Critical analytical review: Rare and recent applications of refractive index detector in HPLC chromatographic drug analysis

In this review article, the first collection of drugs analyzed through high-performance liquid chromatography coupled with a refractive index detector (HPLC-RI) was discussed. The list of all analyzed drugs was shown, and chromatographic conditions for each method were enumerated, demonstrating a helpful guide for all analysts in quality control units. Also, the efficiency of the RI detector was compared to others used in HPLC methods [e.g., ultraviolet (UV), fluorescence, electrochemical detector, evaporative light scattering (ELS), and mass spectrophotometry (MS)]. Furthermore, the efficiency of coupling the RI detector with UV or MS was demonstrated, the capabilities of RI in detecting degradates, and impurities for drugs were discussed. Finally, the theory of RI detectors, advantages, disadvantages, and the factors affecting separation efficiency were briefly addressed. All publications from common online manuscript databases (e.g., Scopus, Web of Science) containing HPLC-RI methods were screened and recorded when searching in the titles. The majority of recorded HPLC-RI methods for drug determination were conducted in Egypt (29%, n = 4), India (29%, n = 4), and China (14%, n = 2). The RI detector was the least-mentioned HPLC detector when searching the titles from the Scopus or WOS databases. Concerning the RI detector sensitivity, all the measured drug concentrations were in milligrams and micrograms per mL levels, indicating the relatively low sensitivity of RI compared to UV or MS detectors. The highest sensitivity was observed during heparin analysis, and concentrations as low as 0.1 µg mL−1 may be detected by the method. The lowest sensitivity was recorded during the analysis of mucopolysaccharide polysulfate and the anti-inflammatory mixture of methyl salicylate, camphor, and menthol. The linearity range for mucopolysaccharide polysulfate was 0.09–1.58 mg mL−1. On the other hand, the linearity ranges for the anti-inflammatory mixture were 2.40–9.60, 0.32–1.28, and 0.80–3.20 mg mL−1 for methyl salicylate, camphor, and menthol, respectively. Lastly, scoring all the HPLC-RI methods mentioned here using a greenness assessment tool will provide a comprehensive perspective of the eco-friendly features of the RI detector. Furthermore, there is a need to conduct a comparative analysis of actual drugs in pharmaceuticals using both RI and UV detectors. This is needed to highlight the advantages and disadvantages of each detector concerning accuracy, precision, sensitivity, and selectivity. Such analysis will be similar to the study for sugar analysis in actual honey samples that Jalaludin and Kim recently conducted in South Korea.