB. Development and evaluation of a solid-phase microextraction probe for in vivo pharmacokinetic studies. Anal Chem. 2003;75:5103–15. https://doi.org/10.1021/ac0343230.

    Article  CAS  Google Scholar 

  12. Rule G, Chapple M, Henion J. A 384-well solid-phase extraction for LC/MS/MS determination of methotrexate and its 7-hydroxy metabolite in human urine and plasma. Anal Chem. 2001;73:439–43. https://doi.org/10.1021/ac000897i.

    Article  CAS  Google Scholar 

  13. Rule G, Henion J. High-throughput sample preparation and analysis using 96-well membrane solid-phase extraction and liquid chromatography-tandem mass spectrometry for the determination of steroids in human urine. J Am Soc Mass Spectrom. 1999;10:1322–7. https://doi.org/10.1016/S1044-0305(99)00107-5.

    Article  CAS  Google Scholar 

  14. Kaye B, Herron WJ, Macrae PV, Robinson S, Stopher DA, Venn RF, et al. Rapid, solid phase extraction technique for the high-throughput assay of darifenacin in human plasma. Anal Chem. 1996;68:1658–60. https://doi.org/10.1021/ac9507552.

    Article  CAS  Google Scholar 

  15. Hutchinson JP, Setkova L, Pawliszyn J. Automation of solid-phase microextraction on a 96-well plate format. J ChromatogrA. 2007;1149:127–37. https://doi.org/10.1016/j.chroma.2007.02.117.

    Article  CAS  Google Scholar 

  16. Roddy TP, Horvath CR, Stout SJ, Kenney KL, Ho P-I, Zhang J-H, et al. Mass spectrometric techniques for label-free high-throughput screening in drug discovery. Anal Chem. 2007;79:8207–13. https://doi.org/10.1021/ac062421q.

    Article  CAS  Google Scholar 

  17. Biddlecombe RA, Benevides C, Pleasance S. A clinical trial on a plate? The potential of 384-well format solid phase extraction for high-throughput bioanalysis using liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom. 2001;15:33–40. https://doi.org/10.1002/1097-0231(20010115)15:1<33::AID-RCM188>3.0.CO;2-4.

    Article  CAS  Google Scholar 

  18. Vatinno R, Vuckovic D, Zambonin CG, Pawliszyn J. Automated high-throughput method using solid-phase microextraction-liquid chromatography-tandem mass spectrometry for the determination of ochratoxin A in human urine. J Chromatogr A. 2008;1201:215–21. https://doi.org/10.1016/j.chroma.2008.05.079.

    Article  CAS  Google Scholar 

  19. Cudjoe E, Vuckovic D, Hein D, Pawliszyn J. Investigation of the effect of the extraction phase geometry on the performance of automated solid-phase microextraction. Anal Chem. 2009;81:4226–32. https://doi.org/10.1021/ac802524w.

    Article  CAS  Google Scholar 

  20. Cudjoe E, Pawliszyn J. A new approach to the application of solid phase extraction disks with LC–MS/MS for the analysis of drugs on a 96-well plate format. J Pharm Biomed Anal. 2009;50:556–62. https://doi.org/10.1016/j.jpba.2008.07.014.

    Article  CAS  Google Scholar 

  21. Vuckovic D, Cudjoe E, Hein D, Pawliszyn J. Automation of solid-phase microextraction in high-throughput format and applications to drug analysis. Anal Chem. 2008;80:6870–80. https://doi.org/10.1021/ac800936r.

    Article  CAS  Google Scholar 

  22. Deng J, Yang Y, Wang X, Luan T. Strategies for coupling solid-phase microextraction with mass spectrometry. Trends Anal Chem. 2014;55:55–67. https://doi.org/10.1016/j.trac.2013.12.004.

    Article  CAS  Google Scholar 

  23. Marsili RT. SPME−MS−MVA as an electronic nose for the study of off-flavors in milk. J Agric Food Chem. 1999;47:648–54. https://doi.org/10.1021/jf9807925.

    Article  CAS  Google Scholar 

  24. Pérès C, Viallon C, Berdagué J-L. Solid-phase microextraction-mass spectrometry: a new approach to the rapid characterization of cheeses. Anal Chem. 2001;73:1030–6. https://doi.org/10.1021/ac001146j.

