Screening of water / organic solvent mixtures with varying solvent ratios is common for macrocyclic peptides. This is done to improve solubility, optimize NMR lineshape, attenuate the presence of minor conformers, and resolve overlapped signals. Changing water/organic solvent ratios can drastically change the frequency of the water peak, necessitating the frequency flexibility of the water suppression pulse sequence. SAPPHIRE-iES was found to possess the requisite flexibility, as demonstrated on AbA samples in CD3CN/H2O mixtures in Figure . Changing water amount from 10% to 30% by volume moves its chemical shift downfield significantly, by almost one ppm. A typical solvent screen is aimed at finding conditions providing the best compromise between solubility, lineshape, and minimal interference of the water peak with sample resonances. The optimal solvent mixture would then be utilized for more advanced NMR experiments (as an example, see ESI Figure ). In this context, SAPPHIRE-iES was the most useful pure shift experiment because of its ability to selectively suppress the solvent peak without interfering with nearby proton signals of interest. The flexible settings of the selective pulse duration in SAPPHIRE-iES allow facile optimization of solvent suppression versus signal retention for a variety of aqueous/organic solvent mixtures. The new class of ultra-clean pure shift NMR methods with internally encoded water suppression presented here offers a marked improvement for the analysis of aqueous samples. Overall, SAPPHIRE-iES has demonstrated superior, frequency-agnostic performance and we recommend that it should be used as the standard pure shift experiment for both aqueous samples and water/organic solvent mixtures. Although SAPPHIRE-iW5 showed near complete suppression of water resonances even in samples comprised almost entirely of protic water (i.e., 90% H2O), its poorer selectivity can also non-selectively suppress desired analyte peaks close to the solvent resonance. One shared limitation observed for all three SAPPHIRE experiments was their inability to suppress strong coupling artifacts (Fig. . iW5 was found to be the least favorable experiment for the observation of strongly coupled systems. Additionally, we expect that the iES approach can easily be implemented to suppress multiple solvent resonances simultaneously in cases of non-deuterated solvent mixtures.