Advancements in Paper-Based Analytic Devices for Drug Analysis

Over the past decade, paper-based analytical devices (PADs) have been well developed as an economical approach for medical and diagnostic applications. These PADs are designed for separation and detection and apply to a wide variety of analytes, including many drugs. Though this has advanced drug analysis as a whole within our current labs, PADs are even being used to detect small metabolic proteins, DNA, and some microorganisms.


Image Credit: Gorodenkoff/

This is accomplished through the adhesive nature of paper, absorbing different matrices such as serum and blood plasma. Separation is accomplished through electrophoresis. This rough separation of analytes can be used for subsequent individual analysis. Under PAD-based analysis, most detection is carried out through electrochemical methodologies, or the naked eye observations of color change.

Mass spectrometry (MS) in tandem with paper-based analytics

Mass Spectrometry (MS) functions as a multiplexed analytical apparatus and measures the mass to charge ratio (m/z) of each compound in each medium. Structural information of a given analyte can be obtained via tandem MS, making it able to differentiate between enantiomers or diastereomers with identical m/z. Due to the versatile nature of this machinery, scientists have been making progress on integrating MS with PADs, resulting in multiple techniques.

Paper spray, the umbrella term for these techniques, couples PADs and MS for qualitative and quantitative analysis. This process incorporates the use of making paper triangles in which the target analyte and solvent are absorbed, followed by a power supply that generates a spray plume that passes through the paper for the MS inlet to record.

This technique has been used in many fields such as disease diagnostics, and food and drug safety. Though this technology came out in 2010, sample pretreatment generates inconveniences when assaying, causing researchers to progress this technique.

Desorption electrospray ionization (DESI)

DESI has been implemented for direct analysis of liquids (and even some solutes) on paper. This is an electrospray ionization technique where the ionization of a given analyte takes place in a solvent, leading to a protonated/deprotonated analyte. Used mostly for polar molecules, this technique brings a droplet in contact with a thin layer plate, followed by the extracted solvent being sprayed into the mass spectrometer.

This mitigates sample preparation by enabling investigations within a native environment, circumventing the need for further chemical or physical manipulation. However, because the sample is not confined to a high-vacuum region, sensitivity is compromised in this technique, something that should be avoided in the scrupulous analysis of drugs.

Low-temperature plasma-mass spectrometry (LTP-MS) fitted with PAD based technology

Considering all methods, as well as their advantages and disadvantages, Xinrong Zhang et al. have implemented a novel system allowing for the in-situ MS analysis fitted with PADs, which enables rapid assays of complex matrices. Results speak volumes in terms of accuracy, ease, and pre-sample treatment. This incorporates a low-temperature plasma (LTP) probe that directly desorbs and implements soft ionization on an analyte on the surface of the paper, enabling rapid in-situ MS analysis.

What’s more, researchers have now detected peptides and proteins such as insulin and hexarelin through LTP probes. These are new findings, for only compounds of small molecular weights of less than 800 Daltons were observable.

The “transmission LTP probe” when fitted to an MS/PAD apparatus consists of a metal wire placed in plasma, while measurements are taken of the current and voltage passed through the plasma. This plasma will then hit the hydrophobic region of the PAD, where the analyte is held, while the secondary analyte ions generated will be read through the MS inlet.

The LTP probe has a charge-replay that enables the transfer of charge from plasma to the analyte. These ions are briefly directed to one side of the paper strip and pass through to ionize the target molecule absorbed within the paper.

Simply put, charged plasma produces a greater amount of charged species than typical electrospray ionization. This is also accomplished with no solvent molecules attached, eliminating the need for some pre-sample treatment.

Testing the efficacy of low-temperature plasma-mass spectrometry (LTP-MS)

To test the efficacy of this analysis on drugs, Xinrong Zhang et al. assayed a paper microarray, containing doped whole blood absorbed within the PADs. The bovine blood sample had been doped with verapamil hydrochloride and imatinib, used to treat angina and leukemias respectfully. The paper electrophoresis coupled with transmission LTP-MS yielded a good separation and a candid identification of each drug’s structure.

Though this has proven difficult, given that whole blood is a complex matrix environment, this apparatus has proved successful when normalized with an internal standard of amitriptyline hydrochloride (0.8 μM, m/z 278.4). When placed within the charged plasma probe, verapamil hydrochloride migrated to the cathode faster than imatinib, allowing for full separation.

In summary, PAD’s have been a high commodity for the past decade, though broad strides have been made when fitting them to spectrometric means, allowing for in situ rapid analysis of both polar and nonpolar drug moieties. Current studies believe that these MS-based PAD analyses could find innovate other fields of assaying, such as food screening, POC diagnostics, and more.


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  • Yaoyao Zhao, Zhenwei Wei, Hansen Zhao, Jia Jia, Zhenzhen Chen, Sichun Zhang, Zheng Ouyang, Xiaoxiao Ma, and Xinrong Zhang (2016). In Situ Ion-Transmission Mass Spectrometry for Paper-Based Analytical Devices. Analytical Chemistry 88 (22), 10805-10810
  • Hugo Aliaga-Aguilar. (2018). Characterization and Analysis of Paper Spray Ionization of Organic Compounds. Journal of the American Society for Mass Spectrometry 29 (1), 17-25

Further Reading

Last Updated: Oct 19, 2021

Vasco Medeiros

Written by

Vasco Medeiros

Obtaining an International Baccalaureate Degree at Oeiras International School, with higher levels in Chemistry, Biology, and Portuguese, Vasco Medeiros has just graduated from the University of Providence College with a Bachelor of Science. Before his work as an undergraduate, he first began his vocational training at the HIKMA Pharmaceuticals PLC plant in Ribeiro Novo. Here he worked as a validation specialist, tasked with monitoring the gauging and pressure equipment of the plant, as well as the inspection of weights and products.


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