    Article  Google Scholar 

  25. Möder M, Löster H, Herzschuh R, Popp P. Determination of urinary acylcarnitines by ESI-MS coupled with solid-phase microextraction (SPME). J Mass Spectrom. 1997;32:1195–204. https://doi.org/10.1002/(SICI)1096-9888(199711)32:11<1195::AID-JMS578>3.0.CO;2-9.

    Article  Google Scholar 

  26. Chen J, Pawliszyn J. Solid phase microextraction coupled to high-performance liquid chromatography. Anal Chem. 1995;67:2530–2533. https://doi.org/10.1021/ac00111a006.

  27. Ceglarek U, Efer J, Schreiber A, Zwanziger E, Engewald W. Determination of linear alkylbenzenesulfonates in communal wastewater by means of solid phase microextraction coupled with API-MS and HPLC-FLD. Fresenius J Anal Chem. 1999;365:674–81. https://doi.org/10.1007/s002160051544.

    Article  CAS  Google Scholar 

  28. McCooeye MA, Mester Z, Ells B, Barnett DA, Purves RW, Guevremont R. Quantitation of amphetamine, methamphetamine, and their methylenedioxy derivatives in urine by solid-phase microextraction coupled with electrospray ionization−high-field asymmetric waveform ion mobility spectrometry−mass spectrometry. Anal Chem. 2002;74:3071–5. https://doi.org/10.1021/ac011296.

    Article  CAS  Google Scholar 

  29. van Hout MWJ, Jas V, Niederländer HAG, de Zeeuw RA, de Jong GJ. Non-equilibrium solid-phase microextraction coupled directly to ion-trap mass spectrometry for rapid analysis of biological samples. Analyst. 2002;127:355–9. https://doi.org/10.1039/B110729A.

    Article  Google Scholar 

  30. van Hout MWJ, Jas V, Niederländer HAG, de Zeeuw RA, de Jong GJ. Ultra-rapid non-equilibrium solid-phase microextraction at elevated temperatures and direct coupling to mass spectrometry for the analysis of lidocaine in urine. J Sep Sci. 2003;26:1563–8. https://doi.org/10.1002/jssc.200301567.

    Article  Google Scholar 

  31. Mirabelli MF, Wolf J-C, Zenobi R. Direct coupling of solid-phase microextraction with mass spectrometry: sub-pg/g sensitivity achieved using a dielectric barrier discharge ionization source. Anal Chem. 2016;88:7252–8. https://doi.org/10.1021/acs.analchem.6b01507.

    Article  CAS  Google Scholar 

  32. Neu V, Steiner R, Müller S, Fattinger C, Zenobi R. Development and characterization of a capillary gap sampler as new microfluidic device for fast and direct analysis of low sample amounts by ESI-MS. Anal Chem. 2013;85:4628–35. https://doi.org/10.1021/ac400186t.

    Article  CAS  Google Scholar 

  33. Neu V, Dörig P, Fattinger C, Müller S, Zenobi R. Characterization of a miniaturized liquid bridge for nL sample infusion: a comparative study of sample flush-out behavior using flow simulations and direct ESI-MS analysis. Microfluid Nanofluid. 2016;20:62. https://doi.org/10.1007/s10404-016-1732-3.

    Article  Google Scholar 

  34. Mirnaghi FS, Chen Y, Sidisky LM, Pawliszyn J. Optimization of the coating procedure for a high-throughput 96-blade solid phase microextraction system coupled with LC–MS/MS for analysis of complex samples. Anal Chem. 2011;83:6018–25. https://doi.org/10.1021/ac2010185.

    Article  CAS  Google Scholar 

  35. Pawliszyn J, editor. Handbook of solid phase microextraction. Amsterdam: Elsevier; 2011.

    Google Scholar 

  36. Lavaud S, Canivet E, Wuillai A, Maheut H, Randoux C, Bonnet J-M, et al. Optimal anticoagulation strategy in haemodialysis with heparin-coated polyacrylonitrile membrane. Nephrol Dial Transplant. 2003;18:2097–104. https://doi.org/10.1093/ndt/gfg272.

    Article  CAS  Google Scholar 

  37. Nie F-Q, Xu Z-K, Ming Y-Q, Kou R-Q, Liu Z-M, Wang S-Y. Preparation and characterization of polyacrylonitrile-based membranes: effects of internal coagulant on poly(acrylonitrile-co-malefic acid) ultrafiltration hollow fiber membranes. Desalination. 2004;160:43–50. https://doi.org/10.1016/S0011-9164(04)90016-1.

