Screening of synthetic PDE-5 inhibitors and their analogues as adulterants: analytical techniques and challenges

Abstract

The popularity of phosphodiesterase type 5 (PDE-5) enzyme inhibitors for the treatment of erectile dysfunction has led to the increase in prevalence of illicit sexual performance enhancement products. PDE-5 inhibitors, namely sildenafil, tadalafil and vardenafil, and their unapproved designer analogues are being increasingly used as adulterants in the herbal products and health supplements marketed for sexual performance enhancement. To date, more than 50 unapproved analogues of prescription PDE-5 inhibitors were found as adulterants in the literature. To avoid detection of such adulteration by standard screening protocols, the perpetrators of such illegal products are investing time and resources to synthesize exotic analogues and devise novel means for adulteration. A comprehensive review of conventional and advance analytical techniques to detect and characterize the adulterants is presented. The rapid identification and structural elucidation of unknown analogues as adulterants is greatly enhanced by the wide myriad of analytical techniques employed, including high performance liquid chromatography (HPLC), gas chromatography-mass spectrometry (GC-MS), liquid chromatography mass-spectrometry (LC-MS), nuclear magnetic resonance (NMR) spectroscopy, vibrational spectroscopy, liquid chromatography-Fourier transform ion cyclotron resonance-mass spectrometry (LC-FT-ICR-MS), liquid chromatograph-hybrid triple quadrupole linear ion trap mass spectrometer with information dependent acquisition, ultra high performance liquid chromatography-time of flight-mass spectrometry (UHPLC-TOF-MS), ion mobility spectroscopy (IMS) and immunoassay methods. The many challenges in detecting and characterizing such adulterants, and the need for concerted effort to curb adulteration in order to safe guard public safety and interest are discussed.

Keywords: (1)H NMR; (13)C NMR; 1 dimensional nuclear magnetic resonance; 1D NMR; 2 dimensional nuclear magnetic resonance; 2D NMR; Analytical techniques; CART; CE-MS; CID; CNLS; COSY; Challenges; D-PLS; DAD; DCBI; DEPT; DOSY–NMR; Designer analogues; ED; ESI; EU; European Union; FT-ICR-MS; FT-IR; FTIR-ATR; Fourier transform ion cyclotron resonance-mass spectrometry; Fourier transformed infrared; Fourier transformed infrared attenuated total reflectance; GC–MS; HMBC; HMQC; HPLC; HPLC-DCBI–MS/MS; HPTLC; HRMS; HSA; Health Sciences Authority Singapore; IDA; IMS; LC–ESI-MS(n); LC–FT-ICR-MS; LC–LTQ Orbitrap XL FTMS; LC–MS; LC–TIS-MS; LC–TOF-MS; LC–q-TOF-MS/MS; MDMA; MRM; MS; MS(n); MS/MS; NDA; NIR; NMR; NOE; NOESY; New Drug Application; PCA; PDE-5; PDE-5 inhibitors; PIS; PP; PREC; SIM; SIMCA; SRM; SVM; Screening for adulterants; THMPD; TIS; TLC; TOF; TQ-LIT; Traditional Herbal Medicinal Products Directive; UHPLC; USFDA; UV; United States Food and Drug Administration; X-ray diffraction; X-ray fluorescence; XRD; XRF; capillary electrophoresis–mass spectrometry; carbon-13-nuclear magnetic resonance; classification and regression trees; collision induced dissociation; constant neutral loss scan; correlation spectroscopy; desorption corona beam ionization; diffusion ordered spectroscopy–nuclear magnetic resonance; diode array detector; discriminant partial least squares; distortionless enhancement by polarization transfer; electrospray ionization; erectile dysfunction; gas chromatography–mass spectrometry; heteronuclear multiple-bond correlation spectroscopy; heteronuclear multiple-quantum correlation spectroscopy; high performance liquid chromatography; high performance liquid chromatography-desorption corona beam ionization–tandem mass spectrometry; high performance thin layer chromatography; high resolution mass spectrometry; information dependent acquisition; ion mobility spectroscopy; liquid chromatography mass-spectrometry; liquid chromatography-Fourier transform ion cyclotron resonance-mass spectrometry; liquid chromatography–electrospray ionization-tandem mass spectrometer; liquid chromatography–linear ion orbitrap XL Fourier transform mass spectrometry; liquid chromatography–quadrupole-time-of-flight-tandem mass spectrometry; liquid chromatography–time of flight-mass spectrometry; liquid chromatography–turbo ion spray mass spectrometry; mass spectrometry; methylenedioxymethamphetamine; multi-stage mass spectrometry; multiple reaction monitoring; near infrared; nuclear Overhauser effect; nuclear Overhauser effect spectroscopy; nuclear magnetic resonance; phosphodiesterase type 5 enzyme; precursor ion scanning; principal component analysis; product ion scanning; projection pursuit; proton nuclear magnetic resonance; selected ion monitoring; selected reaction monitoring; soft independent modelling by class analogy; support vector machines; tandem mass spectrometry; thin layer chromatography; time of flight; triple quadruple linear ion trap; turbo ion spray; ultra high performance liquid chromatography; ultraviolet.