A Critical Review of Analytical Methods for Sildenafil and Its Metabolites

Sildenafil (SIL), a selective phosphodiesterase type 5 (PDE5) inhibitor, has gained popularity in the clinical management of erectile dysfunction and is being detected more frequently in counterfeit supplements and in environmental samples, which has driven the need for robust analytical techniques. The reviewed articles were retrieved from major scientific databases, including Scopus, Web of Science, ScienceDirect, Google Scholar, and PubMed, and were limited to English-language publications. This review will evaluate chromatographic, spectroscopic, and electrochemical methodologies, along with sample preparation techniques (protein precipitation, liquid-liquid extraction, and solid-phase extraction), and will account for their principles, merits, and challenges in the pharmaceutical, biological, and environmental research spaces. Overall, chromatography, particularly high-performance liquid chromatography and liquid chromatography-mass spectrometry, will continue to provide the benchmark for detection due to its extremely high sensitivity, selectivity, and capacity. Meanwhile, spectroscopic and electrochemical methods could potentially offer rapid, relatively low-cost alternatives, but they exhibit limited ultra-trace detection capacity. Nevertheless, several key challenges remain with SIL, including instability, complex sample matrices, and the high cost or limited accessibility of advanced analytical tools. Emerging directions will involve integrating green chemistry principles to lessen solvent use and impact, while advancing automation and miniaturized platforms for field applications. In parallel with these perspectives, artificial intelligence, machine learning, or similar approaches could become crucial players in data evaluation, pattern recognition, and predictive modeling, accelerating method optimization and increasing accuracy in complex matrices. Together, these issues could revolutionize the assessment of sustainability, accessibility, clinical, and regulatory aspects of SIL.