    Article  CAS  Google Scholar 

  38. Mirnaghi FS, Pawliszyn J. Reusable solid-phase microextraction coating for direct immersion whole-blood analysis and extracted blood spot sampling coupled with liquid chromatography–tandem mass spectrometry and direct analysis in real time–tandem mass spectrometry. Anal Chem. 2012;84:8301–9. https://doi.org/10.1021/ac3018229.

    Article  CAS  Google Scholar 

  39. Mullett WM, Pawliszyn J. The development of selective and biocompatible coatings for solid phase microextraction. J Sep Sci. 2003;26:251–60. https://doi.org/10.1002/jssc.200390031.

    Article  CAS  Google Scholar 

  40. Alam MN, Ricardez-Sandoval L, Pawliszyn J. Numerical modeling of solid-phase microextraction: binding matrix effect on equilibrium time. Anal Chem. 2015;87:9846–54. https://doi.org/10.1021/acs.analchem.5b02239.

    Article  CAS  Google Scholar 

  41. Pawliszyn J. Sample preparation: quo vadis? Anal Chem. 2003;75:2543–58. https://doi.org/10.1021/ac034094h.

    Article  CAS  Google Scholar 

  42. Mulder J. Basic principles of membrane technology. Dordrecht: Kluwer; 1996.

    Book  Google Scholar 

  43. Zhang Z, Poerschmann J, Pawliszyn J. Direct solid phase microextraction of complex aqueous samples with hollow fibre membrane protection. Anal Commun. 1996;33:219–21. https://doi.org/10.1039/AC9963300219.

    Article  Google Scholar 

  44. Rasmussen KE, Pedersen-Bjergaard S, Krogh M, Grefslie Ugland H, Grønhaug T. Development of a simple in-vial liquid-phase microextraction device for drug analysis compatible with capillary gas chromatography, capillary electrophoresis and high-performance liquid chromatography. J Chromatogr A. 2000;873:3–11. https://doi.org/10.1016/S0021-9673(99)01163-2.

    Article  CAS  Google Scholar 

  45. Boos K-S, Grimm C-H. High-performance liquid chromatography integrated solid-phase extraction in bioanalysis using restricted access precolumn packings. Trends Anal Chem. 1999;18:175–80. https://doi.org/10.1016/S0165-9936(98)00102-2.

    Article  CAS  Google Scholar 

  46. Stead AH, Moffat AC. A collection of therapeutic, toxic and fatal blood drug concentrations in man. Hum Toxicol. 1983;2:437–64.

    Article  CAS  Google Scholar 

  47. Brown S. Clarke’s isolation and identification of drugs. J Clin Pathol. 1986;39:1368.

    Article  Google Scholar 

  48. Winek CL, Wahba WW, Winek CL, Balzer TW. Drug and chemical blood-level data 2001. Forensic Sci Int. 2001;122:107–23.

    Article  CAS  Google Scholar 

  49. Schulz M, Schmoldt A. Therapeutic and toxic blood concentrations of more than 500 drugs. Pharmazie. 1997;52:895–911.

    CAS  Google Scholar 

  50. Repetto MR, Repetto M. Habitual, toxic, and lethal, and lethal concentration of 103 drugs of abuse in humans. J Toxicol. 1997;35:1–9. https://doi.org/10.3109/15563659709001158.

    CAS  Google Scholar 

  51. Jones AW, Holmgren A, Holmgren P. High concentrations of diazepam and nordiazepam in blood of impaired drivers: association with age, gender and spectrum of other drugs present. Forensic Sci Int. 2004;146:1–7. https://doi.org/10.1016/j.forsciint.2004.05.020.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We gratefully thank Christof Fattinger for his support of sampler development and during this project and Pablo Dörig for simulations of the flow profile with Comsol Multiphysics. Moreover, we thank the Scientific Center for Optical and Electron Microscopy of ETH Zurich for providing us with resources and services in electron microscopy. We thank the Swiss National Science Foundation for financial support of this project (grant no. 200020_159929). YZ was funded by a Pao Yu-Kong and Pao Zhao-Long scholarship for Chinese scientists studying abroad.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Renato Zenobi.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Electronic supplementary material

ESM 1

(PDF 1.03 mb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ghiasikhou, S., da Silva, M.F., Zhu, Y. et al. The capillary gap sampler, a new microfluidic platform for direct coupling of automated solid-phase microextraction with ESI-MS. Anal Bioanal Chem 409, 6873–6883 (2017). https://doi.org/10.1007/s00216-017-0652-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00216-017-0652-8

Keywords

Navigation