Contents lists available at ScienceDirect European Journal of Pharmaceutical Sciences journal homepage: www.elsevier.com/locate/ejps Review Advances in paper-analytical methods for pharmaceutical analysis Niraj Sharma a , Toni Barstis b , Basant Giri a,⁎ a Center for Analytical Sciences, Kathmandu Institute of Applied Sciences, PO Box 23002, Kalanki-13, Kathmandu, Nepal b Department of Chemistry and Physics, College of Saint Mary, Notre Dame, IN 46556, United States ARTICLE INFO Keywords: Fabrication techniques Detection methods Resource-limited settings Low quality pharmaceuticals Drug delivery ABSTRACT Paper devices have many advantages over other microfluidic devices. The paper substrate, from cellulose to glass fiber, is an inexpensive substrate that can be readily modified to suit a variety of applications. Milli- to micro- scale patterns can be designed to create a fast, cost-effective device that uses small amounts of reagents and samples. Finally, well-established chemical and biological methods can be adapted to paper to yield a portable device that can be used in resource-limited areas (e.g., field work). Altogether, the paper devices have grown into reliable analytical devices for screening low quality pharmaceuticals. This review article presents fabrica- tion processes, detection techniques, and applications of paper microfluidic devices toward pharmaceutical screening. 1. Introduction Microfluidic systems (Whitesides, 2006) have been well studied and used in clinical diagnostics (Suveen et al., 2013), biological, biomedical (Sackmann et al., 2014) and environmental (Jokerst et al., 2012) fields for over the last two decades. Such miniaturized systems offer several advantages such as low consumption of chemicals/reagents/samples, rapid and high throughput analysis, low cost, and automation com- pared to their traditional counterparts (Nguyen and Wereley, 2002; Sackmann et al., 2014; Whitesides, 2006). Different substrates are used for fabricating microfluidic devices on the basis of their applications (Lei, 2014; Nge et al., 2013). During early development, silicon and glass were used as substrate for fabrication of microfluidic device. The high thermal conductivity and resistance as well as relatively high operating temperature makes silicon useful in Polymerase chain and bio-reactions; however due to relatively high cost and optical opacity properties of silicon, this conventional substrate has been replaced by other substrates (Lei, 2014). Glass is commonly used substrate because of its beneficial optical properties, surface stability, solvent compatibility and well-understood fabrication process; whereas, the non-biodegradable and high processing cost of glass may limit its use as disposable devices (Nge et al., 2013). Silicon and glass microfluidic devices have been used in chromatographic separation techniques, such as gas chromatography and liquid chromatography (Iliescu et al., 2012). Recently, polymers (Becker and Locascio, 2002), such as polymethylmethacrylate (Brown et al., 2006), polystyrene (Anderson et al., 2000; Becker and Locascio, 2002), polycarbonate (Liu et al., 2001), and polydimethylsiloxane (Friend and Yeo, 2010) have been widely used as material for microfluidic devices. The polymer substrates offer additional advantages over conventional substrates, namely low cost, ease of fabrication, and efficient design patterning. The past decade has seen cellulosic paper as an alternative substrate material for the fabrication of microfluidic devices due to its ad- vantages, including low manufacturing cost, analyte/reagent low vo- lume requirements, good wicking properties, and biocompatibility. Milli or microfluidic paper analytical devices (mPADs or μPADs, re- spectively) are analytical devices with milli or micro-fluidicially-pat- terned paper as their main component. In general, the μPADs can be considered as either a paper variant of conventional microfluidics or an advanced version of classical dipsticks. (Chen et al., 2015; Costa et al., 2014; Li et al., 2012). Work of translating cellulose paper to chemical testing device can be traced back to Karl Dieterich from Germany. He insulated different strips of paper through saturation with substances like paraffin, ceresin, wax, and varnish with the aim of separating different chemical solu- tions (Dietrich, 1902). Foundation for the realization of fluidic devices made from paper was laid down in middle of twentieth century (Müller and Clegg, 1949). However, Whitesides and his co-workers first in- troduced the term μPAD in 2007 (Martinez et al., 2007). The same group demonstrated two- and three-dimensional paper-device http://dx.doi.org/10.1016/j.ejps.2017.09.031 Received 27 July 2017; Received in revised form 10 September 2017; Accepted 20 September 2017 ⁎ Corresponding author. E-mail address: bgiri@kias.org.np (B. Giri). Abbreviations: AgNPs, silver nanoparticles; APTES, 3-triethoxysilylpropylamine; CCD, charge coupled device; CL, chemiluminescence; ECL, electrochemiluminescence; ePADs, elec- trochemical paper-based analytical devices; LOD, limit of detection; OFLX, ofloxacin; OXY, oxytetracycline; WMRS, wavelength modulated Raman spectroscopy; μPADs, microfluidic paper analytical devices European Journal of Pharmaceutical Sciences 111 (2018) 46–56 Available online 22 September 2017 0928-0987/ © 2017 Elsevier B.V. All rights reserved. MARK