ABSTRACTBackground: Among several others, TRM and HCTZ stand as two of the most commonlyprescribed antihypertensive medicines. However, the quantitative determination of the same duo indrug formulations remains challenging due to the common overlap in UV spectra in the region 200-400 nm for both substances; hence, spectral analysis becomes difficult to achieve without some kindof spectral separation process. Traditional techniques mostly revolved around the reversed-phaseHPLC technique, which was accurate but produced a high amount of organic solvent waste, whichbecame increasingly problematic with time due to stricter environmental regulations in thepharmaceutical industry.Objective: The current study attempts to explore the entire body of literature regarding analyticaltechniques utilized for the quantitative determination of the TRM-HCTZ drug couple between 1989and 2025 based on the following parameters: sensitivity in terms of LOD and LOQ, ICH Q2(R1)validation requirement compliance, and environmental sustainability via AGREE, GAPI, BAGI, andRGB Whiteness scales.Methods: A comprehensive search strategy was employed for articles in PubMed, Scopus, Web ofScience, ScienceDirect, and Google Scholar using controlled terms alongside free text searches. Twoindependent reviewers performed screening for all identified records. Data obtained from selectedstudies were grouped into five categories based on the method used: derivative spectrophotometry, HPLC/LC-MS/MS, multivariate calibration, continuous wavelet transform (CWT), and Greenness-by-Design (GbD) methods that make use of MD and DFT simulations to determine analyte solvent computationally.Results: A total of 66 papers met all eligibility criteria. Derivative spectrophotometry showed LODsof 0.17-1.02 μg/mL and recovery between 97%-103%. HPLC and LC-MS/MS provided muchhigher sensitivity, with LOD values of 0.15 ng/mL, however, with significantly higher consumptionof organic solvents (50-200 mL of solvent per sample). Multivariate calibration and CWT methodswere able to overcome the problem of spectral overlapping by eliminating any need for theseparation step, yielding LODs of 0.09-0.32 μg/mL and correlation coefficients above 0.999. TheGreenness by Design (GbD) method that made use of MD simulations to select ethanol as the mostsuitable solvent attained AGREE 0.81, BAGI 82.5, and RGB Whiteness 78, while decreasing thesolvent consumption by 80-90% compared to HPLC.Conclusions: In the context of the pharmaceutical QC analysis, at the moment, the GbD-basedspectroscopy techniques are the most promising with respect to sensitivity, ICH compliance, andminimized environmental impact. Further interlaboratory validation and inclusion in pharmacopoeiarepresent the only two unresolved issues that need to be addressed.
Malathi S Vigneshwaran M (Tue,) studied this question.